THAP1

Summary

THAP1 (THAP domain containing 1, HGNC:20856) is a protein-coding gene on chromosome 8p11.21, encoding THAP domain-containing protein 1 (Q9NVV9). DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression. It is a selective cancer dependency (DepMap: 88.0% of cell lines).

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.

Source: NCBI Gene 55145 — RefSeq curated summary.

At a glance

• Gene–disease (curated): torsion dystonia 6 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 213 total — 27 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 18
• Cancer dependency (DepMap): dependent in 88.0% of screened cell lines
• MANE Select transcript: NM_018105

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20856
Approved symbol	THAP1
Name	THAP domain containing 1
Location	8p11.21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10477, 4833431A01Rik
Ensembl gene	ENSG00000131931
Ensembl biotype	protein_coding
OMIM	609520
Entrez	55145

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000254250, ENST00000345117, ENST00000529779, ENST00000532093, ENST00000934698, ENST00000934699, ENST00000934700

RefSeq mRNA: 2 — MANE Select: NM_018105 NM_018105, NM_199003

CCDS: CCDS6136, CCDS6137

Canonical transcript exons

ENST00000254250 — 3 exons

Exon	Start	End
ENSE00000901799	42843024	42843325
ENSE00001090345	42839186	42839381
ENSE00002195192	42836674	42838336

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 89.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.2349 / max 110.7990, expressed in 1798 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92933	9.2637	1769
92930	3.6651	1506
92934	0.9958	671
92932	0.2186	76
92931	0.0917	26

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	89.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.47	gold quality
calcaneal tendon	UBERON:0003701	84.19	gold quality
buccal mucosa cell	CL:0002336	83.62	gold quality
choroid plexus epithelium	UBERON:0003911	82.89	gold quality
monocyte	CL:0000576	82.80	gold quality
leukocyte	CL:0000738	82.60	gold quality
mononuclear cell	CL:0000842	82.50	gold quality
cortical plate	UBERON:0005343	82.42	gold quality
muscle of leg	UBERON:0001383	81.75	gold quality
gastrocnemius	UBERON:0001388	81.69	gold quality
ganglionic eminence	UBERON:0004023	81.33	gold quality
islet of Langerhans	UBERON:0000006	81.17	gold quality
hair follicle	UBERON:0002073	80.79	silver quality
muscle organ	UBERON:0001630	80.50	gold quality
skeletal muscle organ	UBERON:0014892	80.50	gold quality
heart right ventricle	UBERON:0002080	80.49	gold quality
biceps brachii	UBERON:0001507	80.06	gold quality
ventricular zone	UBERON:0003053	79.70	gold quality
heart left ventricle	UBERON:0002084	79.35	gold quality
cardiac ventricle	UBERON:0002082	79.19	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.64	gold quality
lower esophagus muscularis layer	UBERON:0035833	78.52	gold quality
lower esophagus	UBERON:0013473	78.50	gold quality
granulocyte	CL:0000094	78.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.44	gold quality
stromal cell of endometrium	CL:0002255	78.36	gold quality
vastus lateralis	UBERON:0001379	78.28	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CCAR1
RRM1	Unknown
TOR1A	Repression

JASPAR motifs

Motif	Name	Family
MA0597.1	THAP1	THAP-related factors
MA0597.2	THAP1	THAP-related factors
MA0597.3	THAP1	THAP-related factors

JASPAR matrix evidence (PMIDs): PMID:15863623

miRNA regulators (miRDB)

103 targeting THAP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 88.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• FDG PET was used to scan [brain glucose metabolism] in 12 nonmanifesting and 11 manifesting DYT1 gene carriers, 6 nonmanifesting DYT6 gene carriers and 7 manifesting DYT6 gene carriers (PMID:15111678)
• the THAP domain of THAP1 is a zinc-dependent DNA-binding domain (PMID:15863623)
• DYT6 carriers had abnormally elevated scores in the torsion dystonia-related pattern. (PMID:16366514)
• the DYT6 gene is in a 23 cM region on chromosome 8q21-22 and does not account for all familial primary torsion dystonia in Amish-Mennonites (PMID:17702011)
• data represent the first structure-function analysis of a functional THAP domain, with demonstrated sequence-specific DNA binding activity (PMID:18073205)
• Discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary torsion dystonia (also known as DYT6 dystonia). (PMID:19182804)
• Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. (PMID:19345147)
• Although mutations in THAP1 might have only a minor role in patients with different, but mainly focal, forms of dystonia, they do seem to be associated with early-onset generalised dystonia with spasmodic dysphonia. (PMID:19345148)
• THAP1 mutations may be present in sporadic, early-onset, cervical, and generalized dystonia. (PMID:19908320)
• The results of this study expand the mutational spectrum of DYT6-PTD and implicate that this genetic form of dystonia is rare in Italy. (PMID:19908325)
• A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia. (PMID:20083799)
• The THAP zinc finger uses its double-stranded beta-sheet to fill the DNA major groove and provides a unique combination of contacts from the beta-sheet, the N-terminal tail and surrounding loops toward the five invariant base pairs of the THABS sequence (PMID:20144952)
• THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. (PMID:20200153)
• These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations. (PMID:20211909)
• These findings suggest that THAP1 sequence variations in primary dystonia seem to be associated with different ages of onset and distribution of symptoms (PMID:20669277)
• The variant of THAP1( c.71+9C>A) in intron 19 was found in 3 late onset dystonia patients (0.6%) and one control subject (0.5%). (PMID:20687191)
• Three subjects were found to have the GAG deletion in the TOR1A gene, and two patients were detected with THAP1 gene mutations/variations (PMID:20825472)
• This study demonstrated a physical interaction between THAP1 and the TOR1A promoter that is abolished by pathophysiologic mutations. (PMID:20865765)
• Mutations in these two known primary torsion dystonia (PTD) genes, TOR1A and THAP1, are responsible for about 10% of the PTD cases in our Brazilian cohort suggesting genetic heterogeneity and supporting the role of other genes in PTD. (PMID:20925076)
• found five heterozygous mutations in THAP1 in autosomal dominant primary torsion dystonia 6 (PMID:21110056)
• This study indicated that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians. (PMID:21370264)
• The data of this study suggested that homozygous THAP1 mutations cause dystonia and may be associated with a less severe dysfunction of the encoded protein compared with heterozygous disease-causing mutations. (PMID:21425335)
• This study demonistrated that Truncating mutations in THAP1 define the nuclear localization signal. (PMID:21495072)
• this study presented that the DYT6 phenotypes in association with new THAP1 frameshift mutations. (PMID:21520283)
• This study demonistrated that THAP1 mutations are infrequent in spasmodic dysphonia in Dutch patient. (PMID:21538522)
• Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African-Americans (PMID:21601506)
• The results of this study suggested that No evidence for THAP1/DYT6 variants as disease modifiers in DYT1 dystonia. (PMID:21638323)
• These observations offer additional insight into the role of the coiled-coil domain in THAP1, which may facilitate future analyses of DYT6 mutations in this region (PMID:21752024)
• THAP1 mutations do not seem to play a major role in primary focal/segmental dystonia in this sample of southern German origin. (PMID:21782490)
• the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of DYT6 dystonia ( THAP1 ) (PMID:21793105)
• One silent mutation (c.267G>A) was shown to affect THAP1 expression. (PMID:21800139)
• Mutation frequency of the THAP1 gene is 0.87% in Chinese patients with primary pure dystonia, similar to the mutation frequency found in other ethnic groups. (PMID:21839475)
• THAP1 mutations are rare in unselected dystonia patients and functional analysis is necessary to distinguish between benign variants and pathogenic mutations. (PMID:21847143)
• THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1. (PMID:22377579)
• The role of THAP1 as a major genetic modifier in DYT1 dystonia and suggest the presence of other genetic or environmental factors that may influence the manifestation of DYT1 dystonia. (PMID:22508326)
• Truncated THAP1 mutations (F22fs71X and F25fs53X) can alter subcellular distributions in DYT6 dystonia, while some missense mutations (C54F and L180S) cannot. (PMID:22652465)
• this study demonstrated marked intrafamilial variations of dystonia in a single Japanese family with DYT6 and limited efficiency of deep brain stimulation. (PMID:22821615)
• Evaluation of the effect of missense mutations, within the THAP domain, on the structure, stability and DNA binding. (PMID:22844099)
• This study supported that THAP1 mutations are an important cause of dystonia. (PMID:22903657)
• in dystonia DYT1 and DYT6 gene mutation carriers, diffusion tensor imaging detected fewer fibers in the cerebello-thalamo-cortical pathways (PMID:22987473)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Thap1	ENSMUSG00000037214
rattus_norvegicus	Thap1	ENSRNOG00000056956
drosophila_melanogaster	CG13894	FBGN0035157

