TOR1A

Chr 9

torsin family 1 member A

Also known as: AMC5, DQ2, DYT1

NCBI Gene: 1861 ENSG00000136827 UniProt: O14656

The protein is an AAA family ATPase located in the endoplasmic reticulum lumen and expressed prominently in the substantia nigra pars compacta. Mutations cause torsion dystonia 1 (DYT1), which follows autosomal dominant inheritance with reduced penetrance, as well as autosomal recessive arthrogryposis multiplex congenita 5. The pathogenic mechanism involves dominant-negative effects that disrupt normal protein function.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a member of the AAA family of adenosine triphosphatases (ATPases), is related to the Clp protease/heat shock family and is expressed prominently in the substantia nigra pars compacta. Mutations in this gene result in the autosomal dominant disorder, torsion dystonia 1. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.06

Clinical Summary— TOR1A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 143 VUS of 268 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 — TOR1A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.001

Z-score 1.43

OE 0.56 (0.32–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.54Z-score

OE missense 0.89 (0.78–1.01)

160 obs / 180.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.32–1.06)

0≤0.351.4

Missense OE?0.89 (0.78–1.01)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 7 / 12.4Missense obs/exp: 160 / 180.2Syn Z: -0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTOR1A-related arthrogryposis multiplex congenitaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.82top 10%

GOF

0.6150th %ile

LOF

0.2190th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNEffect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 15505207 ↗

ClinVar Variant Classifications

268 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic11

VUS143

Likely Benign67

Benign27

Conflicting9

Pathogenic

Likely Pathogenic

143

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	10	1	0	0	11
VUS	9	109	23	2	143
Likely Benign	0	6	23	38	67
Benign	0	1	24	2	27
Conflicting	—				9
Total	22	119	70	42	262

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap TOR1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →