RALGAPA2 (AS250) - the catalytic brake on RalA that behaves as a tumour suppressor, fused to KMT2A exon 22 in an osteosarcoma and predicted out of frame, which makes allele DISRUPTION the better hypothesis than a chimera

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

• This entry must not be read as a menin-inhibitor rationale. Menin is a TUMOUR SUPPRESSOR in mesenchyme, and the only non-haematologic menin trial with a result, NCT05731947, was terminated by the sponsor after phase 1b for not meeting pre-defined efficacy signals. An MBM-retaining KMT2A fusion in a sarcoma is a test of a hypothesis, not an indication.
• If menin inhibition were tried here off the gene name alone, the predicted direction of effect is not obviously anti-tumour: displacing menin from chromatin in a mesenchymal cell removes a tumour suppressor from its targets. See risk-a-menin-inhibitor-prescribed-off-a-kmt2a-gene-name-in-a-solid-tumour.
• Every quantitative statement about the fusion in this entry is a coordinate derivation from transcript records. If the panel's exon numbering differs from RefSeq's, the frame prediction, the retained-residue count and the MBM claim all move together - one systematic error, not several independent ones.
• The partner here is a candidate TUMOUR SUPPRESSOR, which inverts the usual therapeutic logic: there is nothing to inhibit on the RALGAPA2 side, and if the lesion removes a brake on RalA then the tractable node is RalA itself - where the available tool compound, RBC8, is a research-grade inhibitor with no clinical development, not a drug.
• A loss-of-function CRISPR dependency screen cannot evaluate a tumour suppressor, so the near-zero DepMap score must not be read as evidence against the hypothesis. Reading it that way would be the same error this graph records for floor-compressed genes: an instrument returning its predicted null being mistaken for a measurement.
• Akt signalling inhibits this GAP, so an Akt-pathway inhibitor would be expected to RESTORE the RalA brake - which is a rationale-shaped thought and nothing more, because no RalA measurement exists in any KMT2A-rearranged tumour and the direction has never been tested in a mesenchymal cell.
• Three of the seven cases in this cohort are predicted to supply no partner protein at all. Any summary that presents these seven as chimeric oncoproteins overstates what the exon table supports, and the overstatement would travel into a treatment argument more easily than the caveat would.

1. Is case S18 a chimera or a disrupted allele? The frame prediction says frameshift and the partner is a candidate tumour suppressor, so the two lines of evidence agree - and the test is ordinary: RNA across the junction plus RALGAPA2 expression and copy number from the intact allele in archival material.
2. Does RalA activity actually rise in KMT2A-rearranged osteosarcoma? The loss-of-function hypothesis predicts it, an active-RalA pulldown would measure it, and no such measurement exists in any sarcoma with a KMT2A rearrangement.
3. Is RALGAPA2 a tumour suppressor outside the liver? The published evidence is hepatocellular carcinoma, the cell type in which the gene was first characterised, so the finding may be lineage-conditioned - and osteosarcoma is about as far from hepatocyte biology as a mesenchymal tumour gets.
4. How many of this cohort's KMT2A fusions are gene disruptions rather than chimeras? Three of the seven are predicted to supply no partner protein (RALGAPA2 and C2CD3 by frameshift, AHDC1 by an untranslated exon), which reframes the cohort - and the question is answerable from the panel's own transcript models without any new sequencing.
5. Does the isolated KMT2A 1-1987 fragment predicted here do anything? It carries the whole targeting module - MBM, both LEDGF motifs, three AT-hooks and CXXC - and roughly half of KMT2A, with no partner, and this graph has no measured phenotype for such a fragment.

1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   RALGAPA2 (Q2PPJ7, 1,873 aa) is the catalytic subunit of the heterodimeric RalGAP2 complex that acts as a GTPase activator for the Ras-like GTPases RALA and RALB, requires heterodimerisation with RALGAPB for activity, and carries a single annotated module - a Rap-GAP domain at 1635-1843 - with no chromatin, DNA-binding or catalytic-transfer domain anywhere in the protein.

