ARX

Chr XXLRX-linked

aristaless related homeobox

Also known as: CT121, EIEE1, ISSX, MRX29, MRX32, MRX33, MRX36, MRX38

NCBI Gene: 170302ENSG00000004848UniProt: Q96QS3OMIM: 300382

The protein is a homeobox transcription factor that regulates central nervous system development and contains a conserved aristaless domain and homeobox domain. Mutations cause a spectrum of X-linked disorders including developmental and epileptic encephalopathy, intellectual disability, lissencephaly, and other neurodevelopmental syndromes with varying combinations of seizures, cognitive impairment, and brain malformations. The pathogenic mechanism involves loss of function, with polyalanine tract expansions being a common mutation type.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismXLR/X-linkedLOEUF 0.396 OMIM phenotypes
Clinical Summary— ARX
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Gene-Disease Validity (ClinGen)
X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
33 unique Pathogenic / Likely Pathogenic· 125 VUS of 300 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — ARX
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.39LOEUF
pLI 0.908
Z-score 2.57
OE 0.00 (0.00–0.39)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.05Z-score
OE missense 0.53 (0.45–0.64)
82 obs / 153.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.39)
0≤0.351.4
Missense OE0.53 (0.45–0.64)
0≤0.61.4
Synonymous OE1.10
0≤1.21.6
LoF obs/exp: 0 / 7.7Missense obs/exp: 82 / 153.6Syn Z: -0.66
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveARX-related neurodevelopmental spectrum including lissencephaly with genital anomalies and epilepsy to non-syndromic intellectual disabilityLOFXLR
DN
0.3296th %ile
GOF
0.2895th %ile
LOF
0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 48% of P/LP variants are LoF · LOEUF 0.39

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic6
VUS125
Likely Benign139
Benign1
27
Pathogenic
6
Likely Pathogenic
125
VUS
139
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
2
13
0
27
Likely Pathogenic
4
1
1
0
6
VUS
1
115
7
2
125
Likely Benign
0
5
23
111
139
Benign
0
0
1
0
1
Total1712345113298

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ARX · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cellular Functional Analyses of ARX Variants Reveal New Insights Into Genotype-Phenotype Correlations in Neurodevelopmental Disorders Among Male and Female Patients.
Faraj R et al.·Hum Mutat
2026Open AccessCohort
ARX mutation-associated interneuron defects provide insights into mechanisms underlying developmental epilepsies.
Lim Y et al.·Brain
2026Functional
An arts-based approach for communicating paleopathological research to public audiences: the Phoenix Bioscience Core's Artist + Researcher (ARx) program.
Titelbaum AR et al.·Int J Paleopathol
2026
Dual developmental effects of ARX poly-alanine mutations on human cortical excitatory and inhibitory neurons.
Nieto-Estevez V et al.·Cell Rep
2026Open Access
Cholinergic modulation of hippocampal CA1 pyramidal cell excitability in ArxGCG+7 mice.
Johnson CM et al.·Exp Neurol
2026
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients