SETX

Chr 9ADAR

senataxin

Also known as: ALS4, AOA2, SCAN2, SCAR1, STEX, Sen1, bA479K20.2

NCBI Gene: 23064ENSG00000107290UniProt: Q7Z333

This gene encodes a protein named for its homology to the Sen1p protein of fungi which has RNA helicase activity encoded by a domain at the C-terminal end of the protein. The protein encoded by this gene contains a DNA/RNA helicase domain at its C-terminal end which suggests that it may be involved in both DNA and RNA processing. Mutations in this gene have been associated with ataxia-ocular apraxia-2 (AOA2) and an autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS4). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 4, juvenileMIM #602433
AD
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2MIM #606002
AR
675
ClinVar variants
23
Pathogenic / LP
0.95
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SETX
🧬
Gene-Disease Validity (ClinGen)
distal hereditary motor neuropathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 315 VUS of 675 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.30LOEUF
pLI 0.955
Z-score 7.45
OE 0.21 (0.14–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
-0.11Z-score
OE missense 1.01 (0.96–1.05)
1392 obs / 1380.3 exp
Tolerant

Tolerant to missense variation

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.0.21 (0.14–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.96–1.05)
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.1.11
0≤1.21.6
LoF obs/exp: 21 / 102.3Missense obs/exp: 1392 / 1380.3Syn Z: -1.95

ClinVar Variant Classifications

675 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic14
VUS315
Likely Benign200
Benign100
Conflicting37
9
Pathogenic
14
Likely Pathogenic
315
VUS
200
Likely Benign
100
Benign
37
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
3
0
9
Likely Pathogenic
9
1
4
0
14
VUS
2
279
31
3
315
Likely Benign
0
39
80
81
200
Benign
0
40
43
17
100
Conflicting
—37
Total17359161101675

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

View in ClinVar →

Protein Context — Lollipop Plot

SETX · 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
SENATAXIN; SETX
MIM #608465 · *

Amyotrophic lateral sclerosis 4, juvenile

MIM #602433

Molecular basis of disorder known

Autosomal dominant

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

MIM #606002

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SETX
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.
Coutelier M et al.·JAMA Neurol
2018
Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.
Martínez-Rubio D et al.·Int J Mol Sci
2023
Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.
Winkelsas A et al.·HGG Adv
2025
Juvenile Amyotrophic Lateral Sclerosis: A Review.
Lehky T et al.·Genes (Basel)
2021Review
Genetic approach in amyotrophic lateral sclerosis.
Cervantes-Aragón I et al.·Gac Med Mex
2019Review
Clinical and Genetic Characterization of Brazilian Patients with Ataxia and Oculomotor Apraxia.
da Costa SCG et al.·Mov Disord
2022Cohort
Senataxin RNA/DNA helicase promotes replication restart at co-transcriptional R-loops to prevent MUS81-dependent fork degradation.
Rao S et al.·Nucleic Acids Res
2024
Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.
De Michele G et al.·Cerebellum
2024Review
Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration.
Groh M et al.·J Mol Biol
2017Review
Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.
Kannan A et al.·Brain
2022Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Amyotrophic Lateral Sclerosis Type 4Inherited Neurological Disorders of RNA Processing

Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing

RECRUITING
NCT04394871National Institute of Neurological Disorders and Stroke (NINDS)Started 2020-12-14

External Resources

Links to major genomics databases and tools