Is ARX p.Arg330His (c.989G>A) pathogenic?

ARX p.Arg330His (c.989G>A) is classified Likely pathogenic in ARX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-16). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with ARX-related disorder.

What condition is associated with ARX p.Arg330His (c.989G>A)?

ARX p.Arg330His (c.989G>A) is associated with ARX-related disorder, developmental and epileptic encephalopathy, 1 (ClinVar).

How common is ARX p.Arg330His (c.989G>A) in the general population?

ARX p.Arg330His (c.989G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARX p.Arg330His (c.989G>A)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

ARX p.Arg330His

c.989G>A · rs886039308 · VCV265040

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ARX-related disorder

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 7% in ARX
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -14.22	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 7.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 5,714 bp · p 1e-11 · 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

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: ARX
Protein: p.Arg330His
Coding: c.989G>A
MANE Select: NM_139058
dbSNP: rs886039308
Type: single nucleotide variant
Location: chrX:25013006 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 330: a DNA-binding region

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

Disease context

Also linked: developmental and epileptic encephalopathy, 1

Similar variants

ARX p.Arg330Cys Uncertain significance ★ ⚠ same residue
ARX p.Arg332Gly Pathogenic/Likely pathogenic ★★ same condition
ARX p.Arg332His Pathogenic ★★ same condition
ARX p.Arg371Ter Pathogenic ★★ same condition
ARX p.Arg384Cys Pathogenic/Likely pathogenic ★★ same condition
ARX p.Glu294Ter Pathogenic ★★ same condition
ARX p.Pro353Leu Pathogenic ★★ same condition
ARX p.Ser319Ter 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/arx-p-arg330his (accessed [today's date]).

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