Is BRIP1 p.Arg419= (c.1257G>A) pathogenic?

BRIP1 p.Arg419= (c.1257G>A) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-18). Ultra-rare (popmax 0.029%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Arg419= (c.1257G>A)?

BRIP1 p.Arg419= (c.1257G>A) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, familial ovarian cancer (ClinVar).

How common is BRIP1 p.Arg419= (c.1257G>A) in the general population?

BRIP1 p.Arg419= (c.1257G>A) is ultra-rare (popmax 0.029%, eas) (gnomAD).

BRIP1 p.Arg419=

c.1257G>A · rs148429663 · VCV182360

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -2.6, phastCons 0.98
Overall
CADD	8.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,872 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000868% 14/1,613,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg419=
Coding: c.1257G>A
MANE Select: NM_032043
dbSNP: rs148429663
Type: single nucleotide variant
Location: chr17:61799183 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 419: 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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRIP1 p.Arg419Gln Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg419Gly Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg419Pro Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg419Leu Uncertain significance ★ ⚠ same residue
BRIP1 p.Arg419Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Arg419fs Pathogenic ★ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C 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-arg419 (accessed [today's date]).

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