Is BRCA2 p.Ala3028Pro (c.9082G>C) pathogenic?

BRCA2 p.Ala3028Pro (c.9082G>C) is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.662); Very rare (popmax 0.000509%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ala3028Pro (c.9082G>C)?

BRCA2 p.Ala3028Pro (c.9082G>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D1 (ClinVar).

How common is BRCA2 p.Ala3028Pro (c.9082G>C) in the general population?

BRCA2 p.Ala3028Pro (c.9082G>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Ala3028Pro (c.9082G>C)?

AlphaMissense predicts likely pathogenic (score 0.662) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala3028Pro

c.9082G>C · rs80359161 · VCV126199

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.662	likely pathogenic ✓ concordant with ClinVar · top 6% in BRCA2
REVEL	0.354	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -3.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	17.65	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 0.000509% European (non-Finnish) · 6/1,179,830 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,461,518 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.Ala3028Pro
Coding: c.9082G>C
MANE Select: NM_000059
dbSNP: rs80359161
Type: single nucleotide variant
Location: chr13:32379878 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 hereditary breast carcinoma

Similar variants

BRCA2 p.Ala3028Val Uncertain significance ★★ same residue
BRCA2 p.Ala3028Ser Uncertain significance ★ same residue
BRCA2 p.Ala3028Thr Uncertain significance ★ same residue
BRCA2 p.Ala3028= Likely benign ★ 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-ala3028pro (accessed [today's date]).

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