# NM_004656.4(BAP1):c.272dup (p.Cys91fs)

https://sugi.bio/variant/bap1-p-cys91fs

## Summary

**BAP1 p.Cys91fs (c.272dup)** is classified **Likely pathogenic** in BAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-27). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2153228146 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BAP1 gene that is considered likely disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Cys91fs |
| Coding change (HGVS c.) | c.272dup |
| MANE Select transcript | [NM_004656](https://www.ncbi.nlm.nih.gov/nuccore/NM_004656) |
| dbSNP | [rs2153228146](https://www.ncbi.nlm.nih.gov/snp/rs2153228146/) |
| Variant type | Duplication |
| Location | chr3:52408060-52408061 (GRCh38) |
| ClinVar | [VCV1338577](https://www.ncbi.nlm.nih.gov/clinvar/variation/1338577/) |

**All HGVS expressions:** `LRG_529:g.6933dup`, `NC_000003.11:g.52442077dup`, `NC_000003.12:g.52408061dup`, `NG_031859.1:g.6933dup`, `NM_004656.4:c.272dup`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.564, GERP -2.52, phastCons 0.87 — weakly conserved position
- 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 5 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 duplication 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 **91** lies in the uch catalytic domain; an active site; a UniProt-annotated variant site (in kuris); a UniProt-annotated variant site (in kuris; loss-of-function variant; unable to rescue impaired h2ak119ub deubiquitination when expressed in bap1-deficient cells; does not affect localization to the nucleus); a UniProt-annotated variant site (in kuris; loss-of-function variant; increased steady-state level of ubiquitinated h2a are found in patient cells; unable to rescue impaired h2ak119ub deubiquitination when expressed in bap1-deficient cells; abolishes deubiquitinase activity; does not affect its ability to interfere with brca1 e3 ligase activity; does not affect localization to the nucleus; has a dominant negative effect on cell growth; does not affect interaction with foxk1 and foxk2; has no effect on pr-dub complex assembly; unable to activate transcription); a UniProt-annotated variant site (found in a malignant pleural mesothelioma sample); an α-helix.

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.Cys91fs falls in the uch catalytic domain.


### 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-04-27.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-04-27 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **91** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BAP1 p.Cys91Ser](/variant/bap1-p-cys91ser), [BAP1 p.Cys91Ter](/variant/bap1-p-cys91ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 p.Cys91Ser](/variant/bap1-p-cys91ser), [BAP1 p.Cys91Tyr](/variant/bap1-p-cys91tyr), [BAP1 p.Cys91Ter](/variant/bap1-p-cys91ter), [BAP1 p.Cys91Arg](/variant/bap1-p-cys91arg), [BAP1 p.Cys91Gly](/variant/bap1-p-cys91gly), [BAP1 p.Cys91Trp](/variant/bap1-p-cys91trp), [BAP1 p.Arg146fs](/variant/bap1-p-arg146fs), [BAP1 p.Asn504fs](/variant/bap1-p-asn504fs).

### 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 1338577). 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.*