# NM_004656.4(BAP1):c.1480_1481del (p.Asp494fs)

https://sugi.bio/variant/bap1-p-asp494fs

## Summary

**BAP1 p.Asp494fs (c.1480_1481del)** is classified **Pathogenic** in BAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-24). No gnomAD frequency available for this variant; Associated with BAP1-related tumor predisposition syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2153226700 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BAP1 gene that is considered 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 |
| Diagnostic panels | BAP1 is a diagnostic-grade gene on 15 Genomics England panels |

**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.Asp494fs |
| Coding change (HGVS c.) | c.1480_1481del |
| MANE Select transcript | [NM_004656](https://www.ncbi.nlm.nih.gov/nuccore/NM_004656) |
| dbSNP | [rs2153226700](https://www.ncbi.nlm.nih.gov/snp/rs2153226700/) |
| Variant type | Deletion |
| Location | chr3:52403664-52403665 (GRCh38) |
| ClinVar | [VCV1698777](https://www.ncbi.nlm.nih.gov/clinvar/variation/1698777/) |

**All HGVS expressions:** `LRG_529:g.11329_11330del`, `NC_000003.11:g.52437681_52437682del`, `NC_000003.12:g.52403665_52403666del`, `NG_031859.1:g.11329_11330del`, `NM_004656.3:c.1480_1481delGA`, `NM_004656.4:c.1480_1481del`, `NM_004656.4:c.1480_1481delGA`

## 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 4.532, GERP 0.989, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.324, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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: LOEUF 0.324, pLI 1, missense-Z 3.277. *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 **494** lies in a UniProt-annotated variant site (in tpds1); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.87, 32% of residues very-high.

**4 experimental structure(s)** (PDB): [7VPW](https://www.rcsb.org/structure/7VPW), [8H1T](https://www.rcsb.org/structure/8H1T), [8SVF](https://www.rcsb.org/structure/8SVF), [9U5U](https://www.rcsb.org/structure/9U5U).

## 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.Asp494fs falls in the disordered region.


### Pathways affected {#pathways}

BAP1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | curated |

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

**Molecular function:** chromatin binding, cysteine-type deubiquitinase activity, histone H2A deubiquitinase activity.

**Biological process:** regulation of cell growth, protein deubiquitination, monoubiquitinated protein deubiquitination, negative regulation of DNA-templated transcription, regulation of cell cycle, protein K48-linked deubiquitination.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-24.

**Submitter consensus:** unanimous (2/2 Pathogenic).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics and Molecular Pathology, SA Pathology | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-24 |
| Molecular Pathology, Peter Maccallum Cancer Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-24 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 c.123-10_129del](/variant/bap1-c-123-minus-10-129del), [BAP1 c.1729+1del](/variant/bap1-c-1729-plus-1del), [BAP1 c.1984-3_1999del](/variant/bap1-c-1984-minus-3-1999del), [BAP1 p.Ala138fs](/variant/bap1-p-ala138fs), [BAP1 p.Arg207fs](/variant/bap1-p-arg207fs), [BAP1 p.Arg518fs](/variant/bap1-p-arg518fs), [BAP1 p.Asn363fs](/variant/bap1-p-asn363fs), [BAP1 p.Asp400_Tyr401insTer](/variant/bap1-p-asp400-tyr401inster).

### 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 1698777). 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.*