# NM_004656.4(BAP1):c.118C>T (p.Gln40Ter)

https://sugi.bio/variant/bap1-p-gln40ter

## Summary

**BAP1 p.Gln40Ter (c.118C>T)** is classified **Pathogenic/Likely pathogenic** in BAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). Absent from gnomAD v4.1; Associated with BAP1-related tumor predisposition syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1553646284 · 2 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BAP1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to BAP1-related tumor predisposition syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013219/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BAP1](https://sugi.bio/atlas/gene/BAP1/) |
| Protein change (HGVS p.) | p.Gln40Ter |
| Coding change (HGVS c.) | c.118C>T |
| MANE Select transcript | [NM_007212](https://www.ncbi.nlm.nih.gov/nuccore/NM_007212) (variant reported on NM_004656) |
| dbSNP | [rs1553646284](https://www.ncbi.nlm.nih.gov/snp/rs1553646284/) |
| Variant type | single nucleotide variant |
| Location | chr3:52409558-52409558 (GRCh38) |
| ClinVar | [VCV539912](https://www.ncbi.nlm.nih.gov/clinvar/variation/539912/) |

**All HGVS expressions:** `LRG_529:g.5436C>T`, `LRG_529t1:c.118C>T`, `NC_000003.11:g.52443574G>A`, `NC_000003.12:g.52409558G>A`, `NG_031859.1:g.5436C>T`, `NM_004656.2:c.118C>T`, `NM_004656.4:c.118C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.775, GERP 1.43, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 43.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.79 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BAP1** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **BAP1-related tumor predisposition syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **40** lies in the 'interaction with hip2' region.

AlphaFold model confidence (whole protein): pLDDT 78.27, 44% of residues very-high.

**28 experimental structure(s)** (PDB): [28OE](https://www.rcsb.org/structure/28OE), [2H0D](https://www.rcsb.org/structure/2H0D), [3GS2](https://www.rcsb.org/structure/3GS2), [3H8H](https://www.rcsb.org/structure/3H8H), [3IXS](https://www.rcsb.org/structure/3IXS), [3RPG](https://www.rcsb.org/structure/3RPG).

## What this gene does {#gene-function}

*Describes the biological roles of BAP1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BAP1's established molecular role includes chromatin binding. p.Gln40Ter falls in the interaction with hip2 region.


### Pathways affected {#pathways}

BAP1 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | other |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | other |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | other |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | other |
| [SUMOylation of DNA methylation proteins](https://reactome.org/content/detail/R-HSA-4655427) | other |
| [SUMOylation of RNA binding proteins](https://reactome.org/content/detail/R-HSA-4570464) | other |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | other |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | other |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** chromatin binding, zinc ion binding, RING-like zinc finger domain binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, epigenetic regulation of gene expression.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2023–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-26 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-10 |

## Associated conditions {#conditions}

[BAP1-related tumor predisposition syndrome](https://sugi.bio/atlas/disease/bap1-related-tumor-predisposition-syndrome/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** BAP1-related tumor predisposition syndrome, Hereditary cancer-predisposing syndrome, COMMON Syndrome, TUMOR PREDISPOSITION SYNDROME 1, BAP1 tumor predisposition syndrome, Tumor susceptibility linked to germline BAP1 mutations, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition.

## Same-residue context {#hotspot}

Residue **40** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BAP1 p.Gln40fs](/variant/bap1-p-gln40fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 p.Gln40Arg](/variant/bap1-p-gln40arg), [BAP1 p.Gln40His](/variant/bap1-p-gln40his), [BAP1 p.Gln40fs](/variant/bap1-p-gln40fs), [BAP1 c.1117-1G>A](/variant/bap1-c-1117-minus-1g-a), [BAP1 c.122+1G>A](/variant/bap1-c-122-plus-1g-a), [BAP1 c.122+1G>T](/variant/bap1-c-122-plus-1g-t), [BAP1 c.122+5G>A](/variant/bap1-c-122-plus-5g-a), [BAP1 c.122+5G>C](/variant/bap1-c-122-plus-5g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 539912). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*