Paralogs (7): THAP3 (ENSG00000041988), ARL14EP (ENSG00000152219), THAP8 (ENSG00000161277), THAP2 (ENSG00000173451), THAP6 (ENSG00000174796), THAP7 (ENSG00000184436), ARL14EPL (ENSG00000268223)

Protein

Protein identifiers

THAP domain-containing protein 1 — Q9NVV9 (reviewed: Q9NVV9)

All UniProt accessions (2): E9PIS9, Q9NVV9

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression. Specifically binds the 5’-[AT]NTNN[GT]GGCA[AGT]-3’ core DNA sequence and acts by modulating expression of pRB-E2F cell-cycle target genes, including RRM1. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. May also have pro-apoptotic activity by potentiating both serum-withdrawal and TNF-induced apoptosis.

Subunit / interactions. Homodimer. Interacts with PAWR. Component of a THAP1/THAP3-HCFC1-OGT complex that contains, either THAP1 or THAP3, HCFC1 and OGT. Interacts with OGT. Interacts (via the HBM) with HCFC1 (via the Kelch-repeat domain); the interaction recruits HCFC1 to the RRM1 promoter.

Subcellular location. Nucleus. Nucleoplasm. PML body.

Tissue specificity. Highly expressed in heart, skeletal muscle, kidney and liver. Weaker expression in brain and placenta.

Disease relevance. Dystonia 6, torsion (DYT6) [MIM:602629] A primary torsion dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Dystonia type 6 is characterized by onset in early adulthood, cranial or cervical involvement in about half of the cases, and frequent progression to involve multiple body regions. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the THAP1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NVV9-1	1	yes
Q9NVV9-2	2

RefSeq proteins (2): NP_060575, NP_945354 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006612	THAP_Znf	Domain
IPR026516	THAP1/10	Family
IPR038441	THAP_Znf_sf	Homologous_superfamily

Pfam: PF05485

UniProt features (108 total): sequence variant 46, mutagenesis site 42, strand 6, helix 4, splice variant 2, sequence conflict 2, chain 1, zinc finger region 1, turn 1, region of interest 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2JTG	SOLUTION NMR
2KO0	SOLUTION NMR
2L1G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVV9-F1	71.61	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (42):

Position	Phenotype
4	does not affect dna-binding.
5	abolishes dna- and zinc-binding.
6	does not affect dna-binding.
8	does not affect dna-binding.
10	abolishes dna- and zinc-binding.
11	partially affects dna-binding.
16	does not affect dna-binding.
24	strongly affects dna-binding.
26	abolishes dna- and zinc-binding.
27	partially affects dna-binding.
28–30	strongly affects dna-binding.
28	does not affect dna-binding.
29	strongly affects dna-binding.
30	does not affect dna-binding.
31	does not affect dna-binding.
32	does not affect dna-binding.
33	does not affect dna-binding.
34	does not affect dna-binding.
35	does not affect dna-binding.
36	abolishes dna- and zinc-binding.
37	partially affects dna-binding.
40	partially affects dna-binding.
41–43	strongly affects dna-binding.
41	does not affect dna-binding.
42	strongly affects dna-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 161 (showing top): YY1_Q6, YY1_02, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MITOTIC_CELL_CYCLE, CCCNNNNNNAAGWT_UNKNOWN, GOBP_EPITHELIAL_CELL_PROLIFERATION, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, CTCAAGA_MIR526B, GCCATNTTG_YY1_Q6, GOCC_NUCLEAR_BODY, GRYDER_PAX3FOXO1_TOP_ENHANCERS, GOCC_PML_BODY, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, ATGGYGGA_UNKNOWN

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), endothelial cell proliferation (GO:0001935), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), regulation of mitotic cell cycle (GO:0007346)

GO Molecular Function (11): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), PML body (GO:0016605)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
negative regulation of DNA-templated transcription	1
epithelial cell proliferation	1
gene expression	1
RNA biosynthetic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
mitotic cell cycle	1
regulation of cell cycle	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
transition metal ion binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
DNA binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear body	1

