ATXN1

Chr 6AD

ataxin 1

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism (PubMed:21475249). In concert with CIC and ATXN1L, involved in brain development (By similarity)

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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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