Is BRCA2 p.Ala3122Val (c.9365C>T) pathogenic?

BRCA2 p.Ala3122Val (c.9365C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.2054); Very rare (popmax 0.00133%, afr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Ala3122Val (c.9365C>T)?

BRCA2 p.Ala3122Val (c.9365C>T) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Ala3122Val (c.9365C>T) in the general population?

BRCA2 p.Ala3122Val (c.9365C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Ala3122Val (c.9365C>T)?

AlphaMissense predicts likely benign (score 0.2054) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala3122Val

c.9365C>T · rs571971903 · VCV220639

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.2054	likely benign
REVEL	0.528	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	22.7	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 0.00133% African / African-American · 1/75,054 alleles

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

Overall 0.000372% 6/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,054
European (non-Finnish)	0.000424%	235,998

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.Ala3122Val
Coding: c.9365C>T
MANE Select: NM_000059
dbSNP: rs571971903
Type: single nucleotide variant
Location: chr13:32394797 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

Similar variants

BRCA2 p.Ala3122Pro Likely pathogenic ★★★ same residue
BRCA2 p.Ala3122Gly Uncertain significance ★★ ⚠ same residue
BRCA2 p.Ala3122Glu Uncertain significance ★ ⚠ same residue
BRCA2 p.Ala3122Ser Uncertain significance ★ same residue
BRCA2 p.Ala3122Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala3122= Likely benign ★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>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-ala3122val (accessed [today's date]).

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