Is BRCA2 p.Val1255Ala (c.3764T>C) pathogenic?

BRCA2 p.Val1255Ala (c.3764T>C) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-27). AlphaMissense: likely benign (0.1753); Very rare (popmax 0.00034%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Val1255Ala (c.3764T>C)?

BRCA2 p.Val1255Ala (c.3764T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Val1255Ala (c.3764T>C) in the general population?

BRCA2 p.Val1255Ala (c.3764T>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Val1255Ala (c.3764T>C)?

AlphaMissense predicts likely benign (score 0.1753) — an in-silico prediction, not a clinical call.

BRCA2 p.Val1255Ala

c.3764T>C · rs1593900450 · VCV1496807

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1753	likely benign
REVEL	0.244	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.001	GERP -3.4
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	14.87	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,177,482 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,608,476 alleles · very rare exomes 4/1,456,174 · genomes 0/152,302 · 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: BRCA2
Protein: p.Val1255Ala
Coding: c.3764T>C
MANE Select: NM_000059
dbSNP: rs1593900450
Type: single nucleotide variant
Location: chr13:32338119 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1255: the 'interaction with rad51' region

Full BRCA2 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: hereditary breast ovarian cancer syndrome

Similar variants

BRCA2 p.Val1255= Likely benign ★★ same residue
BRCA2 p.Val1255Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val1255Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val1255Leu Uncertain significance ★ ⚠ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C 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/brca2-p-val1255ala (accessed [today's date]).

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