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

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.
• Nothing here supports targeting AHDC1. It is a developmental dosage-sensitive gene whose heterozygous truncation causes a neurodevelopmental syndrome with intellectual disability, so partial loss of function in a patient is a known pathogenic state rather than a tolerated one.
• The Ewing analogy is an argument for caution, not for translation: AHDC1 knockdown lowers BRD4, and BET inhibition already fails in this disease for reasons of on-target toxicity and rapid adaptation - a second route into the same node is not a new route out.
• If the S16 mechanism is AHDC1 haploinsufficiency rather than a chimera, then the therapeutic logic inverts entirely: the lesion would be loss of a chromatin-architecture factor, which nothing in the menin or DOT1L pharmacology addresses.

1. Does the commercial panel number AHDC1's exons from the first transcribed exon or from the first CODING exon? The whole 'partner contributes no protein' conclusion for case S16 turns on that one annotation convention, and it is resolvable by asking for the panel's transcript model or the junction sequence.
2. Is AHDC1 a cofactor of KMT2A fusions as well as of EWS-FLI1? It was recovered by BioID against EWS-ETS proteins, no proximity-labelling experiment has ever been done on a KMT2A fusion, and exp-turboid-map-of-kmt2a-aff1 is the queued experiment that would answer it - AHDC1 is now a named thing to look for in its output.
3. Does AHDC1 loss raise DNA methylation in mesenchymal tumour cells as it does in developing skin? Leiomyosarcoma is a mesenchymal tumour and the published methylation effect is at GATA3-dependent MESODERMAL genes, so the systems are closer than usual - but nobody has looked.
4. Why does AHDC1 knockdown lower BRD4 and BRG1 PROTEIN? If that is a chromatin-level effect rather than stability, an AT-hook architecture factor would be upstream of two modules this graph already holds entries for.
5. Is the S16 leiomyosarcoma's AHDC1 allele disrupted in a way that matters? A breakpoint in the 5'-UTR could destroy one allele's promoter or leave it intact, and a haploinsufficiency mechanism would be a completely different story from a chimera - the Xia-Gibbs literature says AHDC1 is dosage-sensitive in development.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   AHDC1 (Q5TGY3) is a 1,603-residue nuclear protein whose UniProt recommended name is now 'Transcription factor Gibbin', carrying two AT-hook DNA-binding motifs at 396-408 and 544-556, extensive disordered regions and no catalytic or histone-modifying module; truncating variants cause Xia-Gibbs syndrome.

   UniProtKB Q5TGY3 (AHDC1_HUMAN) - Transcription factor Gibbin (AT-hook DNA-binding motif-containing protein 1) · 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 AHDC1, entry AHDC1_HUMAN, length 1,603 aa (rules 62, 65, 66 satisfied; accession AND length asserted). IDENTIFIER TRAP WORTH RECORDING: the recommended protein name is 'Transcription factor Gibbin' and contains neither the symbol AHDC1 nor anything resembling it, with 'AT-hook DNA-binding motif-containing protein 1' demoted to an alternative name - so the rule-65 defence of reading the protein name back makes a CORRECT record look like a failed lookup, the same shape as DPF2 returning REQU_HUMAN. Domain boundaries are UniProt feature-table calls; there is no PDB entry for AHDC1 and the protein is predicted largely disordered, so 'domain' here means motif annotation, not structure.

   ▸Evidence that argues against this (1)

   • An AT-hook is a minor-groove AT-rich DNA-binding motif with no sequence specificity and no modification specificity, so annotating two of them does not establish that AHDC1 selects its own sites. The Nature study's own model has Gibbin brought to specific loci by dozens of sequence-specific zinc-finger transcription factors, which implies the AT-hooks are not the targeting determinant - and the same caution applies to KMT2A's own three AT-hooks. Collier A et al. 2022
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Enhancer- and promoter-bound Gibbin/AHDC1 interacts with dozens of sequence-specific zinc-finger transcription factors and with methyl-CpG-binding proteins to maintain local enhancer-promoter chromatin architecture, and its loss increases DNA methylation at GATA3-dependent mesodermal genes, breaking dermal-epidermal signalling in human skin organoids and reproducing patient patterning defects in chimeric CRISPR mice.

