# NM_004656.4(BAP1):c.1547C>T (p.Pro516Leu)

https://sugi.bio/variant/bap1-p-pro516leu

## Summary

**BAP1 p.Pro516Leu (c.1547C>T)** is classified **Conflicting classifications of pathogenicity** in BAP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1653); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs755719248 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the BAP1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Pro516Leu |
| Coding change (HGVS c.) | c.1547C>T |
| MANE Select transcript | [NM_004656](https://www.ncbi.nlm.nih.gov/nuccore/NM_004656) |
| dbSNP | [rs755719248](https://www.ncbi.nlm.nih.gov/snp/rs755719248/) |
| Variant type | single nucleotide variant |
| Location | chr3:52403598-52403598 (GRCh38) |
| ClinVar | [VCV472672](https://www.ncbi.nlm.nih.gov/clinvar/variation/472672/) |

**All HGVS expressions:** `LRG_529:g.11396C>T`, `LRG_529t1:c.1547C>T`, `NC_000003.11:g.52437614G>A`, `NC_000003.12:g.52403598G>A`, `NG_031859.1:g.11396C>T`, `NM_004656.4:c.1547C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1653)
- REVEL 0.187 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.88 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.946, GERP 2.07, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.1**. 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 (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.00114% · FAF99 0.000971% · 1/44,900 in the highest group · 28/1,614,052 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00469% | 21,338 |
| East Asian (grpmax) | 0.00223% | 44,900 |
| European (non-Finnish) | 0.00178% | 56,192 |
| Admixed American | 0.00167% | 60,000 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| South Asian | 0.0011% | 91,078 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **516** 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.Pro516Leu 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-10.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Benign).

**Submission history:** 5 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-10 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-17 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2025-07-15 |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-03 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, BAP1-related tumor predisposition syndrome, not provided, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, none provided, BAP1 tumor predisposition syndrome, COMMON Syndrome.

## Similar variants {#similar}

Related BAP1 variant pages (same residue, condition, or type): [BAP1 p.Pro516Ser](/variant/bap1-p-pro516ser), [BAP1 p.Pro516=](/variant/bap1-p-pro516), [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 472672). 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.*