# NM_004656.4(BAP1):c.1083A>C (p.Leu361=)

https://sugi.bio/variant/bap1-p-leu361

## Summary

**BAP1 p.Leu361= (c.1083A>C)** is classified **Likely benign** in BAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs2153227010 · 2 submitters · 2 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the BAP1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Leu361= |
| Coding change (HGVS c.) | c.1083A>C |
| MANE Select transcript | [NM_007212](https://www.ncbi.nlm.nih.gov/nuccore/NM_007212) (variant reported on NM_004656) |
| dbSNP | [rs2153227010](https://www.ncbi.nlm.nih.gov/snp/rs2153227010/) |
| Variant type | single nucleotide variant |
| Location | chr3:52405143-52405143 (GRCh38) |
| ClinVar | [VCV1786890](https://www.ncbi.nlm.nih.gov/clinvar/variation/1786890/) |

**All HGVS expressions:** `LRG_529:g.9851A>C`, `LRG_529t1:c.1083A>C`, `NC_000003.11:g.52439159T>G`, `NC_000003.12:g.52405143T>G`, `NG_031859.1:g.9851A>C`, `NM_001410772.1:c.1029A>C`, `NM_004656.4:c.1083A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.305, GERP -0.433, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.12**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.18**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.18**.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,036 in the highest group · 1/1,461,808 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}


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.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-24.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-10-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-24 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [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), [BAP1 c.1251-1G>A](/variant/bap1-c-1251-minus-1g-a), [BAP1 c.1251-1G>C](/variant/bap1-c-1251-minus-1g-c), [BAP1 c.1251-2A>G](/variant/bap1-c-1251-minus-2a-g).

### 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 1786890). 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.*