Is BRCA2 p.Phe81Ile (c.241T>A) pathogenic?

BRCA2 p.Phe81Ile (c.241T>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2025-11-30). AlphaMissense: likely pathogenic (0.6274); Very rare (popmax 0.00483%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Phe81Ile (c.241T>A)?

BRCA2 p.Phe81Ile (c.241T>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Phe81Ile (c.241T>A) in the general population?

BRCA2 p.Phe81Ile (c.241T>A) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Phe81Ile (c.241T>A)?

AlphaMissense predicts likely pathogenic (score 0.6274) — an in-silico prediction, not a clinical call.

BRCA2 p.Phe81Ile

c.241T>A · rs80358507 · VCV37785

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely pathogenic

0.6274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6274	likely pathogenic · top 6% in BRCA2
REVEL	0.307	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 5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	21.1	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 0.00483% European (non-Finnish) · 57/1,179,754 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00359% 58/1,613,700 alleles · very rare exomes 56/1,461,512 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,697
Admixed American	0.00167%	59,996

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.Phe81Ile
Coding: c.241T>A
MANE Select: NM_000059
dbSNP: rs80358507
Type: single nucleotide variant
Location: chr13:32319250 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 81: 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 BRCA2-related cancer predisposition

Similar variants

BRCA2 p.Phe81= Likely benign ★★★ same residue
BRCA2 p.Phe81Val Uncertain significance ★★ same residue
BRCA2 p.Phe81Leu Uncertain significance ★ same residue
BRCA2 p.Phe81fs 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-phe81ile (accessed [today's date]).

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