Protein interactions and networks

STRING

1020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THAP1	TOR1A	O14656	958
THAP1	THAP11	Q96EK4	905
THAP1	THAP12	O43422	891
THAP1	PAWR	Q96IZ0	887
THAP1	THAP7	Q9BT49	865
THAP1	SGCE	O43556	852
THAP1	GNAL	P38405	807
THAP1	ANO3	Q9BYT9	777
THAP1	CIZ1	Q9ULV3	764
THAP1	RRM1	P23921	745
THAP1	HPCA	P32076	729
THAP1	TUBB4A	P04350	670
THAP1	PRKRA	O75569	664
THAP1	GCH1	P30793	656
THAP1	DRD2	P14416	637

IntAct

478 interactions, top by confidence:

A	B	Type	Score
THAP1	NUP62	psi-mi:“MI:0915”(physical association)	0.890
THAP1	THAP1	psi-mi:“MI:0915”(physical association)	0.870
NTAQ1	THAP1	psi-mi:“MI:0915”(physical association)	0.830
THAP1	NTAQ1	psi-mi:“MI:0915”(physical association)	0.830
THAP1	ZCCHC10	psi-mi:“MI:0915”(physical association)	0.790
ZCCHC10	THAP1	psi-mi:“MI:0915”(physical association)	0.790
THAP1	CSNK2A1	psi-mi:“MI:0915”(physical association)	0.780
THAP1	STRBP	psi-mi:“MI:0915”(physical association)	0.780
MMTAG2	THAP1	psi-mi:“MI:0915”(physical association)	0.780
BAG5	THAP1	psi-mi:“MI:0915”(physical association)	0.780
CSNK2A1	THAP1	psi-mi:“MI:0915”(physical association)	0.780
STRBP	THAP1	psi-mi:“MI:0915”(physical association)	0.780
THAP1	MMTAG2	psi-mi:“MI:0915”(physical association)	0.780
THAP1	BAG5	psi-mi:“MI:0915”(physical association)	0.780
THAP1	TRAF5	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (184): THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid), THAP1 (Two-hybrid)

ESM2 similar proteins: A4IGQ8, B0BLU1, B5XCB8, O75113, O75132, P14629, Q0IIM1, Q0V8G8, Q17RS7, Q1JPT7, Q1RMM0, Q28GK6, Q28J92, Q3T0G1, Q4R3Q6, Q4R7M0, Q4V7W2, Q5FWF4, Q5NVM3, Q5QJC4, Q5RCE4, Q5SZJ8, Q5U208, Q5U560, Q5ZHN5, Q6A037, Q6DDT6, Q6DIN8, Q6INS5, Q6IR68, Q6NZP1, Q6PFX2, Q6TGZ4, Q7Z6K1, Q7ZYM8, Q80XJ2, Q86VD1, Q8BMI4, Q8BZ05, Q8C4P0

Diamond homologs: B5XCB8, Q0IHI7, Q0P5B4, Q1JPT7, Q1RMM0, Q2TBI2, Q3T0G1, Q4R3Q6, Q4R7M0, Q5RCE4, Q5U208, Q5U560, Q5ZHN5, Q642B6, Q6DDT6, Q6DIN8, Q6P3Z3, Q7Z6K1, Q8BJ25, Q8CHW1, Q8WTV1, Q8WY91, Q9D305, Q9H0W7, Q9NVV9, Q8NA92, Q9H5L6, Q8VCZ3, Q9BT49, A0PT73, A0QIQ0, A0R6J8, A1KM55, A1T297, A3PTJ4, A5U669, B2HLY1, O64527, P9WFG6, P9WFG7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA Splicing - Major Pathway	6	12.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