   UniProtKB Q2PPJ7 (RGPA2_HUMAN) - Ral GTPase-activating protein subunit alpha-2 (AS250, 250 kDa substrate of Akt; p220) · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   Accession resolved this cycle by gene_exact query with gene_primary read back: exactly one reviewed human record, primary symbol RALGAPA2, entry RGPA2_HUMAN, length 1,873 aa, matching NP_065076.2 exactly (rules 62, 65, 66). THE RECORD IS UNUSUALLY THIN AND THAT IS THE CAVEAT: the FUNCTION and SUBUNIT comments are ENTIRELY ECO:0000250, by similarity, with no source accession given - there is NO experimental human function annotation on this record at all - and the only localisation comment carries a citation that is not a localisation paper (see E2). Everything substantive about this protein in this entry comes from reading the primary literature rather than from the database. PARALOGUE HAZARD: RALGAPA1 is the closely related catalytic subunit sharing the same regulatory partner RALGAPB, and RalGAP knockdown and pharmacology are not generally paralogue-selective, so a RalGAP result is not automatically a RALGAPA2 result.

   ▸Evidence that argues against this (1)

   • A record whose entire function annotation is 'by similarity' is a statement about curation effort, and the similarity is to a non-human orthologue whose accession the comment does not even name. The GAP activity IS experimentally established for the human protein - but in the primary literature under the names AS250 and RGC2, not under the approved symbol, which is why the database looks emptier than the field is. Chen XW et al. 2011
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   RALGAPA2 was identified in adipocytes as AS250, a 250 kDa substrate of the insulin-activated kinase Akt with a predicted GAP domain at its carboxy terminus, existing in a complex with a 1,484-residue partner then called KIAA1219 - an arrangement the authors described as notably similar to the tuberin/hamartin tuberous sclerosis complex in subunit size, GAP-domain location and Akt phosphorylation - and shRNA knockdown of AS250 in 3T3-L1 adipocytes had no effect on insulin activation of Akt, p70 S6 kinase or ERK1/2 and only a slight effect on insulin-stimulated GLUT4 translocation.

   Adipocytes contain a novel complex similar to the tuberous sclerosis complex. · Gridley S, Chavez JA, Lane WS et al · Cellular Signalling 2006
   PMID 16490346DOI
   ▸What this evidence cannot show

   3T3-L1 MOUSE adipocytes plus human cDNA sequencing and tandem mass spectrometry of phosphosites (rule 73: the system is in the claim). Note the negative half of the result, which the abstract states plainly: knocking AS250 down did NOT change insulin activation of Akt, p70 S6K or ERK1/2 and affected GLUT4 translocation only slightly - so the paper identifies a complex and an Akt substrate without establishing a phenotype. RULE 91 FLAG: this is the SOLE ECO:0000269 citation behind UniProt's 'Cytoplasm' localisation comment for RALGAPA2, and its abstract describes NO localisation experiment - the compartment is not among its findings. Abstract read; full text not read, so a fractionation panel in a figure cannot be excluded (rule 80). The GAP domain is described here as PREDICTED, by homology to tuberin and Rap1GAP; the catalytic activity was demonstrated later (E3).

   ▸Evidence that argues against this (1)

   • The tuberous-sclerosis-complex comparison is an argument from architecture - subunit size, domain position and Akt phosphorylation - not from function, and TSC2 acts on RHEB in mTORC1 signalling while RALGAPA2 acts on RalA in exocyst-mediated trafficking. The analogy predicted the tumour-suppressor phenotype correctly, which is a point in its favour, but it should not be extended to shared downstream biology. Tian L et al. 2022
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   A Ral GAP complex composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit - RGC2 being the protein previously identified as AS250, i.e. RALGAPA2 - directly stimulates GTP hydrolysis by RalA; knockdown of RGC proteins increases RalA activity and glucose uptake in adipocytes; and insulin inhibits the GAP complex through Akt2-catalysed phosphorylation of RGC2 both in vitro and in vivo, with activated Akt relieving the complex's inhibition of RalA.

   A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. · Chen XW, Leto D, Xiong T et al · Molecular Biology of the Cell 2011
   PMID 21148297DOI
   ▸What this evidence cannot show

   Adipocytes and in-vitro GAP assays - insulin action and GLUT4 trafficking, not cancer and not a haematopoietic or mesenchymal system. This is the paper that establishes the catalytic activity the UniProt record asserts only by similarity, and it establishes it under the name RGC2 rather than RALGAPA2 - which is why searching the approved symbol under-recalls this protein's own founding biochemistry. Abstract read; full text not read. The knockdown targets RGC proteins, so the individual contributions of the catalytic and regulatory subunits are not separated by that experiment.

   ▸Evidence that argues against this (1)

   • The regulatory logic here is a brake released by growth-factor signalling in a metabolic context, and generalising it to a tumour requires the Akt pathway to be the dominant input - which is an assumption, not a finding. And because the knockdown hit RGC proteins collectively, an effect attributed to RALGAPA2 could belong to RALGAPB or to the paralogue RALGAPA1. UniProt Consortium 2026
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In human hepatocellular carcinoma RALGAPA2 is significantly down-regulated in patients' tumours, its knockdown increases RalA activity and promotes intrahepatic and extrahepatic metastasis in vivo, and tumours combining RALGAPA2 down-regulation with RalA up-regulation show significantly more frequent venous invasion, more advanced tumour stage and poorer overall survival - so RALGAPA2 behaves as a tumour suppressor.

   Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular carcinoma. · Tian L, Zhao L, Sze KM et al · Hepatology 2022
   PMID 34767674DOI
   ▸What this evidence cannot show

   HUMAN HEPATOCELLULAR CARCINOMA - in-house and TCGA RNA-sequencing plus qPCR, cell-line knockdown and in-vivo metastasis models (rule 73: the system is in the claim). Not a sarcoma and not a haematopoietic disease, and hepatocytes are the cell type in which RALGAPA2 function was originally characterised, so the finding may be lineage-conditioned. The paper's principal subject is RalA up-regulation by copy-number gain and SP1/ETS2 transcription; RALGAPA2 is the second, negative arm of its 'dual regulatory mechanisms'. Abstract read; full text not read, so the magnitude of the down-regulation and the number of cases in the combined-marker analysis are not inspected here.

   ▸Evidence that argues against this (1)

   • Down-regulation in tumour tissue plus a knockdown phenotype is consistent with tumour suppression and does not establish it: RALGAPA2 could be reduced as a consequence of the transcriptional programme that raises RalA rather than as a cause. No RALGAPA2 mutation, deletion or promoter-methylation frequency is reported in the abstract, and a tumour-suppressor claim would normally rest on recurrent biallelic loss, which is not shown. Broad Institute DepMap; joined locally from analyses/depmap-kmt2a-selective-scan-full 2026
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In case S18 of a pan-sarcoma KMT2A-rearrangement series, a conventional-type osteosarcoma carried KMT2A exon 22 fused to RALGAPA2 exon 2 (NM_020343) - the latest KMT2A breakpoint among the seven cases with KMT2A as the 5-prime partner.

   Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions. · Massoth LR, Hung YP, Nardi V et al · Modern Pathology 2020
   PMID 32461620DOI
   ▸What this evidence cannot show

   This is ONE patient (case S18, conventional-type osteosarcoma) in a commercial targeted RNA-panel series enriched for advanced disease. The source authors call the non-recurrent KMT2A partners of UNCLEAR SIGNIFICANCE and several may be passengers. No fusion protein has been observed for this or any other sarcoma KMT2A fusion by any method, no reciprocal transcript was reported, no functional experiment has been done, and the panel targets specific KMT2A exons, which biases which breakpoints are detectable at all. Supplemental Table 2 reports EXON NUMBERS from the panel's own annotation - the junction nucleotide, the transcript sequence and the reading frame are not given - and it misspells the index gene as KTM2A in two of eighteen rows, so a reader grepping for KMT2A silently loses cases. This graph's parse is at analyses/sarcoma-nonrecurrent-partners/results.json. Naming this case makes it auditable; it does not promote the partner to a driver and it is not a treatment rationale. And one thing specific to this case: no allele-level data of any kind is reported for RALGAPA2 in this tumour - no copy number, no expression from the intact allele, no mutation - so the loss-of-function reading proposed here is a hypothesis generated from the frame prediction plus the partner's published behaviour, and it has no direct support in the source.

