Is BRCA2 p.Ala487Glu (c.1460C>A) pathogenic?

BRCA2 p.Ala487Glu (c.1460C>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 19 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1614); Ultra-rare (popmax 0.0384%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ala487Glu (c.1460C>A)?

BRCA2 p.Ala487Glu (c.1460C>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D1 (ClinVar).

How common is BRCA2 p.Ala487Glu (c.1460C>A) in the general population?

BRCA2 p.Ala487Glu (c.1460C>A) is ultra-rare (popmax 0.0384%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Ala487Glu (c.1460C>A)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala487Glu

c.1460C>A · rs56390402 · VCV37741

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.193	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.8	GERP -3.5
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	11.03	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 0.0384% European (non-Finnish) · 453/1,178,450 alleles

Filtering AF 0.0355% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0343%

Overall 0.0296% 475/1,607,264 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0384%	2,601
Remaining individualsnot grpmax-eligible	0.0241%	4,147
African / African-American	0.00538%	18,595
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,290
Finnishnot grpmax-eligible	0.00313%	31,959

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.Ala487Glu
Coding: c.1460C>A
MANE Select: NM_000059
dbSNP: rs56390402
Type: single nucleotide variant
Location: chr13:32332938 (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 Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2

Similar variants

BRCA2 p.Ala487Thr Uncertain significance ★ ⚠ same residue
BRCA2 p.Ala487Ser Likely benign ★ 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
BRCA2 c.475+1G>T 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-ala487glu (accessed [today's date]).

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