Is BRCA2 p.Ala2231Thr (c.6691G>A) pathogenic?

BRCA2 p.Ala2231Thr (c.6691G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1807); Very rare (popmax 6.84e-05%); Associated with medulloblastoma.

What condition is associated with BRCA2 p.Ala2231Thr (c.6691G>A)?

BRCA2 p.Ala2231Thr (c.6691G>A) is associated with medulloblastoma, hereditary breast ovarian cancer syndrome, Wilms tumor 1 (ClinVar).

How common is BRCA2 p.Ala2231Thr (c.6691G>A) in the general population?

BRCA2 p.Ala2231Thr (c.6691G>A) is very rare (popmax 6.84e-05%) (gnomAD).

How is Medulloblastoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA2 p.Ala2231Thr (c.6691G>A)?

AlphaMissense predicts likely benign (score 0.1807) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala2231Thr

c.6691G>A · rs758379999 · VCV187220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

medulloblastoma

Computational evidence

Protein change
AlphaMissense	0.1807	likely benign
REVEL	0.458	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	23.7	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 6.84e-05%

Overall 6.84e-05% 1/1,461,608 alleles · very rare

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.Ala2231Thr
Coding: c.6691G>A
MANE Select: NM_000059
dbSNP: rs758379999
Type: single nucleotide variant
Location: chr13:32341046 (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

medulloblastoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome Wilms tumor 1 Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma BRCA2-related cancer predisposition prostate cancer, hereditary

For Medulloblastoma (Orphanet):

Inheritance: Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

BRCA2 p.Ala2231= Likely benign ★★★ same residue
BRCA2 p.Ala2231Pro Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ala2231Ser Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ala2231fs Pathogenic ★★★ same residue
BRCA2 p.Ala2231Ter Pathogenic ★ same residue
BRCA2 p.Ala2231Phe 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-ala2231thr (accessed [today's date]).

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