Is BAP1 p.Arg512His (c.1535G>A) pathogenic?

BAP1 p.Arg512His (c.1535G>A) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.4019); Very rare (popmax 0.000424%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Arg512His (c.1535G>A)?

BAP1 p.Arg512His (c.1535G>A) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Arg512His (c.1535G>A) in the general population?

BAP1 p.Arg512His (c.1535G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BAP1 p.Arg512His (c.1535G>A)?

AlphaMissense predicts ambiguous (score 0.4019) — an in-silico prediction, not a clinical call.

BAP1 p.Arg512His

c.1535G>A · rs778596308 · VCV819484

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4019	ambiguous
REVEL	0.265	benign-leaning
SaProt	LLR -6.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,012 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,820 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BAP1
Protein: p.Arg512His
Coding: c.1535G>A
MANE Select: NM_004656
dbSNP: rs778596308
Type: single nucleotide variant
Location: chr3:52403610 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 512: a UniProt-annotated variant site (in tpds1); the 'disordered' region

Full BAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BAP1-related tumor predisposition syndrome

Similar variants

BAP1 p.Arg512Cys Uncertain significance ★★ ⚠ same residue
BAP1 p.Arg512Leu Uncertain significance ★★ ⚠ same residue
BAP1 p.Arg512= Benign/Likely benign ★★ same residue
BAP1 c.1117-1G>A Likely pathogenic ★★ same condition
BAP1 c.122+1G>A Pathogenic ★★ same condition
BAP1 c.122+1G>T Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.122+5G>A Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.122+5G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bap1-p-arg512his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown