Is BRIP1 p.Arg416Trp (c.1246C>T) pathogenic?

BRIP1 p.Arg416Trp (c.1246C>T) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-29). AlphaMissense: likely benign (0.0676); Very rare (popmax 0.00988%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Arg416Trp (c.1246C>T)?

BRIP1 p.Arg416Trp (c.1246C>T) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Arg416Trp (c.1246C>T) in the general population?

BRIP1 p.Arg416Trp (c.1246C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about BRIP1 p.Arg416Trp (c.1246C>T)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg416Trp

c.1246C>T · rs587780225 · VCV128152

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -11.51	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.013, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	19.9	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 0.00988% South Asian · 9/91,068 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00137% 20/1,461,342 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,119
Admixed American	0.00167%	59,922
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000763%	131,063

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.Arg416Trp
Coding: c.1246C>T
MANE Select: NM_032043
dbSNP: rs587780225
Type: single nucleotide variant
Location: chr17:61799194 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 416: 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.Arg416Gln Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg416Leu Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg416= Benign ★ same residue
BRIP1 p.Arg416fs Pathogenic ★★ same residue
BACH1 p.Leu416Phe 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

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-arg416trp (accessed [today's date]).

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