Is BAP1 p.His274Pro (c.821A>C) pathogenic?

BAP1 p.His274Pro (c.821A>C) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.1012); Ultra-rare (popmax 0.0395%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.His274Pro (c.821A>C)?

BAP1 p.His274Pro (c.821A>C) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.His274Pro (c.821A>C) in the general population?

BAP1 p.His274Pro (c.821A>C) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about BAP1 p.His274Pro (c.821A>C)?

AlphaMissense predicts likely benign (score 0.1012) — an in-silico prediction, not a clinical call.

BAP1 p.His274Pro

c.821A>C · rs565400314 · VCV346123

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1012	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -4.40	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 6.2	GERP 0.96, phastCons 1
Overall
CADD	23.3	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 0.0395% South Asian · 36/91,070 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00242% 39/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Remaining individualsnot grpmax-eligible	0.0048%	20,833

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.His274Pro
Coding: c.821A>C
MANE Select: NM_004656
dbSNP: rs565400314
Type: single nucleotide variant
Location: chr3:52405875 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 274: a UniProt-annotated variant site (in tpds1)

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.His274Arg Uncertain significance ★★ ⚠ same residue
BAP1 p.His274Gln Uncertain significance ★★ ⚠ same residue
BAP1 p.His274Tyr Uncertain significance ★★ ⚠ same residue
BAP1 p.His274Asp Uncertain significance ★ ⚠ same residue
BAP1 p.His274Leu Uncertain significance ★ ⚠ same residue
BAP1 p.His274= Likely benign ★ same residue
BAP1 c.1117-1G>A Likely pathogenic ★★ same condition
BAP1 c.122+1G>A 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-his274pro (accessed [today's date]).

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