Is BRCA2 p.Ala3012Gly (c.9035C>G) pathogenic?

BRCA2 p.Ala3012Gly (c.9035C>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.1468); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Ala3012Gly (c.9035C>G)?

BRCA2 p.Ala3012Gly (c.9035C>G) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome, BRCA2-related cancer predisposition (ClinVar).

How common is BRCA2 p.Ala3012Gly (c.9035C>G) in the general population?

BRCA2 p.Ala3012Gly (c.9035C>G) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA2 p.Ala3012Gly (c.9035C>G)?

AlphaMissense predicts likely benign (score 0.1468) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala3012Gly

c.9035C>G · rs768335521 · VCV409449

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1468 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.1468	likely benign
REVEL	0.273	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 0.69, phastCons 0.33
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	21.1	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

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.Ala3012Gly
Coding: c.9035C>G
MANE Select: NM_000059
dbSNP: rs768335521
Type: single nucleotide variant
Location: chr13:32379831 (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

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome BRCA2-related cancer predisposition

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ala3012Glu Uncertain significance ★★ same residue
BRCA2 p.Ala3012= Likely benign ★★ same residue
BRCA2 p.Ala3012Val 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
BRCA2 c.475+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/brca2-p-ala3012gly (accessed [today's date]).

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