ATN1

Chr 12AD

atrophin 1

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

NCBI Gene: 1822ENSG00000111676UniProt: P54259

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]

Primary Disease Associations & Inheritance

Congenital hypotonia, epilepsy, developmental delay, and digital anomaliesMIM #618494
AD
Dentatorubral-pallidoluysian atrophyMIM #125370
AD
421
ClinVar variants
59
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— ATN1
⚡
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.
📋
ClinVar Variants
59 Pathogenic / Likely Pathogenic· 252 VUS of 421 total submissions
💊
Clinical Trials
4 active or recruiting trials — 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.
0.19LOEUF
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?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.
1.76Z-score
OE missense 0.81 (0.76–0.87)
567 obs / 698.0 exp
Tolerant

Mild missense constraint

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.0.07 (0.03–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.76–0.87)
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.0.91
0≤1.21.6
LoF obs/exp: 3 / 40.0Missense obs/exp: 567 / 698.0Syn Z: 1.25

ClinVar Variant Classifications

421 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
Likely Pathogenic9
VUS252
Likely Benign75
Benign19
Conflicting16
50
Pathogenic
9
Likely Pathogenic
252
VUS
75
Likely Benign
19
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
47
0
50
Likely Pathogenic
0
4
5
0
9
VUS
14
211
26
1
252
Likely Benign
0
26
16
33
75
Benign
1
5
7
6
19
Conflicting
—16
Total1524910140421

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

View in ClinVar →

Protein Context — Lollipop Plot

ATN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ATN1-related congenital hypotonia, epilepsy, developmental delay, digit abnormalities

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ATROPHIN 1; ATN1
MIM #607462 · *

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies

MIM #618494

Molecular basis of disorder known

Autosomal dominant

Dentatorubral-pallidoluysian atrophy

MIM #125370

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ATN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A novel variant in the HX repeat motif of ATN1 in a Chinese patient with CHEDDA syndrome and literature review.
Luo S et al.·Mol Genet Genomic Med
2022Review
Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study.
Ibañez K et al.·Lancet Neurol
2022
Dentatorubral-pallidoluysian Atrophy: An Update.
Carroll LS et al.·Tremor Other Hyperkinet Mov (N Y)
2018Review
Pallidal degenerations and related disorders: an update.
Jellinger KA·J Neural Transm (Vienna)
2022Review
Pathological accumulation of atrophin-1 in dentatorubralpallidoluysian atrophy.
Suzuki Y et al.·Int J Clin Exp Pathol
2011Review
Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients.
Yuan RY et al.·Ann Neurol
2025Cohort
Atrophin-1 Function and Dysfunction in Dentatorubral-Pallidoluysian Atrophy.
Nowak B et al.·Mov Disord
2023Review
ATN1-related infantile developmental and epileptic encephalopathy responding to Ketogenic diet.
Xie Y et al.·Seizure
2024Case report
Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington's disease and without mutation in the IT15 gene.
Sułek-Piatkowska A et al.·Neurol Neurochir Pol
2008Cohort
Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype.
Costa MDC et al.·J Hum Genet
2006Cohort
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
Dentatorubral-Pallidoluysian Atrophy

Dentatorubral-pallidoluysian Atrophy Natural History and Biomarkers Study

RECRUITING
NCT06273150University College, LondonStarted 2022-05-01
Positive genetic test for pathological expansion in ATN1
Dentatorubral-Pallidoluysian Atrophy

Personalized Antisense Oligonucleotide for A Single Participant With ATN1 Gene Mutation

ACTIVE NOT RECRUITING
NCT07084311Phase PHASE1, PHASE2n-Lorem FoundationStarted 2024-10-24
nL-ATN1-002
Dentatorubral-Pallidoluysian Atrophy

Personalized Antisense Oligonucleotide Therapy for a Single Participant with ATN1 Gene Mutation

ACTIVE NOT RECRUITING
NCT06706388Phase PHASE1, PHASE2n-Lorem FoundationStarted 2024-02-21
nL-ATN1-002
Dentatorubral-Pallidoluysian Atrophy

Personalized Antisense Oligonucleotide for A Single Participant (nL62541) With ATN1 Gene Mutation

NOT YET RECRUITING
NCT07221760Phase PHASE1, PHASE2n-Lorem FoundationStarted 2025-11
nL-ATN1-001

External Resources

Links to major genomics databases and tools