Is BRIP1 p.Leu594Val (c.1780T>G) pathogenic?

BRIP1 p.Leu594Val (c.1780T>G) is classified Likely pathogenic in BRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.538); Absent from gnomAD v4.1; Associated with Fanconi anemia complementation group J.

What condition is associated with BRIP1 p.Leu594Val (c.1780T>G)?

BRIP1 p.Leu594Val (c.1780T>G) is associated with Fanconi anemia complementation group J, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Leu594Val (c.1780T>G) in the general population?

BRIP1 p.Leu594Val (c.1780T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRIP1 p.Leu594Val (c.1780T>G)?

AlphaMissense predicts ambiguous (score 0.538) — an in-silico prediction, not a clinical call.

BRIP1 p.Leu594Val

c.1780T>G · rs876658256 · VCV229896

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.538 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Fanconi anemia complementation group J

Computational evidence

Protein change
AlphaMissense	0.538	ambiguous
REVEL	0.209	benign-leaning
SaProt	LLR -11.76	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.90	donor gain · deltas
Pangolin	Δ0.73	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRIP1
Protein: p.Leu594Val
Coding: c.1780T>G
MANE Select: NM_032043
dbSNP: rs876658256
Type: single nucleotide variant
Location: chr17:61780854 (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

Fanconi anemia complementation group J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRIP1 p.Leu594Phe Uncertain significance ★★ ⚠ same residue
BRIP1 p.Leu594Ser Uncertain significance ★★ ⚠ same residue
BRIP1 p.Leu594= Benign/Likely benign ★★ same residue
BRIP1 p.Leu594Ter 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
BRIP1 c.1141-2A>T 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-leu594val (accessed [today's date]).

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