Is BAP1 p.Cys649Tyr (c.1946G>A) pathogenic?

BAP1 p.Cys649Tyr (c.1946G>A) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.2337); Ultra-rare (popmax 0.0114%, nfe); Associated with Hereditary cancer.

What condition is associated with BAP1 p.Cys649Tyr (c.1946G>A)?

BAP1 p.Cys649Tyr (c.1946G>A) is associated with Hereditary cancer, BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Cys649Tyr (c.1946G>A) in the general population?

BAP1 p.Cys649Tyr (c.1946G>A) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about BAP1 p.Cys649Tyr (c.1946G>A)?

AlphaMissense predicts likely benign (score 0.2337) — an in-silico prediction, not a clinical call.

BAP1 p.Cys649Tyr

c.1946G>A · rs151308667 · VCV240053

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.2337 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.2337	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -6.32	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 5.9	GERP 0.85, phastCons 1
Overall
CADD	17.96	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 0.0114% European (non-Finnish) · 135/1,180,060 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0092%

Overall 0.00935% 151/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0114%	8,741
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Finnishnot grpmax-eligible	0.00781%	12,810
Admixed American	0.005%	20,000
African / African-American	0.00133%	74,940
South Asian	0.0011%	91,088

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.Cys649Tyr
Coding: c.1946G>A
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs151308667
Type: single nucleotide variant
Location: chr3:52402816 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB

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

Disease context

Hereditary cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BAP1-related tumor predisposition syndrome hereditary neoplastic syndrome

Similar variants

BAP1 p.Cys649= Conflicting classifications of pathogenicity ★ same residue
BAP1 p.Cys649Arg Uncertain significance ★ ⚠ same residue
BAP1 p.Cys649fs Likely 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
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-cys649tyr (accessed [today's date]).

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