Episodic ataxia type 2: genes and variants

Genes linked to Episodic ataxia type 2

• CACNA1A: Voltage-dependent P/Q-type calcium channel subunit alpha-1A

  Its P/Q-type calcium current is a major trigger for neurotransmitter release at central synapses and is especially important in cerebellar circuits. Pathogenic variants cause a spectrum including familial hemiplegic migraine, episodic ataxia, spinocerebellar ataxia type 6, epilepsy, and developmental disorders.

  93 disease-causing and 1,101 uncertain variants in CACNA1A are linked to Episodic ataxia type 2.

• KCNA1: Potassium voltage-gated channel subfamily A member 1

  Its potassium current limits neuronal excitability and shapes action-potential repolarization, especially in axons and presynaptic terminals. Pathogenic variants classically cause episodic ataxia type 1 and can also produce epilepsy, myokymia, and related neurologic phenotypes.

  27 disease-causing and 224 uncertain variants in KCNA1 are linked to Episodic ataxia type 2.

• SCN2A: Sodium channel protein type 2 subunit alpha

  The protein forms Nav1.2, a voltage-gated sodium channel that carries sodium current during neuronal action potentials. By shaping neuronal excitability and signal propagation, it supports brain circuits involved in development, learning, and seizure susceptibility.

  15 disease-causing and 25 uncertain variants in SCN2A are linked to Episodic ataxia type 2.

Where Episodic ataxia type 2 variants cluster

• CACNA1A S4 of repeat III (positions 1339–1357): 8 of 93 disease-causing changes, 11.3× more than its size predicts.
• CACNA1A IV (positions 1550–1813): 27 of 93 disease-causing changes, 2.8× more than its size predicts.
• CACNA1A I (positions 85–363): 22 of 93 disease-causing changes, 2.1× more than its size predicts.
• CACNA1A S6 of repeat II (positions 689–713): 5 of 93 disease-causing changes, 5.4× more than its size predicts.
• KCNA1 Segment S6 (positions 387–415): 6 of 27 disease-causing changes, 3.8× more than its size predicts.

Known disease-causing variants in Episodic ataxia type 2

Showing 60 of 135.

Uncertain variants in Episodic ataxia type 2 that look disease-causing

Which prediction tools work for Episodic ataxia type 2

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

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• AlphaMissense: 97 out of 100
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• ESM1b (LLR): 93 out of 100
• MutPred2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 86 out of 100
• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100

Same protein, different disease

• Spinocerebellar ataxia type 6 is also caused by CACNA1A variants; they fall partly in the same places as the Episodic ataxia type 2 variants (28 disease-causing).
• Migraine, familial hemiplegic, 1 is also caused by CACNA1A variants; they fall partly in the same places as the Episodic ataxia type 2 variants (26 disease-causing).
• Seizures, benign familial infantile, 3 is also caused by SCN2A variants; they fall mostly in different places as the Episodic ataxia type 2 variants (167 disease-causing).
• Complex neurodevelopmental disorder is also caused by SCN2A variants; they fall mostly in different places as the Episodic ataxia type 2 variants (22 disease-causing).
• West syndrome is also caused by SCN2A variants; they fall mostly in different places as the Episodic ataxia type 2 variants (11 disease-causing).
• Benign familial infantile epilepsy is also caused by SCN2A variants; they fall mostly in different places as the Episodic ataxia type 2 variants (6 disease-causing).
• Infantile spasms is also caused by SCN2A variants; they fall mostly in different places as the Episodic ataxia type 2 variants (3 disease-causing).

Diseases related to Episodic ataxia type 2

• Epilepsy, also linked to CACNA1A and SCN2A
• Focal epilepsy, also linked to CACNA1A and SCN2A
• Seizures, benign familial infantile, 3, also linked to SCN2A
• Amyotrophic lateral sclerosis, also linked to SCN2A
• Cardiac arrhythmia, also linked to SCN2A
• Migraine, familial hemiplegic, 1, also linked to CACNA1A
• Complex neurodevelopmental disorder, also linked to SCN2A
• Spinocerebellar ataxia type 6, also linked to CACNA1A
• West syndrome, also linked to SCN2A
• Generalized epilepsy-paroxysmal dyskinesia syndrome, also linked to KCNA1
• Episodic kinesigenic dyskinesia, also linked to KCNA1
• Self-limited epilepsy with centrotemporal spikes, also linked to SCN2A

Frequently asked questions

Which genes are linked to Episodic ataxia type 2?

In CATVariant, Episodic ataxia type 2 is linked to 3 analyzed proteins: CACNA1A (Voltage-dependent P/Q-type calcium channel subunit alpha-1A), KCNA1 (Potassium voltage-gated channel subfamily A member 1) and SCN2A (Sodium channel protein type 2 subunit alpha).

How many genetic variants are linked to Episodic ataxia type 2?

1,598 variants: 135 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,350 are of uncertain significance or have conflicting reports.

Which uncertain variants in Episodic ataxia type 2 look disease-causing?

7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CACNA1A R1672H, CACNA1A R1678C, CACNA1A R1739W, CACNA1A V1392L and CACNA1A R192W. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Episodic ataxia type 2?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 32 disease-causing and 129 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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