Is BRCA2 p.Pro1257Ala (c.3769C>G) pathogenic?

BRCA2 p.Pro1257Ala (c.3769C>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-12-22). AlphaMissense: likely benign (0.097); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Pro1257Ala (c.3769C>G)?

BRCA2 p.Pro1257Ala (c.3769C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Pro1257Ala (c.3769C>G) in the general population?

BRCA2 p.Pro1257Ala (c.3769C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Pro1257Ala (c.3769C>G)?

AlphaMissense predicts likely benign (score 0.097) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro1257Ala

c.3769C>G · rs1060502438 · VCV491260

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.097 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.097	likely benign
REVEL	0.178	moderately 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 -0.31	GERP 0.12
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	13.33	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA2
Protein: p.Pro1257Ala
Coding: c.3769C>G
MANE Select: NM_000059
dbSNP: rs1060502438
Type: single nucleotide variant
Location: chr13:32338124 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1257: the 'interaction with rad51' region; a β-strand

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

Similar variants

BRCA2 p.Pro1257= Likely benign ★★★ same residue
BRCA2 p.Pro1257Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro1257Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro1257Thr Conflicting classifications of pathogenicity ★ ⚠ 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-pro1257ala (accessed [today's date]).

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