SETX

Chr 9

senataxin

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

NCBI Gene: 23064 ENSG00000107290 UniProt: Q7Z333

This gene encodes a protein with DNA/RNA helicase activity that processes both DNA and RNA. Mutations cause either autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) or autosomal recessive spinocerebellar ataxia with axonal neuropathy (ataxia-ocular apraxia-2). The pathogenic mechanism involves disrupted DNA and RNA processing due to loss of helicase function.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.30

Clinical Summary— SETX

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Gene-Disease Validity (ClinGen)

distal hereditary motor neuropathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

57 unique Pathogenic / Likely Pathogenic· 642 VUS of 1280 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SETX

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

-0.11Z-score

OE missense 1.01 (0.96–1.05)

1392 obs / 1380.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.21 (0.14–0.30)

0≤0.351.4

Missense OE?1.01 (0.96–1.05)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 21 / 102.3Missense obs/exp: 1392 / 1380.3Syn Z: -1.95

This gene — mechanism propensity

0.4388th %ile

GOF

0.2497th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF82% of P/LP variants are LoF · LOEUF 0.30

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNWorking synergistically, the N603D-Q653K mutations may confer a partial dominant negative effect, acting on the senataxin N-terminal, further expanding the phenotypic spectrum associated with Senataxin mutations.1

GOFA cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function.INTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease prog2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1280 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic31

VUS642

Likely Benign337

Benign105

Conflicting114

Pathogenic

Likely Pathogenic

642

VUS

337

Likely Benign

105

Benign

114

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	1	5	0	26
Likely Pathogenic	27	3	1	0	31
VUS	17	594	28	3	642
Likely Benign	2	61	101	173	337
Benign	0	68	7	30	105
Conflicting	—				114
Total	66	727	142	206	1,255

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap SETX — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →