Is BRCA2 p.Ala1991Thr (c.5971G>A) pathogenic?

BRCA2 p.Ala1991Thr (c.5971G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0769); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ala1991Thr (c.5971G>A)?

BRCA2 p.Ala1991Thr (c.5971G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Ala1991Thr (c.5971G>A) in the general population?

BRCA2 p.Ala1991Thr (c.5971G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Ala1991Thr (c.5971G>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala1991Thr

c.5971G>A · rs2072543048 · VCV937695

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.274	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 0.53	GERP -4.6, phastCons 0.029
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	6.879	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA2
Protein: p.Ala1991Thr
Coding: c.5971G>A
MANE Select: NM_000059
dbSNP: rs2072543048
Type: single nucleotide variant
Location: chr13:32340326 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1991: the 'interaction with rad51' region

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

Similar variants

BRCA2 p.Ala1991Asp Uncertain significance ★★ same residue
BRCA2 p.Ala1991Gly Uncertain significance ★★ ⚠ same residue
BRCA2 p.Ala1991= Likely benign ★★ same residue
BRCA2 p.Ala1991Pro Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ala1991Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala1991Val Conflicting classifications of pathogenicity ★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>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-ala1991thr (accessed [today's date]).

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