Is BRCA2 p.Pro2408Ala (c.7222C>G) pathogenic?

BRCA2 p.Pro2408Ala (c.7222C>G) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-18). AlphaMissense: ambiguous (0.3465); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Pro2408Ala (c.7222C>G)?

BRCA2 p.Pro2408Ala (c.7222C>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Pro2408Ala (c.7222C>G) in the general population?

BRCA2 p.Pro2408Ala (c.7222C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Pro2408Ala (c.7222C>G)?

AlphaMissense predicts ambiguous (score 0.3465) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro2408Ala

c.7222C>G · rs398122577 · VCV480893

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3465 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3465	ambiguous
REVEL	0.603	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	22.6	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 0.00133% African / African-American · 1/75,020 alleles

Overall 6.2e-05% 1/1,613,884 alleles · very rare exomes 1/1,461,622 · genomes 0/152,262 · joint denominator

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.Pro2408Ala
Coding: c.7222C>G
MANE Select: NM_000059
dbSNP: rs398122577
Type: single nucleotide variant
Location: chr13:32355075 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2408: the 'interaction with fancd2' 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.Pro2408= Likely benign ★★★ same residue
BRCA2 p.Pro2408Leu Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Pro2408Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro2408Thr Uncertain significance ★ 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

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-pro2408ala (accessed [today's date]).

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