Is BRIP1 p.Arg403Gln (c.1208G>A) pathogenic?

BRIP1 p.Arg403Gln (c.1208G>A) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-20). AlphaMissense: ambiguous (0.4519); Very rare (popmax 0.00501%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Arg403Gln (c.1208G>A)?

BRIP1 p.Arg403Gln (c.1208G>A) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Arg403Gln (c.1208G>A) in the general population?

BRIP1 p.Arg403Gln (c.1208G>A) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about BRIP1 p.Arg403Gln (c.1208G>A)?

AlphaMissense predicts ambiguous (score 0.4519) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg403Gln

c.1208G>A · rs786202780 · VCV186213

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4519	ambiguous
REVEL	0.619	indeterminate
SaProt	LLR -15.24	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,906 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00062% 10/1,613,450 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,969
African / African-American	0.00267%	37,435
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,472
South Asian	0.0011%	91,062
European (non-Finnish)	0.00017%	589,835

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.Arg403Gln
Coding: c.1208G>A
MANE Select: NM_032043
dbSNP: rs786202780
Type: single nucleotide variant
Location: chr17:61799232 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group J hereditary breast carcinoma

Similar variants

BRIP1 p.Arg403Gly Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg403Trp 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-arg403gln (accessed [today's date]).

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