ARX

Chr XXLRX-linked

aristaless related homeobox

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

NCBI Gene: 170302 ENSG00000004848 UniProt: Q96QS3

This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 1MIM #308350

XLR

Hydranencephaly with abnormal genitaliaMIM #300215

X-linked

Intellectual developmental disorder, X-linked 29MIM #300419

XLR

Lissencephaly, X-linked 2MIM #300215

X-linked

Partington syndromeMIM #309510

XLR

Proud syndromeMIM #300004

X-linked

UniProtAgenesis of the corpus callosum, with abnormal genitalia

399

ClinVar variants

Pathogenic / LP

0.91

pLI score· haploinsufficient

Active trials

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

65 Pathogenic / Likely Pathogenic· 166 VUS of 399 total submissions

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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

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.39)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.53 (0.45–0.64)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10

0≤1.21.6

LoF obs/exp: 0 / 7.7Missense obs/exp: 82 / 153.6Syn Z: -0.66

ClinVar Variant Classifications

399 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51

Likely Pathogenic14

VUS166

Likely Benign138

Benign11

Conflicting19

Pathogenic

Likely Pathogenic

166

VUS

138

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	1	30	0	51
Likely Pathogenic	4	5	5	0	14
VUS	0	141	22	3	166
Likely Benign	0	7	24	107	138
Benign	0	3	6	2	11
Conflicting	—				19
Total	24	157	87	112	399

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.

Gene2Phenotype Curations

ARX-related neurodevelopmental spectrum including lissencephaly with genital anomalies and epilepsy to non-syndromic intellectual disability

definitive

Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product, Uncertain

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

MIM #300382 · *

Developmental and epileptic encephalopathy 1

MIM #308350