   ▸Evidence that argues against this (1)

   • The cohort's recurrent, morphology- and methylation-defined KMT2A sarcoma arms are YAP1-KMT2A-YAP1 and VIM::KMT2A, and those are what the paper's title and conclusions are about. The seven 5-prime non-recurrent cases are explicitly set aside by the authors as of unclear significance, and a targeted panel run in advanced disease will also detect passenger rearrangements. A single MBM-retaining case is a lead, not an entity. Massoth LR et al. 2020
6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   KMT2A exons 1-22 encode aa 1-1987 - roughly half of KMT2A and the largest KMT2A contribution among the seven cases - and therefore retain the menin-binding motif (6-25), LEDGF IBM1 (123-134) and IBM2 (147-152), all three AT-hooks and the CXXC domain (1147-1195); the exon-22 break lies well downstream of the leukaemic breakpoint cluster region (exons 8-14).

   RefSeq NM_001197104.2 / NP_001184033.1 - Homo sapiens lysine methyltransferase 2A (KMT2A), transcript variant 1 · NCBI RefSeq · NCBI Nucleotide 2026
   ▸What this evidence cannot show

   KMT2A exon-to-residue map, re-derived this cycle from RefSeq NM_001197104.2 (CDS 22..11940, 36 exons, NP_001184033.1) and independently reproducing this graph's own ana-kmt2a-exon-to-domain-map: exon 1 = aa 1-144 (MBM 6-25, LEDGF IBM1 123-134), exon 2 = aa 145-168 (IBM2 147-152), exon 3 = aa 168-1052 (all three AT-hooks), exon 4 = 1053-1112, exons 5-6 = 1112-1212 (CXXC 1147-1195). Exon 3 ends at aa 1052, exon 8 at 1362, exon 9 at 1406, exon 15 at 1668, exon 20 at 1888, exon 22 at 1987. All six KMT2A donor exons in this cohort end at a COMPLETE CODON (phase 0), which is why KMT2A can fuse in frame to so many acceptors. Note NM_001197104.2 encodes 3,972 aa while UniProt Q03164 is 3,969 aa; the three-residue difference lies downstream of every coordinate used here. This is a COORDINATE DERIVATION from a transcript record, not a measurement of a fusion protein: no sarcoma KMT2A fusion protein has ever been observed by any method and no menin-binding assay has been run on one.

   ▸Evidence that argues against this (1)

   • Retaining a motif is not the same as presenting it. The chimera's folding, stability and nuclear import are all unmeasured, and a fusion protein can retain a binding motif in primary sequence while failing to engage its partner. This graph's queued test exp-menin-pulldown-on-yky-versus-kmt2a-aff1 exists precisely because retention has never been shown to imply binding for any sarcoma arm. Massoth LR et al. 2020
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   RALGAPA2 exon 2 in NM_020343.4 (CDS 165..5786) spans nt 271-381 and therefore begins 106 nucleotides after the start codon, which is not a multiple of three; since every KMT2A donor exon in this cohort ends at a complete codon, the reported KMT2A exon 22 :: RALGAPA2 exon 2 junction is predicted OUT OF FRAME, giving a KMT2A 1-1987 fragment rather than a chimeric protein - and since the breakpoint lies near RALGAPA2's 5' end, roughly 1,800 residues upstream of its catalytic Rap-GAP domain, the predicted consequence on the partner allele is loss of the RalA brake.

   RefSeq NM_020343.4 - Homo sapiens Ral GTPase activating protein catalytic subunit alpha 2 (RALGAPA2), mRNA - NP_065076.2, 1,873 aa · NCBI RefSeq · NCBI Nucleotide 2026
   ▸What this evidence cannot show

   A derivation computed this cycle from two RefSeq records, not an observation, and as with C2CD3 in this beat it changes the predicted lesion CLASS rather than a detail. It can be wrong if the commercial panel's exon numbering differs from RefSeq's, if the breakpoint is intra-exonic, or if the tumour expressed a different RALGAPA2 transcript. The junction nucleotide is not reported. THE SECOND HALF OF THE CLAIM IS AN INFERENCE ON TOP OF A DERIVATION and is flagged as such: that a 5' breakpoint disrupts the allele's product follows from the gene structure, but whether the intact allele compensates, and whether RalA activity actually rises in this tumour, are unmeasured. The KMT2A-side conclusions at E6 do NOT depend on any of this.

