Is BRCA2 p.Pro201Ser (c.601C>T) pathogenic?

BRCA2 p.Pro201Ser (c.601C>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.7826); Very rare (popmax 0.00034%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Pro201Ser (c.601C>T)?

BRCA2 p.Pro201Ser (c.601C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro201Ser (c.601C>T) in the general population?

BRCA2 p.Pro201Ser (c.601C>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Pro201Ser (c.601C>T)?

AlphaMissense predicts likely pathogenic (score 0.7826) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro201Ser

c.601C>T · rs1555281093 · VCV462396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7826	likely pathogenic · top 4% in BRCA2
REVEL	0.221	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	23.2	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 0.00034% European (non-Finnish) · 4/1,177,246 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,458,790 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.Pro201Ser
Coding: c.601C>T
MANE Select: NM_000059
dbSNP: rs1555281093
Type: single nucleotide variant
Location: chr13:32326583 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 201: an α-helix; a UniProt-annotated variant site (in bc)

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 breast-ovarian cancer, familial, susceptibility to, 2

Similar variants

BRCA2 p.Pro201Ala Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro201Leu Uncertain significance ★★ same residue
BRCA2 p.Pro201Thr Uncertain significance ★ same residue
BRCA2 p.Pro201= Likely benign ★ same residue
BRCA2 p.Pro201fs Pathogenic ★★★ same residue
BRCA2 p.Pro201Arg Uncertain significance ★ 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-pro201ser (accessed [today's date]).

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