Is BRCA2 p.Val2138Asp (c.6413T>A) pathogenic?

BRCA2 p.Val2138Asp (c.6413T>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0896); Ultra-rare (popmax 0.0162%, amr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Val2138Asp (c.6413T>A)?

BRCA2 p.Val2138Asp (c.6413T>A) is associated with hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Val2138Asp (c.6413T>A) in the general population?

BRCA2 p.Val2138Asp (c.6413T>A) is ultra-rare (popmax 0.0162%, amr) (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.Val2138Asp (c.6413T>A)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2138Asp

c.6413T>A · rs80358877 · VCV52088

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0162%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.215	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 -2.1	GERP -3.5
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	1.783	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 0.0162% Admixed American · 9/55,532 alleles

Filtering AF 0.0084% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00629%

Overall 0.000563% 9/1,598,050 alleles · ultra-rare exomes 7/1,445,806 · genomes 2/152,244 · joint denominator

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.Val2138Asp
Coding: c.6413T>A
MANE Select: NM_000059
dbSNP: rs80358877
Type: single nucleotide variant
Location: chr13:32340768 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2138: a UniProt-annotated variant site (in)

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

Also linked: breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome BRCA2-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Val2138Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val2138Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val2138= Likely benign ★ same residue
BRCA2 p.Val2138Ile Likely benign ★ same residue
BRCA2 p.Val2138fs 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-val2138asp (accessed [today's date]).

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