213 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	13
Uncertain significance	95
Likely benign	28
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1405735	NM_018105.3(THAP1):c.1A>T (p.Met1Leu)	Pathogenic
1406166	NM_018105.3(THAP1):c.108G>A (p.Trp36Ter)	Pathogenic
1457202	NM_018105.3(THAP1):c.348del (p.Ile116fs)	Pathogenic
1458222	NC_000008.10:g.(?42693105)(42698237_?)del	Pathogenic
1647	NM_018105.3(THAP1):c.460del (p.Gln154fs)	Pathogenic
1649	NM_018105.3(THAP1):c.388_389del (p.Val131fs)	Pathogenic
1650	NM_018105.3(THAP1):c.474del (p.Lys158fs)	Pathogenic
1651	NM_018105.3(THAP1):c.25G>T (p.Gly9Cys)	Pathogenic
2113153	NM_018105.3(THAP1):c.115_116insGGCCGGGAGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAGAATGGGAGGCAG (p.Ala38_Ala39insGlyProGlyAlaValAlaHisAlaCysAsnProSerThrLeuGlyGlyArgGlyGlyArgIleThrArgSerXaaXaaXaaXaaLysLysLysLysLysLysLysGluTrpGluAla)	Pathogenic
2584745	NM_018105.3(THAP1):c.134T>G (p.Phe45Cys)	Pathogenic
2816229	NM_018105.3(THAP1):c.100_101insCA (p.Lys34fs)	Pathogenic
31631	NM_018105.3(THAP1):c.70A>G (p.Lys24Glu)	Pathogenic
31632	NM_018105.3(THAP1):c.68A>C (p.His23Pro)	Pathogenic
3720817	NM_018105.3(THAP1):c.63_66del (p.Phe22fs)	Pathogenic
4072017	NM_018105.3(THAP1):c.62C>G (p.Ser21Cys)	Pathogenic
4687251	NC_000008.10:g.(42693480_42694328)_(42694525_42698166)del	Pathogenic
532261	NM_018105.3(THAP1):c.131del (p.Asn44fs)	Pathogenic
532262	NM_018105.3(THAP1):c.289C>T (p.Gln97Ter)	Pathogenic
532263	NM_018105.3(THAP1):c.7C>T (p.Gln3Ter)	Pathogenic
568461	NM_018105.3(THAP1):c.305dup (p.Pro103fs)	Pathogenic
582441	NM_018105.3(THAP1):c.2T>C (p.Met1Thr)	Pathogenic
654563	NM_018105.3(THAP1):c.331C>T (p.Gln111Ter)	Pathogenic
807516	NM_018105.3(THAP1):c.112del (p.Ala38fs)	Pathogenic
817036	NM_018105.3(THAP1):c.135_139delinsGGGTTTA (p.Phe45fs)	Pathogenic
845954	NM_018105.3(THAP1):c.71del (p.Lys24fs)	Pathogenic
871563	NM_018105.3(THAP1):c.390dup (p.Val131fs)	Pathogenic
871843	NM_018105.3(THAP1):c.197_198del (p.Glu66fs)	Pathogenic
2497671	NM_018105.3(THAP1):c.190_191del (p.Lys64fs)	Likely pathogenic
2684079	NM_018105.3(THAP1):c.86G>A (p.Arg29Gln)	Likely pathogenic
2735166	NM_018105.3(THAP1):c.46A>G (p.Lys16Glu)	Likely pathogenic

SpliceAI

384 predictions. Top by Δscore:

Variant	Effect	Δscore
8:42838333:CTTT:C	acceptor_gain	1.0000
8:42838336:TC:T	acceptor_loss	1.0000
8:42838337:C:CC	acceptor_gain	1.0000
8:42839180:TATTA:T	donor_loss	1.0000
8:42839182:TTACC:T	donor_loss	1.0000
8:42839183:TA:T	donor_loss	1.0000
8:42839184:ACC:A	donor_loss	1.0000
8:42839185:CCTTG:C	donor_loss	1.0000
8:42839382:C:CA	acceptor_loss	1.0000
8:42839382:C:CC	acceptor_gain	1.0000
8:42843013:AGGGT:A	donor_gain	1.0000
8:42843019:CTCA:C	donor_loss	1.0000
8:42843020:TCA:T	donor_loss	1.0000
8:42843021:CAC:C	donor_loss	1.0000
8:42843022:A:AC	donor_gain	1.0000
8:42843023:C:CG	donor_gain	1.0000
8:42843023:CTT:C	donor_gain	1.0000
8:42843045:T:TA	donor_gain	1.0000
8:42838334:TTT:T	acceptor_gain	0.9900
8:42838335:TT:T	acceptor_gain	0.9900
8:42838343:C:CT	acceptor_gain	0.9900
8:42838344:A:T	acceptor_gain	0.9900
8:42839184:A:AC	donor_gain	0.9900
8:42839185:C:CC	donor_gain	0.9900
8:42843017:T:TA	donor_gain	0.9900
8:42843023:CT:C	donor_gain	0.9900
8:42843023:CTTGT:C	donor_gain	0.9900
8:42843056:G:C	donor_gain	0.9900
8:42838348:A:C	acceptor_gain	0.9800
8:42839379:AACCT:A	acceptor_gain	0.9800

