Is BRCA2 p.Ala3012Glu (c.9035C>A) pathogenic?

BRCA2 p.Ala3012Glu (c.9035C>A) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-25). AlphaMissense: ambiguous (0.3944); Very rare (popmax 0.00017%, nfe); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Ala3012Glu (c.9035C>A)?

BRCA2 p.Ala3012Glu (c.9035C>A) is associated with hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Ala3012Glu (c.9035C>A) in the general population?

BRCA2 p.Ala3012Glu (c.9035C>A) is very rare (popmax 0.00017%, nfe) (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.Ala3012Glu (c.9035C>A)?

AlphaMissense predicts ambiguous (score 0.3944) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala3012Glu

c.9035C>A · rs768335521 · VCV409530

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.3944	ambiguous
REVEL	0.325	indeterminate
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	20.0	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 0.00017% European (non-Finnish) · 2/1,179,234 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,844 alleles · very rare

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.Ala3012Glu
Coding: c.9035C>A
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: breast-ovarian cancer, familial, susceptibility to, 2

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ala3012= Likely benign ★★ same residue
BRCA2 p.Ala3012Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala3012fs Pathogenic ★★★ 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

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-ala3012glu (accessed [today's date]).

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