Is BRCA2 p.Val2109Ile (c.6325G>A) pathogenic?

BRCA2 p.Val2109Ile (c.6325G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0774); Rare (popmax 0.493%, eas); Associated with malignant pancreatic neoplasm.

What condition is associated with BRCA2 p.Val2109Ile (c.6325G>A)?

BRCA2 p.Val2109Ile (c.6325G>A) is associated with malignant pancreatic neoplasm, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Val2109Ile (c.6325G>A) in the general population?

BRCA2 p.Val2109Ile (c.6325G>A) is rare (popmax 0.493%, eas) (gnomAD).

What do computational predictors say about BRCA2 p.Val2109Ile (c.6325G>A)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2109Ile

c.6325G>A · rs79456940 · VCV41560

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.493%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

malignant pancreatic neoplasm

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.092	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44	GERP -4.3
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	0.094	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.493% East Asian · 221/44,800 alleles

Filtering AF 0.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.419%

Overall 0.014% 226/1,608,786 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.493%	203
Remaining individualsnot grpmax-eligible	0.00804%	12,442

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.Val2109Ile
Coding: c.6325G>A
MANE Select: NM_000059
dbSNP: rs79456940
Type: single nucleotide variant
Location: chr13:32340680 (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

malignant pancreatic neoplasm — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRCA2 p.Val2109= Likely benign ★★★ same residue
BRCA2 p.Val2109Leu Uncertain significance ★ ⚠ same residue
BRCA2 p.Val2109Phe Conflicting classifications of pathogenicity ★ ⚠ 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
BRCA2 c.475+1G>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-val2109ile (accessed [today's date]).

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