Is BRIP1 p.Cys832Arg (c.2494T>C) pathogenic?

BRIP1 p.Cys832Arg (c.2494T>C) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.9928); Very rare (popmax 0.00167%, amr); Associated with hereditary breast carcinoma.

What condition is associated with BRIP1 p.Cys832Arg (c.2494T>C)?

BRIP1 p.Cys832Arg (c.2494T>C) is associated with hereditary breast carcinoma, Fanconi anemia complementation group J, hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Cys832Arg (c.2494T>C) in the general population?

BRIP1 p.Cys832Arg (c.2494T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRIP1 p.Cys832Arg (c.2494T>C)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

BRIP1 p.Cys832Arg

c.2494T>C · rs768222842 · VCV945582

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic · top 2% in BRIP1
REVEL	0.688	pathogenic-leaning
SaProt	LLR -17.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	29.3	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 0.00167% Admixed American · 1/60,006 alleles

Overall 6.86e-05% 1/1,457,616 alleles · very rare

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.Cys832Arg
Coding: c.2494T>C
MANE Select: NM_032043
dbSNP: rs768222842
Type: single nucleotide variant
Location: chr17:61693511 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 832: a UniProt-annotated variant site (in)

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

Disease context

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

Also linked: Fanconi anemia complementation group J hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRIP1 p.Cys832Gly Uncertain significance ★★ ⚠ same residue
BRIP1 p.Cys832Phe Uncertain significance ★★ ⚠ same residue
BRIP1 p.Cys832Ser Uncertain significance ★ ⚠ same residue
BRIP1 p.Cys832Tyr Uncertain significance ★ ⚠ same residue
BRIP1 p.Cys832fs Pathogenic ★ 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-cys832arg (accessed [today's date]).

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