Is BRCA2 p.Arg2973His (c.8918G>A) pathogenic?

BRCA2 p.Arg2973His (c.8918G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.13); Very rare (popmax 0.00839%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg2973His (c.8918G>A)?

BRCA2 p.Arg2973His (c.8918G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, neuroblastoma (ClinVar).

How common is BRCA2 p.Arg2973His (c.8918G>A) in the general population?

BRCA2 p.Arg2973His (c.8918G>A) is very rare (popmax 0.00839%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Arg2973His (c.8918G>A)?

AlphaMissense predicts likely benign (score 0.13) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2973His

c.8918G>A · rs80359143 · VCV38194

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.13 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00839%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.13	likely benign
REVEL	0.449	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	25.9	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 0.00839% European (non-Finnish) · 99/1,179,788 alleles

Filtering AF 0.00702% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00652%

Overall 0.00707% 114/1,613,142 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00839%	11,917
East Asian	0.00669%	14,950
Remaining individualsnot grpmax-eligible	0.0048%	20,815
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,562
Admixed American	0.00334%	29,911
Finnishnot grpmax-eligible	0.00313%	31,968
African / African-American	0.00267%	37,416
South Asian	0.0022%	45,458

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.Arg2973His
Coding: c.8918G>A
MANE Select: NM_000059
dbSNP: rs80359143
Type: single nucleotide variant
Location: chr13:32379480 (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 neuroblastoma breast-ovarian cancer, familial, susceptibility to, 2 hereditary breast carcinoma

Similar variants

BRCA2 p.Arg2973Cys Benign ★★★ same residue
BRCA2 p.Arg2973Gly Uncertain significance ★★ same residue
BRCA2 p.Arg2973Pro Uncertain significance ★★ same residue
BRCA2 p.Arg2973= Likely benign ★★ same residue
BRCA2 p.Arg2973Leu Uncertain significance ★ same residue
BRCA2 p.Arg2973Ser Uncertain significance ★ same residue
BRCA2 p.Arg2973fs Likely pathogenic ★ same residue
BRCA2 c.316+1G>T 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-arg2973his (accessed [today's date]).

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