Is BRCA2 p.Ile2664Phe (c.7990A>T) pathogenic?

BRCA2 p.Ile2664Phe (c.7990A>T) is classified Likely benign in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: ambiguous (0.4981); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ile2664Phe (c.7990A>T)?

BRCA2 p.Ile2664Phe (c.7990A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Ile2664Phe (c.7990A>T) in the general population?

BRCA2 p.Ile2664Phe (c.7990A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Ile2664Phe (c.7990A>T)?

AlphaMissense predicts ambiguous (score 0.4981) — an in-silico prediction, not a clinical call.

BRCA2 p.Ile2664Phe

c.7990A>T · VCV3992665

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4981	ambiguous · top 9% in BRCA2
REVEL	0.645	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	19.86	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA2
Protein: p.Ile2664Phe
Coding: c.7990A>T
MANE Select: NM_000059
Type: single nucleotide variant
Location: chr13:32363192 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2664: the 'interaction with sem1' region

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

Similar variants

BRCA2 p.Ile2664= Likely benign ★★★ same residue
BRCA2 p.Ile2664Val Uncertain significance ★★ same residue
BRCA2 p.Ile2664Met Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ile2664Thr Uncertain significance ★ ⚠ 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-ile2664phe (accessed [today's date]).

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