Is BRCA2 p.Asp596His (c.1786G>C) pathogenic?

BRCA2 p.Asp596His (c.1786G>C) is classified Benign in BRCA2 (ClinVar, Expert panel, 40 submitters; last evaluated 2019-06-18). AlphaMissense: likely benign (0.2728); Ultra-rare (popmax 0.0708%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Asp596His (c.1786G>C)?

BRCA2 p.Asp596His (c.1786G>C) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Asp596His (c.1786G>C) in the general population?

BRCA2 p.Asp596His (c.1786G>C) is ultra-rare (popmax 0.0708%, 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.Asp596His (c.1786G>C)?

AlphaMissense predicts likely benign (score 0.2728) — an in-silico prediction, not a clinical call.

BRCA2 p.Asp596His

c.1786G>C · rs56328701 · VCV51192

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 40 submitters

AlphaMissense

likely benign

0.2728 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0708%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.2728	likely benign
REVEL	0.217	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 3.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	23.0	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 0.0708% European (non-Finnish) · 834/1,177,886 alleles

Filtering AF 0.0668% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0652%

Overall 0.0535% 860/1,608,472 alleles · ultra-rare exomes 823/1,456,390 · genomes 37/152,082 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0708%	1,412
Remaining individualsnot grpmax-eligible	0.0241%	4,148
African / African-American	0.0107%	9,308
Finnishnot grpmax-eligible	0.00313%	31,959
Admixed American	0.00169%	59,040

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.Asp596His
Coding: c.1786G>C
MANE Select: NM_000059
dbSNP: rs56328701
Type: single nucleotide variant
Location: chr13:32333264 (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-ovarian cancer, familial, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast cancer medulloblastoma prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma breast neoplasm

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Asp596= Benign ★★★ same residue
BRCA2 p.Asp596Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp596Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp596Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp596fs Pathogenic ★★★ 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-asp596his (accessed [today's date]).

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