Is BRCA2 p.Ser3250Thr (c.9748T>A) pathogenic?

BRCA2 p.Ser3250Thr (c.9748T>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0811); Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ser3250Thr (c.9748T>A)?

BRCA2 p.Ser3250Thr (c.9748T>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, hereditary breast carcinoma (ClinVar).

How common is BRCA2 p.Ser3250Thr (c.9748T>A) in the general population?

BRCA2 p.Ser3250Thr (c.9748T>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about BRCA2 p.Ser3250Thr (c.9748T>A)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser3250Thr

c.9748T>A · rs1173590589 · VCV633108

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.178	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 0.31	GERP -2.9, phastCons 0.001
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	11.49	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 6.2e-05%

Overall 6.2e-05% 1/1,614,178 alleles · very rare exomes 1/1,461,860 · genomes 0/152,318 · 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.Ser3250Thr
Coding: c.9748T>A
MANE Select: NM_000059
dbSNP: rs1173590589
Type: single nucleotide variant
Location: chr13:32398261 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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 hereditary breast carcinoma

Similar variants

BRCA2 p.Ser3250= Likely benign ★★ same residue
BRCA2 p.Ser3250Ter Pathogenic ★ same residue
BRCA2 p.Ser3250Leu Likely benign ★ same residue
BRCA2 p.Ser3250fs Pathogenic ★★★ 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-ser3250thr (accessed [today's date]).

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