Is BRIP1 p.Arg173His (c.518G>A) pathogenic?

BRIP1 p.Arg173His (c.518G>A) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1642); Very rare (popmax 0.00446%, eas); Associated with familial ovarian cancer.

What condition is associated with BRIP1 p.Arg173His (c.518G>A)?

BRIP1 p.Arg173His (c.518G>A) is associated with familial ovarian cancer, Fanconi anemia complementation group J, hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Arg173His (c.518G>A) in the general population?

BRIP1 p.Arg173His (c.518G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BRIP1 p.Arg173His (c.518G>A)?

AlphaMissense predicts likely benign (score 0.1642) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg173His

c.518G>A · rs761432927 · VCV186661

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.1642	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00446% East Asian · 2/44,830 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.00062% 10/1,613,592 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,415
African / African-American	0.00267%	37,442
European (non-Finnish)	0.000509%	196,629

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.Arg173His
Coding: c.518G>A
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

familial ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRIP1 p.Arg173Pro 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-arg173his (accessed [today's date]).

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