THAP1

Chr 8AD

THAP domain containing 1

Also known as: DYT6

NCBI Gene: 55145ENSG00000131931UniProt: Q9NVV9

The protein encoded by this gene contains a THAP domain, a conserved DNA-binding domain. This protein colocalizes with the apoptosis response protein PAWR/PAR-4 in promyelocytic leukemia (PML) nuclear bodies, and functions as a proapoptotic factor that links PAWR to PML nuclear bodies. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Dystonia 6, torsionMIM #602629
AD
271
ClinVar variants
98
Pathogenic / LP
0.80
pLI score
0
Active trials
Clinical Summary— THAP1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
98 Pathogenic / Likely Pathogenic· 105 VUS of 271 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.49LOEUF
pLI 0.801
Z-score 2.59
OE 0.10 (0.04–0.49)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.37Z-score
OE missense 0.64 (0.53–0.78)
74 obs / 115.5 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.0.10 (0.04–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.53–0.78)
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.0.90
0≤1.21.6
LoF obs/exp: 1 / 9.7Missense obs/exp: 74 / 115.5Syn Z: 0.52

ClinVar Variant Classifications

271 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic24
VUS105
Likely Benign34
Benign22
Conflicting12
74
Pathogenic
24
Likely Pathogenic
105
VUS
34
Likely Benign
22
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
7
52
2
74
Likely Pathogenic
6
10
8
0
24
VUS
2
64
39
0
105
Likely Benign
0
2
9
23
34
Benign
0
1
20
1
22
Conflicting
—12
Total218412826271

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

View in ClinVar →

Protein Context — Lollipop Plot

THAP1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

THAP1-related dystonia, torsion

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Dystonia 6, torsion

MIM #602629

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — THAP1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dystonia.
Balint B et al.·Nat Rev Dis Primers
2018Review
Genetics and Pathogenesis of Dystonia.
Thomsen M et al.·Annu Rev Pathol
2024Review
Genetic Update and Treatment for Dystonia.
Koptielow J et al.·Int J Mol Sci
2024Review
Dystonia.
Morgante F et al.·Continuum (Minneap Minn)
2013Review
Genetics in dystonia.
Klein C·Parkinsonism Relat Disord
2014Review
Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases.
LeDoux MS et al.·Parkinsonism Relat Disord
2012Review
THAP1 mutations and dystonia phenotypes: genotype phenotype correlations.
Xiromerisiou G et al.·Mov Disord
2012Review
The genetics of dystonias.
LeDoux MS·Adv Genet
2012Review
Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review.
Gómez-Garre P et al.·Eur J Neurol
2021Review
Isolated dystonia: clinical and genetic updates.
Domingo A et al.·J Neural Transm (Vienna)
2021Review
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools