ARX

Chr XXLRX-linked

aristaless related homeobox

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

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismXLR/X-linkedLOEUF 0.396 OMIM phenotypes
Clinical SummaryARX
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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

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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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.39LOEUF
pLI 0.908
Z-score 2.57
OE 0.00 (0.000.39)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.05Z-score
OE missense 0.53 (0.450.64)
82 obs / 153.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.000.39)
00.351.4
Missense OE0.53 (0.450.64)
00.61.4
Synonymous OE1.10
01.21.6
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 · 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

0 submitted variants 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
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