Is BRIP1 p.His396Asp (c.1186C>G) pathogenic?

BRIP1 p.His396Asp (c.1186C>G) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-25). AlphaMissense: likely pathogenic (0.9885); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.His396Asp (c.1186C>G)?

BRIP1 p.His396Asp (c.1186C>G) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, familial ovarian cancer (ClinVar).

How common is BRIP1 p.His396Asp (c.1186C>G) in the general population?

BRIP1 p.His396Asp (c.1186C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BRIP1 p.His396Asp (c.1186C>G)?

AlphaMissense predicts likely pathogenic (score 0.9885) — an in-silico prediction, not a clinical call.

BRIP1 p.His396Asp

c.1186C>G · rs1603342316 · VCV659729

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9885	likely pathogenic · top 3% in BRIP1
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -16.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00167% Admixed American · 1/59,918 alleles

Overall 6.84e-05% 1/1,461,238 alleles · very rare

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.His396Asp
Coding: c.1186C>G
MANE Select: NM_032043
dbSNP: rs1603342316
Type: single nucleotide variant
Location: chr17:61799254 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 396: 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 familial ovarian cancer hereditary breast carcinoma

Similar variants

BRIP1 p.His396Tyr Uncertain significance ★★ ⚠ same residue
BRIP1 p.His396= Benign/Likely benign ★★ same residue
BRIP1 p.His396Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.His396Leu 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-his396asp (accessed [today's date]).

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