Is BRCA2 p.Val2102Ile (c.6304G>A) pathogenic?

BRCA2 p.Val2102Ile (c.6304G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.019%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Val2102Ile (c.6304G>A)?

BRCA2 p.Val2102Ile (c.6304G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Val2102Ile (c.6304G>A) in the general population?

BRCA2 p.Val2102Ile (c.6304G>A) is ultra-rare (popmax 0.019%, sas) (gnomAD).

What do computational predictors say about BRCA2 p.Val2102Ile (c.6304G>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2102Ile

c.6304G>A · rs80358869 · VCV234525

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.082	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 -0.21	GERP -3.5
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	3.406	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 0.019% South Asian · 17/89,366 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00994%

Overall 0.00143% 23/1,606,708 alleles · ultra-rare exomes 22/1,454,540 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.019%	5,257
Middle Eastern	0.0166%	6,028
East Asian	0.00223%	44,802
Remaining individualsnot grpmax-eligible	0.00161%	62,080
African / African-American	0.00135%	74,252
European (non-Finnish)	0.00017%	589,095

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.Val2102Ile
Coding: c.6304G>A
MANE Select: NM_000059
dbSNP: rs80358869
Type: single nucleotide variant
Location: chr13:32340659 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRCA2 p.Val2102Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val2102Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val2102= Likely benign ★ same residue
BRCA2 p.Val2102fs Pathogenic ★★★ same residue
BRCA2 p.Val2102_Ser2103insTer 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-val2102ile (accessed [today's date]).

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