ATXN1

Chr 6AD

ataxin 1

Also known as: ATX1, D6S504E, SCA1

NCBI Gene: 6310 ENSG00000124788 UniProt: P54253 OMIM: 601556

ATXN1 encodes a chromatin-binding factor that represses Notch signaling and may be involved in RNA metabolism and brain development. Mutations cause spinocerebellar ataxia type 1 (SCA1), an autosomal dominant cerebellar ataxia characterized by progressive degeneration of the cerebellum, brainstem and spinal cord. The pathogenic mechanism involves expansion of CAG repeats (40-83 repeats versus 6-39 normal) in the coding region, producing an elongated polyglutamine tract in the protein.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames. [provided by RefSeq, Nov 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.321 OMIM phenotype

Clinical Summary— ATXN1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 116 VUS of 191 total submissions

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GeneReview available — ATXN1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.975

Z-score 4.03

OE 0.12 (0.06–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.25Z-score

OE missense 0.84 (0.78–0.91)

434 obs / 513.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.32)

0≤0.351.4

Missense OE?0.84 (0.78–0.91)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 3 / 24.6Missense obs/exp: 434 / 513.8Syn Z: -1.98

This gene — mechanism propensity

0.2598th %ile

GOF

0.2398th %ile

LOF

0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function 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.

LOFprediction above median · 1 literature citation · LOEUF 0.32

GOF1 literature citation

Literature Evidence

GOFToxic gain-of-function mutations in ATXN1 cause the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1).1

LOFHaploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability.2

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

191 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS116

Likely Benign41

Benign18

Conflicting5

Pathogenic

116

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	0	0	0	0	0
VUS	6	107	2	1	116
Likely Benign	0	29	2	10	41
Benign	1	12	1	4	18
Conflicting	—				5
Total	7	148	6	15	181

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap ATXN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →