Is BRCA2 p.Ser1221Pro (c.3661T>C) pathogenic?

BRCA2 p.Ser1221Pro (c.3661T>C) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.6235); Very rare (popmax 0.0017%, nfe); Associated with Breast and/or ovarian cancer.

What condition is associated with BRCA2 p.Ser1221Pro (c.3661T>C)?

BRCA2 p.Ser1221Pro (c.3661T>C) is associated with Breast and/or ovarian cancer, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Ser1221Pro (c.3661T>C) in the general population?

BRCA2 p.Ser1221Pro (c.3661T>C) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Ser1221Pro (c.3661T>C)?

AlphaMissense predicts likely pathogenic (score 0.6235) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser1221Pro

c.3661T>C · rs80358611 · VCV51501

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.6235 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.6235	likely pathogenic · top 6% in BRCA2
REVEL	0.629	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 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	25.1	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 0.0017% European (non-Finnish) · 20/1,179,326 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,612,942 alleles · very rare exomes 20/1,460,604 · genomes 0/152,338 · 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.Ser1221Pro
Coding: c.3661T>C
MANE Select: NM_000059
dbSNP: rs80358611
Type: single nucleotide variant
Location: chr13:32338016 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1221: the 'interaction with rad51' region; a β-strand

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRCA2 p.Ser1221Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser1221Tyr Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser1221= 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

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-ser1221pro (accessed [today's date]).

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