Is BRCA2 p.Pro3039Arg (c.9116C>G) pathogenic?

BRCA2 p.Pro3039Arg (c.9116C>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.1184); Very rare (popmax 0.0011%, sas); Associated with Breast and/or ovarian cancer.

What condition is associated with BRCA2 p.Pro3039Arg (c.9116C>G)?

BRCA2 p.Pro3039Arg (c.9116C>G) is associated with Breast and/or ovarian cancer, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro3039Arg (c.9116C>G) in the general population?

BRCA2 p.Pro3039Arg (c.9116C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRCA2 p.Pro3039Arg (c.9116C>G)?

AlphaMissense predicts likely benign (score 0.1184) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro3039Arg

c.9116C>G · rs80359167 · VCV38213

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.1184	likely benign
REVEL	0.445	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -0.28
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	19.84	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 0.0011% South Asian · 1/91,016 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,014 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,016
European (non-Finnish)	0.000254%	393,127

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.Pro3039Arg
Coding: c.9116C>G
MANE Select: NM_000059
dbSNP: rs80359167
Type: single nucleotide variant
Location: chr13:32379912 (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

Breast and/or ovarian cancer — 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 neoplastic syndrome

Similar variants

BRCA2 p.Pro3039= Pathogenic/Likely pathogenic ★★ same residue
BRCA2 p.Pro3039Ser Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro3039Leu Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Pro3039fs Pathogenic/Likely pathogenic ★★ same residue
BRCA2 p.Pro3039Gln 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-pro3039arg (accessed [today's date]).

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