Is BROX p.His225Arg (c.674A>G) pathogenic?

BROX p.His225Arg (c.674A>G) is classified Uncertain significance in BROX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1137); Ultra-rare (popmax 0.0201%, nfe).

How common is BROX p.His225Arg (c.674A>G) in the general population?

BROX p.His225Arg (c.674A>G) is ultra-rare (popmax 0.0201%, nfe) (gnomAD).

What do computational predictors say about BROX p.His225Arg (c.674A>G)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

BROX p.His225Arg

c.674A>G · VCV4646706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.02	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 11	GERP 2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 17 kb · p 0.43 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.0201% European (non-Finnish) · 232/1,155,618 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.0148% 234/1,580,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0201%	4,981
Remaining individualsnot grpmax-eligible	0.00164%	60,808
African / African-American	0.00134%	74,556

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: BROX
Protein: p.His225Arg
Coding: c.674A>G
MANE Select: NM_144695
Type: single nucleotide variant
Location: chr1:222728746 (GRCh38)
Gene constraint: LOEUF 1.123 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.15 · 7 PDB
Residue 225: the bro1 domain; an α-helix

Full BROX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BROX p.Ala169Val Uncertain significance ★ ⚠ same type
BROX p.Ala191Val Uncertain significance ★ ⚠ same type
BROX p.Ala213Val Uncertain significance ★ ⚠ same type
BROX p.Arg178Gln Uncertain significance ★ ⚠ same type
BROX p.Arg378Lys Uncertain significance ★ ⚠ same type
BROX p.Asn117Ser Uncertain significance ★ ⚠ same type
BROX p.Asn19Ser Uncertain significance ★ ⚠ same type
BROX p.Asn218Ser Uncertain significance ★ ⚠ same type

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/brox-p-his225arg (accessed [today's date]).

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