Familial hemiplegic migraine: genes and variants

Genes linked to Familial hemiplegic migraine

• 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.

  33 disease-causing and 377 uncertain variants in ATP1A2 are linked to Familial hemiplegic migraine.

Weakly linked (only a few uncertain records): CACNA1A.

Where Familial hemiplegic migraine variants cluster

• ATP1A2 Transmembrane (positions 287–306): 3 of 33 disease-causing changes, 4.6× more than its size predicts.
• ATP1A2 Cytoplasmic (positions 821–840): 3 of 33 disease-causing changes, 4.6× more than its size predicts.
• ATP1A2 Transmembrane (positions 800–820): 3 of 33 disease-causing changes, 4.4× more than its size predicts.

Known disease-causing variants in Familial hemiplegic migraine

Uncertain variants in Familial hemiplegic migraine that look disease-causing

Which prediction tools work for Familial hemiplegic migraine

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

• MutPred2: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 99 out of 100
• CADD: 99 out of 100
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 87 out of 100
• phyloP: 82 out of 100
• MetaLR: 73 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Migraine, familial hemiplegic, 1 is also caused by ATP1A2 variants; they fall mostly in different places as the Familial hemiplegic migraine variants (19 disease-causing).
• Alternating hemiplegia of childhood is also caused by ATP1A2 variants; they fall mostly in different places as the Familial hemiplegic migraine variants (7 disease-causing).

Diseases related to Familial hemiplegic migraine

• Migraine, familial hemiplegic, 1, also linked to ATP1A2
• Alternating hemiplegia of childhood, also linked to ATP1A2
• 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 Familial hemiplegic migraine?

In CATVariant, Familial hemiplegic migraine is linked to 1 analyzed protein: ATP1A2 (Sodium/potassium-transporting ATPase subunit alpha-2).

How many genetic variants are linked to Familial hemiplegic migraine?

433 variants: 33 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 377 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial hemiplegic migraine look disease-causing?

10 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ATP1A2 R593Q, ATP1A2 R383C, ATP1A2 T376R, ATP1A2 T378I and ATP1A2 M829T. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Familial hemiplegic migraine?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 17 disease-causing and 10 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.

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