Is BRCA2 p.His2178Arg (c.6533A>G) pathogenic?

BRCA2 p.His2178Arg (c.6533A>G) is classified Uncertain significance in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-04). AlphaMissense: likely benign (0.073); Very rare (popmax 0.00017%, nfe); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.His2178Arg (c.6533A>G)?

BRCA2 p.His2178Arg (c.6533A>G) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.His2178Arg (c.6533A>G) in the general population?

BRCA2 p.His2178Arg (c.6533A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA2 p.His2178Arg (c.6533A>G)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

BRCA2 p.His2178Arg

c.6533A>G · rs2137528396 · VCV2915482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.356	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.7
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	4.39	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 0.00017% European (non-Finnish) · 2/1,178,120 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,453,954 alleles · very 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.His2178Arg
Coding: c.6533A>G
MANE Select: NM_000059
dbSNP: rs2137528396
Type: single nucleotide variant
Location: chr13:32340888 (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 breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.His2178= Likely benign ★★★ same residue
BRCA2 p.His2178Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.His2178Asp Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.His2178fs Pathogenic ★★★ same residue
BRCA2 p.His2178Tyr Likely benign ★ same residue
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-his2178arg (accessed [today's date]).

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