Is BRIP1 p.Met1Val (c.1A>G) pathogenic?

BRIP1 p.Met1Val (c.1A>G) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-13). Ultra-rare (popmax 0.0156%, eas); Associated with Genetic non-acquired premature ovarian failure.

What condition is associated with BRIP1 p.Met1Val (c.1A>G)?

BRIP1 p.Met1Val (c.1A>G) is associated with Genetic non-acquired premature ovarian failure, ovarian cancer, Fanconi anemia complementation group J (ClinVar).

How common is BRIP1 p.Met1Val (c.1A>G) in the general population?

BRIP1 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

BRIP1 p.Met1Val

c.1A>G · rs764585550 · VCV187378

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

Genetic non-acquired premature ovarian failure

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.566	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.8, phastCons 0.99
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,732 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00516%

Overall 0.00081% 13/1,605,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,390
European (non-Finnish)	0.000512%	195,333

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.Met1Val
Coding: c.1A>G
MANE Select: NM_032043
dbSNP: rs764585550
Type: single nucleotide variant
Location: chr17:61861539 (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

Genetic non-acquired premature ovarian failure — 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.Met1Leu Uncertain significance ★★ same residue
BRIP1 p.Met1Ile Uncertain significance ★ same residue
BRIP1 p.Met1fs Conflicting classifications of pathogenicity ★ ⚠ 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
BRIP1 c.1141-2A>T Likely pathogenic ★★ same condition
BRIP1 c.1340+1G>A Pathogenic/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-met1val (accessed [today's date]).

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