Is BRCA2 p.Pro2408Ser (c.7222C>T) pathogenic?

BRCA2 p.Pro2408Ser (c.7222C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.5953); Very rare (popmax 0.00167%, amr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Pro2408Ser (c.7222C>T)?

BRCA2 p.Pro2408Ser (c.7222C>T) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro2408Ser (c.7222C>T) in the general population?

BRCA2 p.Pro2408Ser (c.7222C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Pro2408Ser (c.7222C>T)?

AlphaMissense predicts likely pathogenic (score 0.5953) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro2408Ser

c.7222C>T · rs398122577 · VCV91472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.5953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.5953	likely pathogenic · top 7% in BRCA2
REVEL	0.646	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; 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 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	22.9	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 0.00167% Admixed American · 1/60,000 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,766 alleles · very rare exomes 3/1,461,622 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,000
African / African-American	0.00134%	74,898
European (non-Finnish)	0.00017%	589,936

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.Pro2408Ser
Coding: c.7222C>T
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

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

Similar variants

BRCA2 p.Pro2408= Likely benign ★★★ same residue
BRCA2 p.Pro2408Ala Uncertain significance ★★ same residue
BRCA2 p.Pro2408Leu 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-pro2408ser (accessed [today's date]).

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