Is BRIP1 p.Arg264Trp (c.790C>T) pathogenic?

BRIP1 p.Arg264Trp (c.790C>T) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 25 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1931); Rare (popmax 0.135%, nfe); Associated with Breast and/or ovarian cancer.

What condition is associated with BRIP1 p.Arg264Trp (c.790C>T)?

BRIP1 p.Arg264Trp (c.790C>T) is associated with Breast and/or ovarian cancer, breast cancer, ovarian cancer (ClinVar).

How common is BRIP1 p.Arg264Trp (c.790C>T) in the general population?

BRIP1 p.Arg264Trp (c.790C>T) is rare (popmax 0.135%, nfe) (gnomAD).

What do computational predictors say about BRIP1 p.Arg264Trp (c.790C>T)?

AlphaMissense predicts likely benign (score 0.1931) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg264Trp

c.790C>T · rs28997569 · VCV128195

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 25 submitters

AlphaMissense

likely benign

0.1931 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.1931	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	31.0	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 0.135% European (non-Finnish) · 1,587/1,179,870 alleles

Filtering AF 0.129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.127%

Overall 0.116% 1,871/1,613,856 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.233%	429
European (non-Finnish)grpmax	0.135%	743
Remaining individualsnot grpmax-eligible	0.122%	822
Middle Eastern	0.115%	866
African / African-American	0.068%	1,470
Admixed American	0.0583%	1,714
Finnishnot grpmax-eligible	0.0391%	2,560
South Asian	0.0231%	4,337

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg264Trp
Coding: c.790C>T
MANE Select: NM_032043
dbSNP: rs28997569
Type: single nucleotide variant
Location: chr17:61808595 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 264: the helicase atp-binding domain; a UniProt-annotated variant site (in)

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRIP1 p.Arg264Gly Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg264= Likely benign ★★ same residue
BRIP1 p.Arg264Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Arg264Pro 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-arg264trp (accessed [today's date]).

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