# NM_004656.4(BAP1):c.669C>A (p.Tyr223Ter)

https://sugi.bio/variant/bap1-p-tyr223ter

## Summary

**BAP1 p.Tyr223Ter (c.669C>A)** is classified **Pathogenic** in BAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). Absent from gnomAD v4.1; Associated with BAP1-related tumor predisposition syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2153227498 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BAP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Tyr223Ter |
| Coding change (HGVS c.) | c.669C>A |
| MANE Select transcript | [NM_007212](https://www.ncbi.nlm.nih.gov/nuccore/NM_007212) (variant reported on NM_004656) |
| dbSNP | [rs2153227498](https://www.ncbi.nlm.nih.gov/snp/rs2153227498/) |
| Variant type | single nucleotide variant |
| Location | chr3:52406367-52406367 (GRCh38) |
| ClinVar | [VCV1071927](https://www.ncbi.nlm.nih.gov/clinvar/variation/1071927/) |

**All HGVS expressions:** `LRG_529:g.8627C>A`, `NC_000003.11:g.52440383G>T`, `NC_000003.12:g.52406367G>T`, `NG_031859.1:g.8627C>A`, `NM_004656.4:c.669C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.58) — consistent with the pathogenic call
- Conservation: phyloP 6.556, GERP 0.98, 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 40.0**. 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 deltas (raw): acceptor loss **0.08**, donor loss **0.00**, acceptor gain **0.58**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.08**, donor loss **0.00**, acceptor gain **0.58**, donor gain **0.00**.
- Pangolin: Δ**0.44** (gain), gain 0.44 / loss 0.19. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}


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 Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-16.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-16 |

## 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 p.Tyr223Cys](/variant/bap1-p-tyr223cys), [BAP1 p.Tyr223=](/variant/bap1-p-tyr223), [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).

### 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 1071927). 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.*