   Gibbin mesodermal regulation patterns epithelial development. · Collier A, Liu A, Torkelson J et al · Nature 2022
   PMID 35585237DOI
   ▸What this evidence cannot show

   HUMAN embryonic-stem-cell-derived skin organoids plus in-vivo chimeric CRISPR MICE - a developmental system, not a tumour, and not a haematopoietic or sarcoma cell. Abstract read from the eutils record; full text not read, so the number of zinc-finger partners ('dozens'), the identity of the methyl-CpG-binding proteins and the magnitude of the methylation increase are all taken as stated rather than inspected. The methylation change is measured on Gibbin LOSS, which does not establish that Gibbin protects methylation-free state directly rather than through the transcriptional consequences of losing architecture. This paper is the source of UniProt's FUNCTION comment for AHDC1 and of its 'Chromosome' location comment; rule 91 was checked and it genuinely supports both.

   ▸Evidence that argues against this (1)

   • The direction of causation between architecture and methylation is not settled by a loss-of-function experiment: increased DNA methylation at GATA3-dependent genes is equally consistent with methylation following the loss of transcription as with Gibbin actively excluding methylation. And whatever the mechanism, it bears on the S16 sarcoma case only if AHDC1 protein is altered there - which, given the breakpoint lands in an untranslated exon, it is not. NCBI RefSeq 2026
3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   BioID proximity labelling of EWS-ETS fusion transcription factors in Ewing sarcoma cells recovered AHDC1 as a proximal protein absent from the previously known EWS-FLI1 interactome, and AHDC1 knockdown reduced cell growth, reduced EWS-FLI1 transcriptional activity and lowered BRD4 and BRG1 protein levels.

   AT-hook DNA-binding motif-containing protein one knockdown downregulates EWS-FLI1 transcriptional activity in Ewing's sarcoma cells. · Kitagawa T, Kobayashi D, Baron B et al · PLoS One 2022
   PMID 36194562DOI
   ▸What this evidence cannot show

   Human Ewing sarcoma cell lines - a DIFFERENT fusion family (EWSR1::FLI1) and a different tumour from the KMT2A-rearranged sarcomas this entry is about, so the relevance is analogical (PI dimension 5), not direct. Proximity labelling reports neighbourhood, not contact: a BioID hit is not a binding partner. Knockdown effects on BRD4 and BRG1 PROTEIN levels could be transcriptional, post-translational or indirect, and the abstract distinguishes none of these. Rule 82 flag: this PMID is ALREADY CITED THREE TIMES in this graph - in ana-kmt2a-interactome-systematic-enumeration, exp-turboid-map-of-kmt2a-aff1 and hyp-menin-primacy-is-geometry-not-biology - but in every case as a BioID METHODS precedent, with AHDC1 mentioned only as what the method happened to recover. The protein itself has had no entry until now.

   ▸Evidence that argues against this (1)

   • The graph's own reading of this same paper is a warning about the method rather than an endorsement of the hit: both existing entries note that the CANONICAL EWS-FLI1 partners were reached only INDIRECTLY by this BioID experiment. A screen that under-recovers the known partners is a screen whose novel hits need orthogonal confirmation, and no co-immunoprecipitation or structural evidence for an AHDC1-EWS-FLI1 contact exists. Kitagawa T et al. 2022
4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In case S16 of a pan-sarcoma KMT2A-rearrangement series, a leiomyosarcoma carried KMT2A exon 15 fused to AHDC1 exon 2 (NM_001029882), one of seven cases in that cohort with KMT2A as the 5-prime partner and a breakpoint downstream of exon 1.

   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 S16, leiomyosarcoma) 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.

   ▸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
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   KMT2A exons 1-15 encode aa 1-1668 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-15 break lies 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
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   AHDC1's entire 1,603-residue coding sequence lies within exon 6 of NM_001029882 (CDS 832..5643, exon 6 spanning nt 758-5686); exons 1-5 are wholly 5'-untranslated and exon 2 is nt 99-276, 556 nucleotides upstream of the start codon - so the reported KMT2A exon 15 :: AHDC1 exon 2 junction contributes NO AHDC1 protein sequence and the predicted product is a KMT2A 1-1668 fragment with a UTR-derived tail rather than a chimeric protein.

   RefSeq NM_001029882.3 - Homo sapiens AT-hook DNA binding motif containing 1 (AHDC1), mRNA · NCBI RefSeq · NCBI Nucleotide 2026
   ▸What this evidence cannot show

   A derivation computed this cycle from the RefSeq record the source itself names, not an observation. It can be wrong in three ways: (1) the commercial panel's exon numbering for AHDC1 need not match RefSeq's, and for a gene whose coding sequence is one huge exon the numbering of the small upstream exons is exactly where annotations diverge; (2) the junction nucleotide is unknown; (3) translation could in principle re-initiate at AHDC1's own ATG within exon 6 if that exon were included, which would give a separately initiated wild-type-like AHDC1 rather than a fusion. No transcript sequence or protein was reported for this case, so the predicted product has never been looked for. The claim that the KMT2A side is intact does NOT depend on this derivation and stands on E5.

   ▸Evidence that argues against this (1)

   • If the panel numbered AHDC1's exons from the first CODING exon, 'exon 2' would mean something entirely different and this conclusion inverts - and the same table misspells the index gene as KTM2A in two of eighteen rows, so its annotation is demonstrably not error-free. The finding should be read as: on the RefSeq numbering the source cites, this breakpoint is untranslated. Resolving it needs the panel's own annotation or the junction sequence. Massoth LR et al. 2020
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Transient expression of wild-type and patient-truncated AHDC1 in human cell lines revealed abnormal patterns of nuclear localization, with a short truncated form distributing diffusely and mid-protein truncated forms forming nucleolar aggregates, across a phenotypic analysis of 34 Xia-Gibbs individuals.

   Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome. · Khayat MM, Li H, Chander V et al · Human Mutation 2021
   PMID 33644933DOI
   ▸What this evidence cannot show

   The subnuclear observation is of MUTANT protein in a TRANSIENT OVEREXPRESSION system in unspecified human cell lines, so it is a property of truncated constructs at non-physiological levels and not an address for endogenous wild-type AHDC1. Nucleolar aggregation of an overexpressed disordered fragment is a common artefact class. Abstract read; full text not read. This is nonetheless the paper UniProt cites with ECO:0000269 for 'Nucleus', and rule 91 was checked here: it does contain a localisation experiment, which is more than can be said for three of the other six records in this beat.

   ▸Evidence that argues against this (1)

   • The study's own conclusion is HETEROGENEITY - it reports that most phenotypic features could not be predicted by mutation position, and that the different distributions reflect the syndrome's variability. A genotype-to-localisation map is therefore not what the paper establishes, and no wild-type subnuclear assignment follows from it. Li L et al. 2024
8. E8weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.dataset

   AHDC1 shows no KMT2A-selective dependency in this project's own DepMap scan: mean Chronos -0.153 in 11 KMT2A-rearranged lines against -0.230 in 43 other leukaemia lines, difference +0.077 in the anti-selective direction, at a pan-essentiality of -0.122 across 1,208 lines and selectivity rank 16,255 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 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)

   • A rank of 16,255 of 17,728 is a position in the anti-selective half, which half of any gene set occupies by construction and where this graph's own base rate is 45.3% - so it is the null and not a finding (rule 84). Separately, this screens the wild-type AHDC1 locus, and on the reported breakpoint the fusion does not alter AHDC1 protein at all, so the screen is not even testing the right object. Broad Institute DepMap; joined locally from analyses/depmap-kmt2a-selective-scan-full 2026

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

  KMT2A exon 15 :: AHDC1 exon 2 (case S16); KMT2A 5-prime, aa 1-1668, MBM+CXXC retained - but AHDC1 exon 2 is 5'-untranslated, so no partner protein

• 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 (case S16, leiomyosarcoma)

• 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 S16, leiomyosarcoma

• 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-retaining KMT2A fusion in a leiomyosarcoma - the gene-name-driven prescribing risk

• related to →Menin is the best handle on KMT2A::AFF1 because of where the break falls, not because menin is biologically special

  that entry cites the AHDC1/EWS-FLI1 BioID paper as a methods precedent; AHDC1 is the protein it recovered

• related to →Proximity-labelling map of KMT2A::AFF1 — the experiment nobody has run in twenty years of interactome work

  AHDC1 is a named thing to look for in the output: recovered by BioID as proximal to EWS-FLI1, never tested against a KMT2A fusion

• regulates →BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing

  AHDC1 knockdown in Ewing sarcoma cells lowers BRD4 protein levels (mechanism unresolved)

• 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 in a leiomyosarcoma: predicted menin-sensitive in a lineage where menin is a tumour suppressor

• ← co-occurs withRALGAPA2 (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

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

• 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 withELP4 (PAXNEB) - a required subunit of Elongator, the one partner of the seven with a genuine histone-acetyltransferase connection, and the one whose fusion supplies only its last 43 residues

  the two cases where the partner exon contributes essentially nothing - ELP4's terminal exon gives 43 of 424 residues, AHDC1's exon 2 is wholly 5'-untranslated

• co-occurs with →YAP1 (P46937) - the Hippo pathway's transcriptional co-activator, and a KMT2A fusion partner from a completely different functional class

  both partners of KMT2A in sarcoma whose own normal biology is a transcriptional regulator in mesenchyme - AHDC1 at enhancers, YAP1 as the coactivator of the recurrent arm