Is BRIP1 p.Ile398= (c.1194C>T) pathogenic?

BRIP1 p.Ile398= (c.1194C>T) is classified Benign/Likely benign in BRIP1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.0334%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Ile398= (c.1194C>T)?

BRIP1 p.Ile398= (c.1194C>T) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Ile398= (c.1194C>T) in the general population?

BRIP1 p.Ile398= (c.1194C>T) is ultra-rare (popmax 0.0334%, eas) (gnomAD).

BRIP1 p.Ile398=

c.1194C>T · rs757427498 · VCV183777

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, 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 2.1	GERP -1.8, phastCons 1
Overall
CADD	11.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% East Asian · 15/44,884 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00149% 24/1,613,300 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0334%	2,992
Remaining individualsnot grpmax-eligible	0.0016%	62,472
South Asian	0.0011%	91,044
European (non-Finnish)	0.000593%	168,515

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.Ile398=
Coding: c.1194C>T
MANE Select: NM_032043
dbSNP: rs757427498
Type: single nucleotide variant
Location: chr17:61799246 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 398: the helicase atp-binding domain

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 hereditary breast carcinoma

Similar variants

BRIP1 p.Ile398Ser Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile398Val Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile398Asn 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
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-ile398 (accessed [today's date]).

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