Is BAP1 p.Ile76Thr (c.227T>C) pathogenic?

BAP1 p.Ile76Thr (c.227T>C) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-13). AlphaMissense: likely benign (0.2755); Very rare (popmax 0.000424%, nfe); Associated with Hereditary cancer.

What condition is associated with BAP1 p.Ile76Thr (c.227T>C)?

BAP1 p.Ile76Thr (c.227T>C) is associated with Hereditary cancer, BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Ile76Thr (c.227T>C) in the general population?

BAP1 p.Ile76Thr (c.227T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BAP1 p.Ile76Thr (c.227T>C)?

AlphaMissense predicts likely benign (score 0.2755) — an in-silico prediction, not a clinical call.

BAP1 p.Ile76Thr

c.227T>C · rs1221534458 · VCV489632

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.2755	likely benign
REVEL	0.386	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	27.7	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) · 5/1,179,348 alleles

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

Overall 0.00031% 5/1,612,230 alleles · very rare exomes 4/1,460,016 · genomes 1/152,214 · joint denominator

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.Ile76Thr
Coding: c.227T>C
MANE Select: NM_004656
dbSNP: rs1221534458
Type: single nucleotide variant
Location: chr3:52408502 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 76: the uch catalytic domain; an α-helix

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 Kury-Isidor syndrome

Similar variants

BAP1 p.Ile76= Likely benign ★★ same residue
BAP1 p.Ile76Val Conflicting classifications of pathogenicity ★ ⚠ 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-ile76thr (accessed [today's date]).

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