# NM_004656.4(BAP1):c.34C>G (p.Pro12Ala)

https://sugi.bio/variant/bap1-p-pro12ala

## Summary

**BAP1 p.Pro12Ala (c.34C>G)** is classified **Likely pathogenic** in BAP1 (ClinVar, Single submitter, 3 submitters; last evaluated 2022-03-02). AlphaMissense: likely pathogenic (0.9835); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2153228682 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BAP1 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to neurodevelopmental disorder.

*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 | 210 registered for this condition — see ClinicalTrials.gov |

**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.Pro12Ala |
| Coding change (HGVS c.) | c.34C>G |
| MANE Select transcript | [NM_004656](https://www.ncbi.nlm.nih.gov/nuccore/NM_004656) |
| dbSNP | [rs2153228682](https://www.ncbi.nlm.nih.gov/snp/rs2153228682/) |
| Variant type | single nucleotide variant |
| Location | chr3:52409845-52409845 (GRCh38) |
| ClinVar | [VCV1173077](https://www.ncbi.nlm.nih.gov/clinvar/variation/1173077/) |

**All HGVS expressions:** `LRG_529:g.5149C>G`, `NC_000003.11:g.52443861G>C`, `NC_000003.12:g.52409845G>C`, `NG_031859.1:g.5149C>G`, `NM_004656.4:c.34C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9835) — concordant with the pathogenic call
- REVEL 0.665 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.497 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.42, GERP 1.55, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.0**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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: 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 **12** lies in the uch catalytic domain; a UniProt-annotated variant site (in kuris); a UniProt-annotated variant site (in kuris; loss-of-function variant; increased steady-state levels of ubiquitinated h2a are found in patient cells; unable to rescue impaired h2ak119ub deubiquitination when expressed in bap1-deficient cells; does not affect localization to the nucleus); 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.Pro12Ala 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 2022-03-02.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2021–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Pathogenic | no assertion criteria provided | research | 2021-06-22 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-02-24 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-02 |

## Associated conditions {#conditions}

[neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/), [Kury-Isidor syndrome](https://sugi.bio/atlas/disease/kury-isidor-syndrome/).

**Reported phenotype names (ClinVar):** not provided, Neurodevelopmental disorder, Kury-Isidor syndrome, none provided.

## Same-residue context {#hotspot}

Residue **12** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BAP1 p.Pro12Thr](/variant/bap1-p-pro12thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 p.Pro12Thr](/variant/bap1-p-pro12thr), [BAP1 p.Pro12=](/variant/bap1-p-pro12), [BAP1 p.Pro12Arg](/variant/bap1-p-pro12arg), [BAP1 p.Ala92Val](/variant/bap1-p-ala92val), [BAP1 p.Asn229Lys](/variant/bap1-p-asn229lys), [BAP1 p.Cys91Ser](/variant/bap1-p-cys91ser), [BAP1 p.Gln392Ter](/variant/bap1-p-gln392ter), [BAP1 p.Trp202Ter](/variant/bap1-p-trp202ter).

### 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 1173077). 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.*