Is BRCA2 p.Pro1088Ser (c.3262C>T) pathogenic?

BRCA2 p.Pro1088Ser (c.3262C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 26 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0953); Ultra-rare (popmax 0.0216%, amr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Pro1088Ser (c.3262C>T)?

BRCA2 p.Pro1088Ser (c.3262C>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.Pro1088Ser (c.3262C>T) in the general population?

BRCA2 p.Pro1088Ser (c.3262C>T) is ultra-rare (popmax 0.0216%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Pro1088Ser (c.3262C>T)?

AlphaMissense predicts likely benign (score 0.0953) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro1088Ser

c.3262C>T · rs80358572 · VCV37829

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 26 submitters

AlphaMissense

likely benign

0.0953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0216%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.0953	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; 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 0.33	GERP 0.31
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	2.335	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 0.0216% Admixed American · 12/55,554 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00975%

Overall 0.00579% 92/1,589,698 alleles · ultra-rare exomes 79/1,437,744 · genomes 13/151,954 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0216%	4,630
European (non-Finnish)	0.00676%	14,802
Remaining individualsnot grpmax-eligible	0.00163%	61,314

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.Pro1088Ser
Coding: c.3262C>T
MANE Select: NM_000059
dbSNP: rs80358572
Type: single nucleotide variant
Location: chr13:32337617 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1088: the 'interaction with rad51' 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

Similar variants

BRCA2 p.Pro1088= Benign ★★★ same residue
BRCA2 p.Pro1088Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro1088His Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro1088Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro1088Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro1088fs Pathogenic ★★★ 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-pro1088ser (accessed [today's date]).

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