ATXN3

Chr 14ADMulti

ataxin 3

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

NCBI Gene: 4287ENSG00000066427UniProt: P54252

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]

Primary Disease Associations & Inheritance

{Parkinson disease, late-onset, susceptibility to}MIM #168600
ADMulti
Machado-Joseph diseaseMIM #109150
AD
UniProtSpinocerebellar ataxia 3
104
ClinVar variants
23
Pathogenic / LP
0.11
pLI score
0
Active trials
Clinical Summary— ATXN3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 52 VUS of 104 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.35Z-score
OE missense 0.72 (0.63–0.83)
136 obs / 188.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.15–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.63–0.83)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.81
0≤1.21.6
LoF obs/exp: 7 / 26.7Missense obs/exp: 136 / 188.0Syn Z: 1.21

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic2
VUS52
Likely Benign12
Benign15
Conflicting2
21
Pathogenic
2
Likely Pathogenic
52
VUS
12
Likely Benign
15
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
21
0
21
Likely Pathogenic
1
0
1
0
2
VUS
5
36
11
0
52
Likely Benign
3
3
5
1
12
Benign
2
4
8
1
15
Conflicting
—2
Total1143462104

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

View 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ATAXIN 3; ATXN3
MIM #607047 · *

{Parkinson disease, late-onset, susceptibility to}

MIM #168600

Molecular basis of disorder known

Autosomal dominantMultifactorial

Machado-Joseph disease

MIM #109150

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ATXN3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
Wang Z et al.·Autophagy
2024
Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study.
Ibañez K et al.·Lancet Neurol
2022
Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.
Li Z et al.·Brain
2025
Hereditary Ataxias in Argentina.
Rossi M et al.·Cerebellum
2025Review
Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3.
Tezenas du Montcel S et al.·Neurology
2023Cohort
Biomarkers in Spinocerebellar Ataxias.
Klockgether T et al.·Cerebellum
2025Review
Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3.
Raposo M et al.·Brain
2023
Movement Disorders in Hereditary Cerebellar Ataxia.
Damásio J et al.·Mov Disord Clin Pract
2025
Toward understanding Machado-Joseph disease.
Costa Mdo C et al.·Prog Neurobiol
2012Review
Regional distribution of polymorphisms associated to the disease-causing gene of spinocerebellar ataxia type 3.
Elter TL et al.·J Neurol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
TCF4 intronic CAG repeat length modulates the effect of ATXN3 on age at onset in spinocerebellar ataxia type 3.
Wan N et al.·J Adv Res
2026
Pediatric-onset spinocerebellar ataxia type 3 with dual ATXN3 and HTT gene mutations: a case report and literature-informed hypothesis.
Wang D et al.·Front Genet
2026🔓 Open AccessCase report
Hypoxia promotes progression of cervical cancer by modulating the ATXN3-enhanced P53 stability or STAT5 phosphorylation.
Zhang R et al.·Cell Death Discov
2026🔓 Open Access
Repeat Variants, Biomarkers, and Molecular Signatures in Parkinson's Disease: ATXN2, ATXN3, CACNA1A, PRNP, TBP, C9ORF72, TOMM40, APOE, and POLG-A Swedish Perspective.
Laffita-Mesa JM et al.·Int J Mol Sci
2025🔓 Open Access
Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers and druggable targets for spinocerebellar ataxia type 3.
Liu C et al.·BMC Neurol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools