Is BRCA2 p.Pro59Ala (c.175C>G) pathogenic?

BRCA2 p.Pro59Ala (c.175C>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0945); Rare (popmax 0.345%, afr); Associated with Breast and/or ovarian cancer.

What condition is associated with BRCA2 p.Pro59Ala (c.175C>G)?

BRCA2 p.Pro59Ala (c.175C>G) is associated with Breast and/or ovarian cancer, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Pro59Ala (c.175C>G) in the general population?

BRCA2 p.Pro59Ala (c.175C>G) is rare (popmax 0.345%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Pro59Ala (c.175C>G)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro59Ala

c.175C>G · rs56091799 · VCV51185

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.345%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.6	GERP 0.51, phastCons 0.45
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	13.12	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 0.345% African / African-American · 259/75,036 alleles

Filtering AF 0.311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.297%

Overall 0.0184% 297/1,614,038 alleles · rare exomes 150/1,461,760 · genomes 147/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.345%	290
Middle Eastern	0.033%	3,031
Admixed American	0.0317%	3,159
Remaining individualsnot grpmax-eligible	0.0256%	3,907
European (non-Finnish)	8.47e-05%	1,179,944

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.Pro59Ala
Coding: c.175C>G
MANE Select: NM_000059
dbSNP: rs56091799
Type: single nucleotide variant
Location: chr13:32319184 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 59: the 'disordered' region

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast cancer breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome

Similar variants

BRCA2 p.Pro59Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro59Thr Uncertain significance ★ ⚠ same residue
BRCA2 p.Pro59= Likely benign ★ same residue
BRCA2 p.Pro59fs Pathogenic ★★★ same residue
BRCA2 p.Pro59Leu 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-pro59ala (accessed [today's date]).

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