Is BAP1 p.Arg356Trp (c.1066C>T) pathogenic?

BAP1 p.Arg356Trp (c.1066C>T) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-03-05). AlphaMissense: likely pathogenic (0.8021); Ultra-rare (popmax 0.0164%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Arg356Trp (c.1066C>T)?

BAP1 p.Arg356Trp (c.1066C>T) is associated with hereditary neoplastic syndrome, melanoma, uveal, susceptibility to, 2, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Arg356Trp (c.1066C>T) in the general population?

BAP1 p.Arg356Trp (c.1066C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about BAP1 p.Arg356Trp (c.1066C>T)?

AlphaMissense predicts likely pathogenic (score 0.8021) — an in-silico prediction, not a clinical call.

BAP1 p.Arg356Trp

c.1066C>T · rs761029538 · VCV472658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8021	likely pathogenic
REVEL	0.284	benign-leaning
SaProt	LLR -9.83	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.24	donor loss, 50 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 0.66, phastCons 1
Overall
CADD	26.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000805% 13/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.004%	24,977
Finnishnot grpmax-eligible	0.00313%	31,987
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000508%	196,673

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.Arg356Trp
Coding: c.1066C>T
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs761029538
Type: single nucleotide variant
Location: chr3:52405160 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, uveal, susceptibility to, 2 BAP1-related tumor predisposition syndrome Kury-Isidor syndrome

Similar variants

BAP1 p.Arg356Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BAP1 p.Arg356= 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
BAP1 c.1251-1G>A 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-arg356trp (accessed [today's date]).

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