Is BRCA2 p.Trp31Leu (c.92G>T) pathogenic?

BRCA2 p.Trp31Leu (c.92G>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-30). AlphaMissense: likely pathogenic (0.7396); Absent from gnomAD v4.1; Associated with malignant pancreatic neoplasm.

What condition is associated with BRCA2 p.Trp31Leu (c.92G>T)?

BRCA2 p.Trp31Leu (c.92G>T) is associated with malignant pancreatic neoplasm, hereditary neoplastic syndrome, breast neoplasm (ClinVar).

How common is BRCA2 p.Trp31Leu (c.92G>T) in the general population?

BRCA2 p.Trp31Leu (c.92G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Trp31Leu (c.92G>T)?

AlphaMissense predicts likely pathogenic (score 0.7396) — an in-silico prediction, not a clinical call.

BRCA2 p.Trp31Leu

c.92G>T · rs397508045 · VCV224451

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7396 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

malignant pancreatic neoplasm

Computational evidence

Protein change
AlphaMissense	0.7396	likely pathogenic · top 4% in BRCA2
REVEL	0.351	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	24.6	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

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.Trp31Leu
Coding: c.92G>T
MANE Select: NM_000059
dbSNP: rs397508045
Type: single nucleotide variant
Location: chr13:32319101 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 31: an α-helix; a UniProt-annotated variant site (in bc; abolishes interaction with palb2); the 'interaction with palb2' region

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

malignant pancreatic neoplasm — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome breast neoplasm

Similar variants

BRCA2 p.Trp31Ter Pathogenic ★★★ same residue
BRCA2 p.Trp31Cys Uncertain significance ★★ same residue
BRCA2 p.Trp31Arg Uncertain significance ★ same residue
BRCA2 p.Trp31Gly Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Trp31_Leu35del Uncertain significance ★★ same residue
BRCA2 p.Trp31fs Pathogenic ★ same residue
BRCA2 p.Trp31Ser Likely pathogenic ★★ same residue
BRCA2 c.316+1G>T 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-trp31leu (accessed [today's date]).

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