Is BRIP1 p.His435Arg (c.1304A>G) pathogenic?

BRIP1 p.His435Arg (c.1304A>G) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-05-31). AlphaMissense: likely pathogenic (0.777); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.His435Arg (c.1304A>G)?

BRIP1 p.His435Arg (c.1304A>G) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.His435Arg (c.1304A>G) in the general population?

BRIP1 p.His435Arg (c.1304A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRIP1 p.His435Arg (c.1304A>G)?

AlphaMissense predicts likely pathogenic (score 0.777) — an in-silico prediction, not a clinical call.

BRIP1 p.His435Arg

c.1304A>G · rs730881636 · VCV182348

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.777	likely pathogenic
REVEL	0.686	pathogenic-leaning
SaProt	LLR -12.67	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 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00223% East Asian · 1/44,868 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,118 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
European (non-Finnish)	0.00017%	589,682

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.His435Arg
Coding: c.1304A>G
MANE Select: NM_032043
dbSNP: rs730881636
Type: single nucleotide variant
Location: chr17:61799136 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 435: 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.His435Asp Uncertain significance ★★ ⚠ same residue
BRIP1 p.His435Tyr Uncertain significance ★★ ⚠ same residue
BRIP1 p.His435= Likely benign ★★ same residue
BRIP1 p.His435Asn Uncertain significance ★ ⚠ same residue
BRIP1 p.His435Gln 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

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-his435arg (accessed [today's date]).

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