ARX

Chr XXLRX-linked

aristaless related homeobox

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

NCBI Gene: 170302 ENSG00000004848 UniProt: Q96QS3 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

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

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · X-linked complex neurodevelopmental disorder · XL · ClinGen 2020
Definitive · genetic developmental and epileptic encephalopathy · XL · ClinGen 2019
Strong · X-linked lissencephaly with abnormal genitalia · XL · Ambry Genetics
Strong · developmental and epileptic encephalopathy, 1 · XL · PanelApp Australia

+7 more curated pairs

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

101

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — ARX

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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 OE?0.00 (0.00–0.39)

0≤0.351.4

Missense OE?0.53 (0.45–0.64)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

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

Background carrier burden — how many people carry a rare variant somewhere in ARX?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 230

420 rare PASS variants

Rare truncating (LoF)

1 in 19,000

9 rare PASS variants

Rare synonymous (reference)

1 in 150

333 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARX. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 290	1 in 13,000
South Asian	~36k	1 in 200	none seen
Remaining (unassigned)	~31k	1 in 290	none seen
European (Finnish)	~27k	1 in 470	≈ 1 in 9,600
Admixed American	~23k	1 in 220	none seen
African / African American	~21k	1 in 230	≈ 1 in 16,000
East Asian	~20k	1 in 300	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 1,100	≈ 1 in 7,900
Middle Eastern	~2,758	1 in 270	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 5 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 5.? see exons ↓