THAP1

Chr 8AD

THAP domain containing 1

Also known as: DYT6

NCBI Gene: 55145 ENSG00000131931 UniProt: Q9NVV9 OMIM: 609520

The THAP1 protein contains a conserved DNA-binding domain and functions as a proapoptotic factor that colocalizes with apoptosis response proteins in nuclear bodies. Mutations cause dystonia 6, a form of torsion dystonia, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function mutations, suggesting haploinsufficiency as the likely disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.491 OMIM phenotype

Clinical Summary— THAP1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.

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ClinVar Variants

48 unique Pathogenic / Likely Pathogenic· 95 VUS of 212 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — THAP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.37Z-score

OE missense 0.64 (0.53–0.78)

74 obs / 115.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.49)

0≤0.351.4

Missense OE?0.64 (0.53–0.78)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 1 / 9.7Missense obs/exp: 74 / 115.5Syn Z: 0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTHAP1-related dystonia, torsionLOFAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.3491th %ile

LOF

0.56top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 56% of P/LP variants are LoF · LOEUF 0.49

Literature Evidence

LOFDystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss-of-function mutations in the zinc finger transcription factor THAP1.1

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 30590536 ↗

ClinVar Variant Classifications

212 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic21

VUS95

Likely Benign34

Benign21

Conflicting12

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	8	2	0	27
Likely Pathogenic	10	11	0	0	21
VUS	2	67	26	0	95
Likely Benign	0	2	9	23	34
Benign	0	1	19	1	21
Conflicting	—				12
Total	29	89	56	24	210

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap THAP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →