ATN1

Chr 12AD

atrophin 1

Also known as: B37, CHEDDA, D12S755E, DRPLA, HRS, NOD

NCBI Gene: 1822 ENSG00000111676 UniProt: P54259 OMIM: 607462

This gene encodes atrophin-1, a transcriptional corepressor that recruits other proteins to repress gene transcription and promotes vascular smooth muscle cell migration. Mutations cause dentatorubral-pallidoluysian atrophy (DRPLA), a neurodegenerative disorder with cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia, as well as a congenital form with hypotonia, epilepsy, developmental delay, and digital anomalies. The inheritance pattern is autosomal dominant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.192 OMIM phenotypes

Clinical Summary— ATN1

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Gene-Disease Validity (ClinGen)

dentatorubral-pallidoluysian atrophy · 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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 244 VUS of 387 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ATN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.42

OE 0.07 (0.03–0.19)

Highly constrained

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

Missense Constraint?

1.76Z-score

OE missense 0.81 (0.76–0.87)

567 obs / 698.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.19)

0≤0.351.4

Missense OE?0.81 (0.76–0.87)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 3 / 40.0Missense obs/exp: 567 / 698.0Syn Z: 1.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATN1-related congenital hypotonia, epilepsy, developmental delay, digit abnormalitiesOTHERAD

This gene — mechanism propensity

0.2599th %ile

GOF

0.1699th %ile

LOF

0.90top 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 · LOEUF 0.19

GOF1 literature citation · 80% of P/LP are missense

Literature Evidence

GOFPolyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function.1

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

References

1.PMID 30827498 ↗

ClinVar Variant Classifications

387 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic8

VUS244

Likely Benign77

Benign19

Conflicting16

Pathogenic

Likely Pathogenic

244

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	4	3	0	7
Likely Pathogenic	0	8	0	0	8
VUS	16	224	3	1	244
Likely Benign	0	39	4	34	77
Benign	1	7	5	6	19
Conflicting	—				16
Total	17	282	15	41	371

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

View in ClinVar →

47 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap ATN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →