Is BRCA2 p.Val2138Phe (c.6412G>T) pathogenic?

BRCA2 p.Val2138Phe (c.6412G>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 33 submitters; last evaluated 2026-02-10). AlphaMissense: likely benign (0.0752); Low-frequency (popmax 1.14%, afr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Val2138Phe (c.6412G>T)?

BRCA2 p.Val2138Phe (c.6412G>T) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D1 (ClinVar).

How common is BRCA2 p.Val2138Phe (c.6412G>T) in the general population?

BRCA2 p.Val2138Phe (c.6412G>T) is low-frequency (popmax 1.14%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Val2138Phe (c.6412G>T)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2138Phe

c.6412G>T · rs11571659 · VCV52087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 33 submitters

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.204	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.4	GERP -3.1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	3.942	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 1.14% African / African-American · 842/73,838 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.05%

Overall 0.0605% 967/1,597,802 alleles · low-frequency exomes 487/1,445,486 · genomes 480/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.14%	88
Remaining individualsnot grpmax-eligible	0.133%	752
Admixed American	0.0451%	2,218
Middle Eastern	0.0168%	5,952
South Asian	0.0103%	9,727
East Asian	0.00223%	44,754
European (non-Finnish)	0.000596%	167,890

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.Val2138Phe
Coding: c.6412G>T
MANE Select: NM_000059
dbSNP: rs11571659
Type: single nucleotide variant
Location: chr13:32340767 (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

Also linked: hereditary breast ovarian cancer syndrome Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome breast neoplasm

Similar variants

BRCA2 p.Val2138Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val2138Gly 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-val2138phe (accessed [today's date]).

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