Is BRIP1 p.Arg173Pro (c.518G>C) pathogenic?

BRIP1 p.Arg173Pro (c.518G>C) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-13). AlphaMissense: likely pathogenic (0.5925); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with BRIP1 p.Arg173Pro (c.518G>C)?

BRIP1 p.Arg173Pro (c.518G>C) is associated with hereditary breast carcinoma, Fanconi anemia complementation group J, hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Arg173Pro (c.518G>C) in the general population?

BRIP1 p.Arg173Pro (c.518G>C) is very rare (popmax 8.48e-05%, nfe) (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.Arg173Pro (c.518G>C)?

AlphaMissense predicts likely pathogenic (score 0.5925) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg173Pro

c.518G>C · rs761432927 · VCV629007

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.5925	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -9.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	28.1	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 8.48e-05% European (non-Finnish) · 1/1,179,768 alleles

Overall 6.2e-05% 1/1,613,710 alleles · very rare exomes 1/1,461,452 · genomes 0/152,258 · joint denominator

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.Arg173Pro
Coding: c.518G>C
MANE Select: NM_032043
dbSNP: rs761432927
Type: single nucleotide variant
Location: chr17:61847210 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 173: 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

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.Arg173His Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg173Ser Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg173Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Arg173= Likely benign ★ same residue
BRIP1 p.Arg173fs 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-arg173pro (accessed [today's date]).

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