| Variant class | Typical molecular effect | Associated clinical entities | Sex effects (males vs females) | Key citations |
|---|---|---|---|---|
| Truncating variants / exon deletions / null alleles | Severe loss of function; absent or markedly impaired ARX transcriptional activity; loss of homeodomain binding/transcriptional capacity in many cases | Classically associated with the severe malformation spectrum, especially XLAG / ARX-related lissencephaly with agenesis of the corpus callosum and ambiguous genitalia; may also underlie hydranencephaly-abnormal genitalia phenotypes; severe developmental impairment and early lethal epileptic encephalopathy are typical | Hemizygous males are usually severely affected; female carriers often asymptomatic or milder, but de novo female variants can produce severe ID/DEE; variable expression partly attributed to X-inactivation | (pqac-00000031, pqac-00000032, pqac-00000034, pqac-00000035, pqac-00000037) |
| Critical homeodomain missense variants | Typically severe loss of function through impaired DNA binding, altered transcriptional capacity, and/or nuclear mislocalization; some HD missense variants are as severe as truncating alleles | XLAG is strongly associated with missense variants at critical homeodomain residues; severe DEE/ID and cortical malformations can also occur | Males usually show severe phenotypes; females may be unaffected, mildly affected, or severely affected if de novo, with variable expressivity | (pqac-00000031, pqac-00000032, pqac-00000034, pqac-00000035) |
| Polyalanine expansions, including c.428_451dup24 (Dup24) | Hypomorphic / partial loss of function; altered transcriptional repression; nuclear mislocalization; aggregation/intranuclear inclusions reported, suggesting an additional toxic gain-of-function component in some models | Usually associated with non-malformative or less-malformative ARX disorders: infantile spasms, DEE1, familial intellectual disability with epilepsy, dystonia/hand dystonia, and Partington-spectrum phenotypes; Dup24 is a recurrent variant in ID/epilepsy/Partington-like disease | Males are typically clinically affected; female relatives are often asymptomatic or mildly affected, though learning difficulties, epilepsy, or ID can occur | (pqac-00000030, pqac-00000032, pqac-00000034, pqac-00000035, pqac-00000036, pqac-00000050) |
| Other polyalanine/triplet-repeat insertions, including 33-bp exon 2 duplication | Hypomorphic effect with altered ARX activity; may impair interneuron development and network function; some duplications linked to early epileptic encephalopathy rather than gross malformation | 33-bp exon 2 duplication has been linked to EIEE / Ohtahara syndrome; other polyalanine insertions are associated with epilepsy, learning impairment, and interneuronopathy in mouse models | Reported mainly in affected males; female heterozygotes can show variable neuropsychiatric or cognitive manifestations | (pqac-00000030, pqac-00000037, pqac-00000049) |
| Missense variants outside the homeodomain | Often milder functional disturbance than HD variants; may alter repression or cofactor interactions rather than abolish DNA binding | More often associated with intellectual disability with or without dystonia, infantile spasms, and non-syndromic or less-malformative ARX phenotypes rather than classic XLAG | Males generally more consistently affected; females may be unaffected or mildly affected, but penetrance/expressivity are variable | (pqac-00000030, pqac-00000033, pqac-00000034, pqac-00000037) |


*Table: This table summarizes the main ARX pathogenic variant classes, their usual molecular consequences, and the clinical spectrum they are most strongly associated with. It is useful for quickly linking genotype class to expected severity, malformation risk, and sex-specific expression patterns.*