   ▸Evidence that argues against this (1)

   • An in-frame prediction is not a demonstration of a product, and the same calculation returns the opposite answer for other members of this cohort: C2CD3 exon 24 and RALGAPA2 exon 2 both begin at phase 1 and are predicted FRAMESHIFTED, and AHDC1 exon 2 is entirely 5'-untranslated. That the derivation discriminates between cases is a reason to trust the method, not any one result. Massoth LR et al. 2020
8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   RALGAPA2 has no epigenetic content in any direction and is not a reported fusion partner in any tumour: histone, methylation and epigenetic conjunctions all return zero, the single chromatin record is off topic, and its only annotated module is a Rap-GAP domain - a GAP accelerates its substrate's own GTP hydrolysis rather than modifying it covalently, so RALGAPA2 is not a writer, eraser or reader in any sense.

   UniProtKB Q2PPJ7 (RGPA2_HUMAN) - Ral GTPase-activating protein subunit alpha-2 (AS250, 250 kDa substrate of Akt; p220) · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   BOUNDED 2026-09-22, one [tiab] per term with querytranslation read back (rules 94, 95): RALGAPA2[tiab] AND histone[tiab] = 0; AND methylation[tiab] = 0; AND epigenetic[tiab] = 0; AND chromatin[tiab] = 1 (PMID 37723664, autophagy in colitis-associated colon cancer - off topic); AND fusion[tiab] = 0; AND translocation[tiab] = 1 (PMID 32108446, a MyD88 skeletal-muscle adiposity study - incidental); AND KMT2A[tiab] = 0; AND MLL[tiab] = 0. Aliases searched: KIAA1272[tiab] = 0, AS250[tiab] AND Akt[tiab] = 2, and RALGAPA2[tiab] OR 'RalGAPalpha2'[tiab] = 16 against 12 for the bare symbol. Positive controls through the IDENTICAL one-tag-per-term query shape, run 2026-09-22 (rule 67, rule 94): EWSR1[tiab] AND fusion[tiab] = 1,208; EWSR1[tiab] AND translocation[tiab] = 462; AFF1[tiab] AND KMT2A[tiab] = 104; MLLT3[tiab] AND MLL[tiab] = 84; KMT2A[tiab] AND histone[tiab] = 218. Every query was written with one [tiab] per term and its querytranslation read back from the esearch response, so no parenthesised group silently expanded to [All Fields]. Bounded by TITLES AND ABSTRACTS, not by papers (rule 80): supporting figures were not searched. THE HONEST LIMITATION IS THE SIZE OF THE LITERATURE: RALGAPA2[tiab] returns 12 records in total, the smallest of the seven partners by a factor of three, and a gene with a 12-record literature returns zero for nearly any conjunction. So these counts corroborate the architecture argument and do not carry the claim on their own - and note that the founding biochemistry publishes under AS250 and RGC2 rather than the approved symbol, so symbol-only searching under-recalls this gene in general.

   ▸Evidence that argues against this (1)

   • An architecture-plus-absence argument cannot exclude a role this small a literature has never looked for, and RalA signalling does reach transcription through the exocyst and through ZONAB/YAP-adjacent routes in other systems - so an indirect effect on chromatin state via RalA is not excluded, only unreported. What IS excluded is intrinsic writer, eraser or reader activity. Massoth LR et al. 2020
9. E9weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.dataset

   RALGAPA2 is not a dependency in either leukaemia arm of this project's own DepMap scan: mean Chronos -0.084 in 11 KMT2A-rearranged lines against +0.019 in 43 other leukaemia lines, difference -0.103, pan-essentiality -0.002 across 1,208 lines, selectivity rank 1,079 of 17,728.

   DepMap CRISPR (Chronos) gene-effect scan of 11 KMT2A-rearranged versus 43 other leukaemia lines (this project's own scan) · Broad Institute DepMap; joined locally from analyses/depmap-kmt2a-selective-scan-full · analyses/depmap-kmt2a-selective-scan-full 2026
   ▸What this evidence cannot show

