Is BAP1 p.Gly594Ala (c.1781G>C) pathogenic?

BAP1 p.Gly594Ala (c.1781G>C) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.0773); Very rare (popmax 0.00999%, amr); Associated with BAP1-related tumor predisposition syndrome.

What condition is associated with BAP1 p.Gly594Ala (c.1781G>C)?

BAP1 p.Gly594Ala (c.1781G>C) is associated with BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Gly594Ala (c.1781G>C) in the general population?

BAP1 p.Gly594Ala (c.1781G>C) is very rare (popmax 0.00999%, amr) (gnomAD).

How is BAP1-related tumor predisposition syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BAP1 p.Gly594Ala (c.1781G>C)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

BAP1 p.Gly594Ala

c.1781G>C · rs144172190 · VCV472678

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00999%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BAP1-related tumor predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 2, phastCons 0.94
Overall
CADD	14.06	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 0.00999% Admixed American · 6/60,032 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00624%

Overall 0.00669% 108/1,614,172 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00999%	10,005
European (non-Finnish)	0.00805%	12,421
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.00266%	37,526

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.Gly594Ala
Coding: c.1781G>C
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs144172190
Type: single nucleotide variant
Location: chr3:52403247 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB

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

Disease context

Also linked: hereditary neoplastic syndrome

For BAP1-related tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

BAP1 p.Gly594= Benign/Likely benign ★★ same residue
BAP1 p.Gly594Arg Uncertain significance ★ ⚠ same residue
BAP1 p.Gly594Glu Uncertain significance ★ ⚠ same residue
BAP1 p.Gly594Trp Uncertain significance ★ ⚠ same residue
BAP1 p.Gly594fs Pathogenic ★★ 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

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-gly594ala (accessed [today's date]).

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