ATXN3
Chr 14ADMultiataxin 3
Also known as: AT3, ATX3, JOS, MJD, MJD1, SCA3
The protein functions as a deubiquitinating enzyme that maintains protein homeostasis by trimming long polyubiquitin chains and regulating transcription, autophagy, and mTORC1 signaling. CAG repeat expansions from the normal 12-44 to 52-86 repeats cause Machado-Joseph disease (spinocerebellar ataxia-3), an autosomal dominant neurodegenerative disorder with earlier age of onset correlating with higher repeat numbers. The pathogenic mechanism involves a dominant-negative effect of the mutant protein.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
ATXN3 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools