Is BRIP1 p.Arg403Trp (c.1207C>T) pathogenic?

BRIP1 p.Arg403Trp (c.1207C>T) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.8243); Very rare (popmax 0.00441%, nfe); Associated with familial ovarian cancer.

What condition is associated with BRIP1 p.Arg403Trp (c.1207C>T)?

BRIP1 p.Arg403Trp (c.1207C>T) is associated with familial ovarian cancer, ovarian cancer, Fanconi anemia complementation group J (ClinVar).

How common is BRIP1 p.Arg403Trp (c.1207C>T) in the general population?

BRIP1 p.Arg403Trp (c.1207C>T) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about BRIP1 p.Arg403Trp (c.1207C>T)?

AlphaMissense predicts likely pathogenic (score 0.8243) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg403Trp

c.1207C>T · rs369631413 · VCV136141

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.8243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.8243	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -17.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.51, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00441% European (non-Finnish) · 52/1,179,634 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00353% 57/1,613,330 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,685
African / African-American	0.00267%	37,423
Admixed American	0.00167%	59,884
Finnishnot grpmax-eligible	0.00156%	63,970
South Asian	0.0011%	91,062

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: BRIP1
Protein: p.Arg403Trp
Coding: c.1207C>T
MANE Select: NM_032043
dbSNP: rs369631413
Type: single nucleotide variant
Location: chr17:61799233 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 403: the helicase atp-binding domain

Full BRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ovarian cancer Fanconi anemia complementation group J hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRIP1 p.Arg403Gln Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg403Gly Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg403= Benign/Likely benign ★★ same residue
BRIP1 p.Arg403Pro Uncertain significance ★ ⚠ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>G Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>T 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-arg403trp (accessed [today's date]).

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