Machado-Joseph disease: genes and variants
Explore variant evidence for Machado-Joseph disease across 7 analyzed proteins (CACNA1A, SPTBN2, FAT2, ATXN1, ATXN2 and 2 more). Linked ClinVar records include 38 pathogenic or likely pathogenic variants, 73 variants of uncertain significance and 45 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Machado-Joseph disease
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 ClinVar pathogenic / likely pathogenic and 39 uncertain variants in CACNA1A have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 43 uncertain variants in SPTBN2 have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
FAT2: Protocadherin Fat 2
A large atypical cadherin involved in cell migration and tissue organization. It may also help organize the parallel fibers of cerebellar granule cells during development, based partly on evidence from related species.
1 ClinVar pathogenic / likely pathogenic and 27 uncertain variants in FAT2 have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 7 uncertain variants in ATXN1 have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in ATXN2 have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in TBP have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
ATXN3: Ataxin-3
It functions as a deubiquitinating enzyme involved in protein-quality control and ubiquitin signaling. Expansion of its polyglutamine tract causes spinocerebellar ataxia type 3, also called Machado-Joseph disease, through toxic protein misfolding and neurodegeneration.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in ATXN3 have source records linked to Machado-Joseph disease. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): COL6A3.
Where Machado-Joseph disease variants cluster
- CACNA1A S6 of repeat II (positions 689–713): 4 of 28 ClinVar pathogenic / likely pathogenic variants, 14.3× more than its size predicts.
- CACNA1A IV (positions 1550–1813): 10 of 28 ClinVar pathogenic / likely pathogenic variants, 3.4× more than its size predicts.
- SPTBN2 Spectrin 2 (positions 427–527): 3 of 9 ClinVar pathogenic / likely pathogenic variants, 7.9× more than its size predicts.
- SPTBN2 Actin-binding (positions 2–278): 4 of 9 ClinVar pathogenic / likely pathogenic variants, 3.8× more than its size predicts.
- CACNA1A III (positions 1230–1513): 5 of 28 ClinVar pathogenic / likely pathogenic variants, 1.6× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Machado-Joseph disease
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| CACNA1A R1666P | 1666 | IV | Pathogenic / likely pathogenic (★★) |
| CACNA1A R1666Q | 1666 | IV | Pathogenic / likely pathogenic (★★) |
| SPTBN2 R437Q | 437 | Spectrin 2 | Pathogenic / likely pathogenic (★★) |
| SPTBN2 R437W | 437 | Spectrin 2 | Pathogenic / likely pathogenic (★★) |
| CACNA1A D302N | 302 | I | Pathogenic / likely pathogenic (★★) |
| CACNA1A R582Q | 582 | II | Pathogenic / likely pathogenic (★★) |
| CACNA1A I711M | 711 | II | Pathogenic / likely pathogenic (★★) |
| CACNA1A A712T | 712 | II | Pathogenic / likely pathogenic (★★) |
| CACNA1A V713M | 713 | II | Pathogenic / likely pathogenic (★★) |
| CACNA1A R1663Q | 1663 | IV | Pathogenic / likely pathogenic (★★) |
| SPTBN2 M436T | 436 | Spectrin 2 | Pathogenic / likely pathogenic (★★) |
| CACNA1A P1360Q | 1360 | III | Pathogenic / likely pathogenic (★★) |
| CACNA1A V1392M | 1392 | III | Pathogenic / likely pathogenic (★★) |
| CACNA1A V1808I | 1808 | IV | Pathogenic / likely pathogenic (★★) |
| CACNA1A L1344P | 1344 | III | Pathogenic / likely pathogenic (★★) |
| CACNA1A A1507T | 1507 | III | Pathogenic / likely pathogenic (★★) |
| CACNA1A D1633N | 1633 | IV | Pathogenic / likely pathogenic (★★) |
| CACNA1A R1672P | 1672 | IV | Pathogenic / likely pathogenic (★★) |
| CACNA1A I613M | 613 | II | Pathogenic / likely pathogenic (★★) |
| CACNA1A I1708T | 1708 | IV | Pathogenic / likely pathogenic (★) |
| CACNA1A D1316E | 1316 | III | Pathogenic / likely pathogenic (★) |
| CACNA1A S218P | 218 | I | Pathogenic / likely pathogenic (★) |
| CACNA1A L617S | 617 | II | Pathogenic / likely pathogenic (★) |
| CACNA1A I624F | 624 | II | Pathogenic / likely pathogenic (★) |
| CACNA1A G700E | 700 | II | Pathogenic / likely pathogenic (★) |
| CACNA1A I1707T | 1707 | IV | Pathogenic / likely pathogenic (★) |
| CACNA1A V1806A | 1806 | IV | Pathogenic / likely pathogenic (★) |
| FAT2 E1211A | 1211 | Cadherin 10 | Pathogenic / likely pathogenic (★) |
| SPTBN2 K65Q | 65 | Calponin-homology (CH) 1 | Pathogenic / likely pathogenic (★) |
| SPTBN2 I157T | 157 | Calponin-homology (CH) 1 | Pathogenic / likely pathogenic (★) |
| SPTBN2 D255Y | 255 | Calponin-homology (CH) 2 | Pathogenic / likely pathogenic (★) |
| SPTBN2 T271I | 271 | Calponin-homology (CH) 2 | Pathogenic / likely pathogenic (★) |
| SPTBN2 R351P | 351 | Spectrin 1 | Pathogenic / likely pathogenic (★) |
| CACNA1A E1755G | 1755 | IV | Pathogenic / likely pathogenic (★) |
| SPTBN2 D1453V | 1453 | Spectrin 11 | Pathogenic / likely pathogenic (★) |
| CACNA1A D173E | 173 | I | Pathogenic / likely pathogenic |
| CACNA1A L602R | 602 | II | Pathogenic / likely pathogenic |
| CACNA1A R782P | 782 | Cytoplasmic | Pathogenic / likely pathogenic |
Which prediction tools work for Machado-Joseph disease
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- 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 also has ClinVar records linked to CACNA1A variants; they fall mostly in different places as the Machado-Joseph disease variants (93 pathogenic / likely pathogenic).
- Migraine, familial hemiplegic, 1 also has ClinVar records linked to CACNA1A variants; they fall mostly in different places as the Machado-Joseph disease variants (26 pathogenic / likely pathogenic).
- CACNA1A-related complex neurodevelopmental disorder also has ClinVar records linked to CACNA1A variants; they fall mostly in different places as the Machado-Joseph disease variants (3 pathogenic / likely pathogenic).
Diseases related to Machado-Joseph disease
- 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 have records linked to Machado-Joseph disease?
This view contains 7 analyzed proteins: CACNA1A, SPTBN2, FAT2, ATXN1, ATXN2 and 2 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 38 pathogenic or likely pathogenic variants, 73 variants of uncertain significance and 45 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 0 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 193 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses 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