Is BRIP1 p.Arg855Cys (c.2563C>T) pathogenic?

BRIP1 p.Arg855Cys (c.2563C>T) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.164); Very rare (popmax 0.00134%, afr); Associated with familial ovarian cancer.

What condition is associated with BRIP1 p.Arg855Cys (c.2563C>T)?

BRIP1 p.Arg855Cys (c.2563C>T) is associated with familial ovarian cancer, ovarian cancer, Fanconi anemia complementation group J (ClinVar).

How common is BRIP1 p.Arg855Cys (c.2563C>T) in the general population?

BRIP1 p.Arg855Cys (c.2563C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about BRIP1 p.Arg855Cys (c.2563C>T)?

AlphaMissense predicts likely benign (score 0.164) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg855Cys

c.2563C>T · rs146031731 · VCV216789

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.164	likely benign
REVEL	0.666	pathogenic-leaning
SaProt	LLR -10.13	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.21	donor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	27.9	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 0.00134% African / African-American · 1/74,866 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,612,868 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,866
European (non-Finnish)	0.000678%	147,385

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.Arg855Cys
Coding: c.2563C>T
MANE Select: NM_032043
dbSNP: rs146031731
Type: single nucleotide variant
Location: chr17:61693442 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB

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.Arg855His Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855Leu Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855Ser Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855= Likely benign ★★ same residue
BRIP1 p.Arg855Pro 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-arg855cys (accessed [today's date]).

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