Is BRCA2 p.Arg2991His (c.8972G>A) pathogenic?

BRCA2 p.Arg2991His (c.8972G>A) is classified Benign/Likely benign in BRCA2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.1321); Ultra-rare (popmax 0.0267%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg2991His (c.8972G>A)?

BRCA2 p.Arg2991His (c.8972G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Arg2991His (c.8972G>A) in the general population?

BRCA2 p.Arg2991His (c.8972G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Arg2991His (c.8972G>A)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2991His

c.8972G>A · rs80359150 · VCV38200

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.511	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	27.5	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 0.0267% Admixed American · 16/59,970 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00385% 62/1,611,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,748
South Asian	0.00879%	11,377
Remaining individualsnot grpmax-eligible	0.00481%	20,804
European (non-Finnish)	0.0028%	35,700
East Asian	0.00223%	44,838
African / African-American	0.00134%	74,800

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.Arg2991His
Coding: c.8972G>A
MANE Select: NM_000059
dbSNP: rs80359150
Type: single nucleotide variant
Location: chr13:32379768 (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.Arg2991Pro Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg2991= Likely benign ★★ same residue
BRCA2 p.Arg2991Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2991Leu 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-arg2991his (accessed [today's date]).

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