ATXN3

Chr 14ADMulti

ataxin 3

Also known as: AT3, ATX3, JOS, MJD, MJD1, SCA3

NCBI Gene: 4287 ENSG00000066427 UniProt: P54252 OMIM: 607047

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/MultiLOEUF 0.492 OMIM phenotypes

Clinical Summary— ATXN3

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

📋

ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 48 VUS of 111 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — ATXN3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.106

Z-score 3.53

OE 0.26 (0.15–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.35Z-score

OE missense 0.72 (0.63–0.83)

136 obs / 188.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.15–0.49)

0≤0.351.4

Missense OE?0.72 (0.63–0.83)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 7 / 26.7Missense obs/exp: 136 / 188.0Syn Z: 1.21

This gene — mechanism propensity

0.74top 25%

GOF

0.6931th %ile

LOF

0.2580th %ile

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.

GOFprediction above median · 1 literature citation

DNprediction above median

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

GOFComparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 28854700 ↗

ClinVar Variant Classifications

111 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS48

Likely Benign12

Benign15

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	1	0	0	0	1
VUS	6	40	2	0	48
Likely Benign	3	6	2	1	12
Benign	2	11	1	1	15
Conflicting	—				2
Total	12	57	6	2	79

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap ATXN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →