Is BRCA2 p.Phe12Val (c.34T>G) pathogenic?

BRCA2 p.Phe12Val (c.34T>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.328); Very rare (popmax 0.00267%, afr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Phe12Val (c.34T>G)?

BRCA2 p.Phe12Val (c.34T>G) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Phe12Val (c.34T>G) in the general population?

BRCA2 p.Phe12Val (c.34T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Phe12Val (c.34T>G)?

AlphaMissense predicts likely benign (score 0.328) — an in-silico prediction, not a clinical call.

BRCA2 p.Phe12Val

c.34T>G · rs80358597 · VCV51477

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.328	likely benign
REVEL	0.11	moderately 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 6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	25.5	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 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00136% 22/1,614,006 alleles · very rare exomes 20/1,461,796 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Finnishnot grpmax-eligible	0.00312%	32,021
African / African-Americangrpmax	0.00267%	37,462
European (non-Finnish)	0.00119%	84,283

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe12Val
Coding: c.34T>G
MANE Select: NM_000059
dbSNP: rs80358597
Type: single nucleotide variant
Location: chr13:32316494 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 12: the 'interaction with palb2' region

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRCA2 p.Phe12Ser Uncertain significance ★★ same residue
BRCA2 p.Phe12Tyr Uncertain significance ★ ⚠ same residue
BRCA2 p.Phe12_Glu13insTer Pathogenic ★★★ same residue
BRCA2 p.Phe12fs 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
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-phe12val (accessed [today's date]).

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