Is BRCA2 p.Arg155Ile (c.464G>T) pathogenic?

BRCA2 p.Arg155Ile (c.464G>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-03-30). AlphaMissense: likely benign (0.3124); Very rare (popmax 0.00034%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg155Ile (c.464G>T)?

BRCA2 p.Arg155Ile (c.464G>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Arg155Ile (c.464G>T) in the general population?

BRCA2 p.Arg155Ile (c.464G>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Arg155Ile (c.464G>T)?

AlphaMissense predicts likely benign (score 0.3124) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg155Ile

c.464G>T · rs377639990 · VCV236869

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3124	likely benign
REVEL	0.168	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.6	GERP 0.53, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,176,888 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000275% 4/1,457,092 alleles · very rare

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.Arg155Ile
Coding: c.464G>T
MANE Select: NM_000059
dbSNP: rs377639990
Type: single nucleotide variant
Location: chr13:32326139 (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

Similar variants

BRCA2 p.Arg155Ser Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg155= Likely benign ★★ same residue
BRCA2 p.Arg155Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg155Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg155_Asp156insTer 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

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-arg155ile (accessed [today's date]).

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