Is BRIP1 p.Ile504Met (c.1512C>G) pathogenic?

BRIP1 p.Ile504Met (c.1512C>G) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0798); Absent from gnomAD v4.1; Associated with Fanconi anemia complementation group J.

What condition is associated with BRIP1 p.Ile504Met (c.1512C>G)?

BRIP1 p.Ile504Met (c.1512C>G) is associated with Fanconi anemia complementation group J, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Ile504Met (c.1512C>G) in the general population?

BRIP1 p.Ile504Met (c.1512C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRIP1 p.Ile504Met (c.1512C>G)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

BRIP1 p.Ile504Met

c.1512C>G · rs876660478 · VCV233545

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia complementation group J

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -8.24	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 0.19	GERP -1.3
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	10.9	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

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.Ile504Met
Coding: c.1512C>G
MANE Select: NM_032043
dbSNP: rs876660478
Type: single nucleotide variant
Location: chr17:61784386 (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.Ile504Thr Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile504= Benign/Likely benign ★★ same residue
BRIP1 p.Ile504fs Pathogenic ★★ same residue
BRIP1 p.Ile504Phe Uncertain significance ⚠ 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-ile504met (accessed [today's date]).

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