   Joined 2026-09-22 from analyses/depmap-kmt2a-selective-scan-full/results.json (generated 2026-09-19T10:12:06Z), this project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies, including that the 11 KMT2A-rearranged lines are drawn from nine individuals and that the arm is myeloid-enriched. The scan records a generation timestamp and NOT a DepMap RELEASE, which is rule 83 exposure carried forward rather than fixed here. A pan-essentiality of -0.002 is indistinguishable from zero and the comparator arm mean is POSITIVE, so the rank of 1,079 is the unstable-sorting artefact of a near-zero floor rather than a signal - the z-is-not-an-effect-size problem this project documents. AND THE STRUCTURAL OBJECTION, WHICH MATTERS MORE HERE THAN FOR ANY OTHER GENE IN THIS BEAT: RALGAPA2 behaves as a TUMOUR SUPPRESSOR, and a loss-of-function CRISPR screen is the wrong instrument in principle for a tumour suppressor - knocking one out is expected to help cells, not hurt them, so a near-zero or positive score is the predicted result and carries no information. A rank is not an effect size and a difference is not a dependency (this graph's DepMap rules). Check pan_essentiality_all_lines before reading anything as selective, and note the anti-selective half is 50% of any gene set by construction, with this graph's own base rate at 45.3% - so a tally of genes in that half is the null (rule 84). The decisive limitation here is lineage: the screen is leukaemia lines, and for a sarcoma fusion that is the wrong tissue. Cellosaurus holds 592 KMT2A-commented cell lines and ZERO are sarcoma or any mesenchymal tumour, so no cell-line screen can address these cases at all.

   ▸Evidence that argues against this (1)

   • If RALGAPA2 really is a brake on RalA, the informative screen is the opposite one: knockout should confer a growth or migration ADVANTAGE, which a proliferation-based Chronos score in standard culture is poorly powered to detect and a migration or metastasis assay would be. The DepMap row is reported here to close the dependency question, and it should not be read as evidence against the tumour-suppressor hypothesis. Tian L et al. 2022

• fuses with →KMT2A / MLL1 — the gene that breaks

  KMT2A exon 22 :: RALGAPA2 exon 2 (case S18, conventional osteosarcoma); KMT2A 5-prime aa 1-1987, the largest KMT2A contribution of the seven; junction predicted OUT OF FRAME

• part of →Seven KMT2A-rearranged sarcomas retain the menin-binding motif, three of them carry the complete leukaemic N-terminal module, and all sixteen partner names were in one unopened supplementary table

  one of the seven MBM-retaining 5-prime sarcoma partners, and the case where allele disruption is the better hypothesis than a chimera

• depends on →Which KMT2A exon carries which interface: exon 1 is the menin-binding motif, exons 5-6 are the CXXC zinc finger (computed, not recalled)

  retained-module claim is a coordinate derivation against that map, re-verified from NM_001197104.2

• related to →KMT2A-rearranged soft tissue sarcoma - the same gene as infant B-ALL, in a young adult's leg, as a solid tumour

  partner in case S18, conventional-type osteosarcoma

• related to →The predictable clinical error this beat exists to prevent: a menin inhibitor given for a KMT2A-rearranged sarcoma because of the gene name

  MBM and CXXC retained in an osteosarcoma - and the partner is a candidate tumour suppressor, so the therapeutic logic inverts

• tests →Menin dependency tracks the availability of an intact menin-binding motif, in cis or in trans — not the fusion family

  MBM retained in cis with the largest KMT2A contribution of the seven, in a bone-forming mesenchymal tumour

• co-occurs with →AHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon

  the two cases in this cohort where ALLELE DISRUPTION rather than a chimera is a live alternative hypothesis

• co-occurs with →C2CD3 - the centriole-elongation regulator fused to KMT2A exon 8 in an MPNST, predicted OUT OF FRAME, and the partner whose RefSeq transcript is 390 residues shorter than UniProt's canonical

  the two cases predicted frameshifted by the same exon-phase derivation, so a systematic numbering error would move both together

• refutes →In leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that.

  polarity is not inverted in this case - KMT2A is 5-prime, the leukaemic orientation

• supports →Every published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions

  names one of the 16 non-recurrent partners the census recorded as a group because Supplemental Table 2 had not been opened

• related to →Nobody has ever asked whether a KMT2A-rearranged sarcoma needs menin: zero records, and the reason is that no model exists

  an MBM-retaining arm with no menin binding or dependence measurement of any kind - this is one of the cases that absence is about

• ← co-occurs withTMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall

  the two latest KMT2A breakpoints of the seven (exons 20 and 22), both well downstream of the leukaemic breakpoint cluster region