Alternating hemiplegia of childhood: genes and variants

Genes linked to Alternating hemiplegia of childhood

• ATP1A3: Sodium/potassium-transporting ATPase subunit alpha-3

  It rapidly restores neuronal sodium and potassium gradients after repetitive firing, making it particularly important in highly active neurons. Pathogenic variants cause overlapping syndromes including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and CAPOS syndrome.

  23 disease-causing and 16 uncertain variants in ATP1A3 are linked to Alternating hemiplegia of childhood.

• ATP1A2: Sodium/potassium-transporting ATPase subunit alpha-2

  It restores sodium and potassium gradients after activity in astrocytes and other excitable tissues and thereby supports neuronal ion homeostasis. Pathogenic variants are a major cause of familial hemiplegic migraine type 2 and can produce severe episodic neurologic disease.

  7 disease-causing and 23 uncertain variants in ATP1A2 are linked to Alternating hemiplegia of childhood.

Where Alternating hemiplegia of childhood variants cluster

• ATP1A3 Transmembrane (positions 307–345): 4 of 23 disease-causing changes, 4.5× more than its size predicts.
• ATP1A3 Transmembrane (positions 943–966): 3 of 23 disease-causing changes, 5.5× more than its size predicts.

Known disease-causing variants in Alternating hemiplegia of childhood

Which prediction tools work for Alternating hemiplegia of childhood

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• SIFT: 97 out of 100
• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome is also caused by ATP1A3 variants; they fall mostly in different places as the Alternating hemiplegia of childhood variants (18 disease-causing).
• ATP1A3-associated neurological disorder is also caused by ATP1A3 variants; they fall in the same places as the Alternating hemiplegia of childhood variants (4 disease-causing).
• Familial hemiplegic migraine is also caused by ATP1A2 variants; they fall mostly in different places as the Alternating hemiplegia of childhood variants (33 disease-causing).
• Migraine, familial hemiplegic, 1 is also caused by ATP1A2 variants; they fall mostly in different places as the Alternating hemiplegia of childhood variants (19 disease-causing).

Diseases related to Alternating hemiplegia of childhood

• Migraine, familial hemiplegic, 1, also linked to ATP1A2
• Familial hemiplegic migraine, also linked to ATP1A2
• Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, also linked to ATP1A3
• ATP1A3-associated neurological disorder, also linked to ATP1A3
• Hereditary ataxia, also linked to ATP1A3
• Dystonic disorder, also linked to ATP1A3
• Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, also linked to ATP1A2
• Paroxysmal central nervous system disorders, also linked to ATP1A2

Frequently asked questions

Which genes are linked to Alternating hemiplegia of childhood?

In CATVariant, Alternating hemiplegia of childhood is linked to 2 analyzed proteins: ATP1A3 (Sodium/potassium-transporting ATPase subunit alpha-3) and ATP1A2 (Sodium/potassium-transporting ATPase subunit alpha-2).

How many genetic variants are linked to Alternating hemiplegia of childhood?

97 variants: 30 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 39 are of uncertain significance or have conflicting reports.

Which uncertain variants in Alternating hemiplegia of childhood look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Alternating hemiplegia of childhood?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 27 disease-causing and 15 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center