Is BRCA2 p.Phe1241= (c.3723T>C) pathogenic?

BRCA2 p.Phe1241= (c.3723T>C) is classified Likely benign in BRCA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-11). Very rare (popmax 0.00221%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Phe1241= (c.3723T>C)?

BRCA2 p.Phe1241= (c.3723T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Phe1241= (c.3723T>C) in the general population?

BRCA2 p.Phe1241= (c.3723T>C) is very rare (popmax 0.00221%, sas) (gnomAD).

BRCA2 p.Phe1241=

c.3723T>C · rs587782723 · VCV824126

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.51	GERP -1.6, phastCons 0.005
Overall
CADD	7.486	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% South Asian · 2/90,350 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000186% 3/1,611,474 alleles · very rare exomes 3/1,459,134 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,175
European (non-Finnish)	8.48e-05%	1,179,028

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.Phe1241=
Coding: c.3723T>C
MANE Select: NM_000059
dbSNP: rs587782723
Type: single nucleotide variant
Location: chr13:32338078 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1241: the 'interaction with rad51' region; an α-helix

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.Phe1241Leu Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Phe1241Ser Uncertain significance ★ ⚠ same residue
BRCA2 p.Phe1241Val Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Phe1241fs 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-phe1241 (accessed [today's date]).

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