Is BRIP1 p.Arg378Met (c.1133G>T) pathogenic?

BRIP1 p.Arg378Met (c.1133G>T) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-06). AlphaMissense: likely pathogenic (0.9644); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Arg378Met (c.1133G>T)?

BRIP1 p.Arg378Met (c.1133G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Arg378Met (c.1133G>T) in the general population?

BRIP1 p.Arg378Met (c.1133G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRIP1 p.Arg378Met (c.1133G>T)?

AlphaMissense predicts likely pathogenic (score 0.9644) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg378Met

c.1133G>T · rs1555607637 · VCV925714

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9644 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9644	likely pathogenic · top 7% in BRIP1
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -14.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: BRIP1
Protein: p.Arg378Met
Coding: c.1133G>T
MANE Select: NM_032043
dbSNP: rs1555607637
Type: single nucleotide variant
Location: chr17:61801260 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 378: the helicase atp-binding domain

Full BRIP1 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

BRIP1 p.Arg378Lys Uncertain significance ★★ ⚠ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>G Likely pathogenic ★★ same condition
BRIP1 c.1340+1G>A Pathogenic/Likely pathogenic ★★ same condition
BRIP1 c.1341-1G>A Likely pathogenic ★★ same condition
BRIP1 c.1473+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1473+1G>T Likely pathogenic ★★ same condition
BRIP1 c.1473+3A>T Pathogenic/Likely 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/brip1-p-arg378met (accessed [today's date]).

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