Is BRCA2 p.Pro168Ala (c.502C>G) pathogenic?

BRCA2 p.Pro168Ala (c.502C>G) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-17). AlphaMissense: ambiguous (0.4627); Ultra-rare (popmax 0.0166%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Pro168Ala (c.502C>G)?

BRCA2 p.Pro168Ala (c.502C>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro168Ala (c.502C>G) in the general population?

BRCA2 p.Pro168Ala (c.502C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about BRCA2 p.Pro168Ala (c.502C>G)?

AlphaMissense predicts ambiguous (score 0.4627) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro168Ala

c.502C>G · rs80358726 · VCV126130

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4627	ambiguous · top 9% in BRCA2
REVEL	0.147	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 0.0166% Middle Eastern · 1/6,018 alleles

Overall 6.84e-05% 1/1,461,030 alleles · ultra-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.Pro168Ala
Coding: c.502C>G
MANE Select: NM_000059
dbSNP: rs80358726
Type: single nucleotide variant
Location: chr13:32326268 (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 breast-ovarian cancer, familial, susceptibility to, 2 hereditary breast carcinoma

Similar variants

BRCA2 p.Pro168Thr Benign ★★★ ⚠ same residue
BRCA2 p.Pro168Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro168Gln Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro168Ser Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro168Leu 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

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-pro168ala (accessed [today's date]).

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