# NM_004656.4(BAP1):c.824del (p.Lys275fs)

https://sugi.bio/variant/bap1-p-lys275fs

## Summary

**BAP1 p.Lys275fs (c.824del)** is classified **Pathogenic** in BAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-18). Very rare (popmax 0.00133%, afr); Associated with BAP1-related tumor predisposition syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1559589252 · 3 submitters · 2 linked conditions · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the BAP1 gene that is considered disease-causing, submitted by 3 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.Lys275fs |
| Coding change (HGVS c.) | c.824del |
| MANE Select transcript | [NM_007212](https://www.ncbi.nlm.nih.gov/nuccore/NM_007212) (variant reported on NM_004656) |
| dbSNP | [rs1559589252](https://www.ncbi.nlm.nih.gov/snp/rs1559589252/) |
| Variant type | Deletion |
| Location | chr3:52405872-52405872 (GRCh38) |
| ClinVar | [VCV565856](https://www.ncbi.nlm.nih.gov/clinvar/variation/565856/) |

**All HGVS expressions:** `LRG_529:g.9122del`, `LRG_529t1:c.824del`, `NC_000003.11:g.52439889del`, `NC_000003.12:g.52405873del`, `NG_031859.1:g.9122del`, `NM_004656.2:c.824delA`, `NM_004656.4:c.824del`

## 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 0.848, GERP -0.309, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — 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.*
- 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 (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/75,042 in the highest group · 1/1,461,826 alleles overall — very rare (popmax 0.00133%, afr).

*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 **275** lies in an α-helix.

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-18.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-17 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-06 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-18 |

## 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, Tumor susceptibility linked to germline BAP1 mutations, BAP1 tumor predisposition syndrome, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 p.Lys275Asn](/variant/bap1-p-lys275asn), [BAP1 p.Lys275Glu](/variant/bap1-p-lys275glu), [BAP1 p.Lys275Thr](/variant/bap1-p-lys275thr), [BAP1 p.Lys275=](/variant/bap1-p-lys275), [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 c.659+1del](/variant/bap1-c-659-plus-1del).

### 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 565856). 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.*