Spinocerebellar ataxia type 6: genes and variants

Genes linked to Spinocerebellar ataxia type 6

• 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.

  28 disease-causing and 39 uncertain variants in CACNA1A are linked to Spinocerebellar ataxia type 6.

• SPTBN2: Spectrin beta chain, non-erythrocytic 2

  It organizes the neuronal membrane cytoskeleton and is particularly important for Purkinje-cell structure and signaling in the cerebellum. Dominant variants cause spinocerebellar ataxia type 5 or early-onset developmental ataxia, while biallelic variants can cause a more severe SCAR phenotype.

  9 disease-causing and 43 uncertain variants in SPTBN2 are linked to Spinocerebellar ataxia type 6.

• FAT2: Protocadherin Fat 2

  1 disease-causing and 27 uncertain variants in FAT2 are linked to Spinocerebellar ataxia type 6.

• ATXN1: Ataxin-1

  It participates in nuclear transcriptional and RNA-regulatory complexes in neurons. Expansion of its polyglutamine tract causes spinocerebellar ataxia type 1 through a toxic gain of function that progressively injures cerebellar and brainstem neurons.

  0 disease-causing and 7 uncertain variants in ATXN1 are linked to Spinocerebellar ataxia type 6.

• ATXN2: Ataxin-2

  It participates in RNA metabolism, stress-granule biology, and neuronal protein homeostasis. CAG-repeat expansion causes spinocerebellar ataxia type 2, while intermediate-length expansions also increase susceptibility to amyotrophic lateral sclerosis.

  0 disease-causing and 0 uncertain variants in ATXN2 are linked to Spinocerebellar ataxia type 6.

• TBP: TATA-box-binding protein

  It binds TATA and related promoter elements as a core component of transcription-initiation complexes used by all three nuclear RNA polymerases. Expansion of its polyglutamine tract causes spinocerebellar ataxia type 17 with progressive ataxia, cognitive and psychiatric symptoms, and movement abnormalities.

  0 disease-causing and 1 uncertain variants in TBP are linked to Spinocerebellar ataxia type 6.

Weakly linked (only a few uncertain records): ATXN3 and COL6A3.

Where Spinocerebellar ataxia type 6 variants cluster

• CACNA1A S6 of repeat II (positions 689–713): 4 of 28 disease-causing changes, 14.3× more than its size predicts.
• CACNA1A IV (positions 1550–1813): 10 of 28 disease-causing changes, 3.4× more than its size predicts.
• SPTBN2 Spectrin 2 (positions 427–527): 3 of 9 disease-causing changes, 7.9× more than its size predicts.
• SPTBN2 Actin-binding (positions 2–278): 4 of 9 disease-causing changes, 3.8× more than its size predicts.
• CACNA1A III (positions 1230–1513): 5 of 28 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Spinocerebellar ataxia type 6

Which prediction tools work for Spinocerebellar ataxia type 6

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

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 92 out of 100
• SIFT: 81 out of 100
• EVE: 76 out of 100
• PolyPhen-2: 72 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Episodic ataxia type 2 is also caused by CACNA1A variants; they fall mostly in different places as the Spinocerebellar ataxia type 6 variants (93 disease-causing).
• Migraine, familial hemiplegic, 1 is also caused by CACNA1A variants; they fall mostly in different places as the Spinocerebellar ataxia type 6 variants (26 disease-causing).
• CACNA1A-related complex neurodevelopmental disorder is also caused by CACNA1A variants; they fall mostly in different places as the Spinocerebellar ataxia type 6 variants (3 disease-causing).

Diseases related to Spinocerebellar ataxia type 6

• Episodic ataxia type 2, also linked to CACNA1A
• Migraine, familial hemiplegic, 1, also linked to CACNA1A
• Epilepsy, also linked to CACNA1A
• Autosomal recessive spinocerebellar ataxia 12, also linked to SPTBN2
• Disorder of sexual differentiation, also linked to CACNA1A
• Focal epilepsy, also linked to CACNA1A
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, also linked to CACNA1A
• Cerebellar ataxia, also linked to SPTBN2

Frequently asked questions

Which genes are linked to Spinocerebellar ataxia type 6?

In CATVariant, Spinocerebellar ataxia type 6 is linked to 6 analyzed proteins: CACNA1A (Voltage-dependent P/Q-type calcium channel subunit alpha-1A), SPTBN2 (Spectrin beta chain, non-erythrocytic 2), FAT2 (Protocadherin Fat 2), ATXN1 (Ataxin-1), ATXN2 (Ataxin-2) and TBP (TATA-box-binding protein).

How many genetic variants are linked to Spinocerebellar ataxia type 6?

193 variants: 38 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 118 are of uncertain significance or have conflicting reports.

Which uncertain variants in Spinocerebellar ataxia type 6 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 Spinocerebellar ataxia type 6?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 22 disease-causing and 28 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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