AlphaMissense

1405 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:42838116:A:G	L163P	1.000
8:42838128:A:G	L159P	1.000
8:42838149:A:G	L152P	1.000
8:42839220:G:C	P78R	1.000
8:42839220:G:T	P78H	1.000
8:42839221:G:A	P78S	1.000
8:42839221:G:T	P78T	1.000
8:42839238:A:G	L72P	1.000
8:42839238:A:T	L72Q	1.000
8:42839264:A:C	F63L	1.000
8:42839264:A:T	F63L	1.000
8:42839265:A:G	F63S	1.000
8:42839266:A:G	F63L	1.000
8:42839279:A:C	F58L	1.000
8:42839279:A:T	F58L	1.000
8:42839280:A:C	F58C	1.000
8:42839280:A:G	F58S	1.000
8:42839281:A:C	F58V	1.000
8:42839281:A:G	F58L	1.000
8:42839281:A:T	F58I	1.000
8:42839282:G:C	H57Q	1.000
8:42839282:G:T	H57Q	1.000
8:42839291:A:C	C54W	1.000
8:42839292:C:A	C54F	1.000
8:42839292:C:G	C54S	1.000
8:42839292:C:T	C54Y	1.000
8:42839293:A:C	C54G	1.000
8:42839293:A:G	C54R	1.000
8:42839293:A:T	C54S	1.000
8:42839295:A:C	I53S	1.000

dbSNP variants (sampled 300 via entrez): RS1000957050 (8:42842602 C>A), RS1002288190 (8:42840270 C>T), RS1002623346 (8:42838676 T>G), RS1003447588 (8:42840720 G>A), RS1003479030 (8:42843255 T>C), RS1003980881 (8:42841408 C>T), RS1004420264 (8:42844750 C>G,T), RS1004431759 (8:42845005 T>G), RS1004951353 (8:42840054 G>A), RS1005422213 (8:42843289 G>A,C,T), RS1005431946 (8:42843467 C>G,T), RS1005624341 (8:42836828 C>G), RS1005979423 (8:42838296 G>A,C), RS1006008614 (8:42838857 T>A,C), RS1006063298 (8:42839995 G>A,C)

Disease associations

OMIM: gene MIM:609520 | disease phenotypes: MIM:602629, MIM:620887

GenCC curated gene-disease

Disease	Classification	Inheritance
torsion dystonia 6	Strong	Autosomal dominant

Mondo (4): torsion dystonia 6 (MONDO:0011264), young-onset Parkinson disease (MONDO:0017279), multiple mitochondrial dysfunctions syndrome 9b (MONDO:0971174), dystonic disorder (MONDO:0003441)

Orphanet (2): Primary dystonia, DYT6 type (Orphanet:98806), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000473	Torticollis
HP:0000643	Blepharospasm
HP:0001260	Dysarthria
HP:0001304	Torsion dystonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001618	Dysphonia
HP:0002356	Writer’s cramp
HP:0002451	Limb dystonia
HP:0003621	Juvenile onset
HP:0003829	Typified by incomplete penetrance
HP:0007325	Generalized dystonia
HP:0011462	Young adult onset
HP:0012048	Oromandibular dystonia
HP:0012049	Laryngeal dystonia
HP:0012179	Craniofacial dystonia
HP:0031008	Lingual dystonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003225_24	Pelvic organ prolapse (moderate/severe)	2.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
C538003	Dystonia 6, torsion (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	decreases methylation, increases abundance, decreases expression	2
Hydrogen Peroxide	affects expression	2
Valproic Acid	affects expression, decreases expression	2
bisphenol F	increases expression, affects cotreatment	1
bisphenol A	affects cotreatment, increases expression	1
sulforaphane	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects expression	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Copper	affects binding, decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	increases expression	1
Disulfiram	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Gold	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Nitrogen Dioxide	decreases methylation, increases abundance	1
Dronabinol	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Zinc	affects cotreatment, increases expression	1

Cellosaurus cell lines

19 cell lines: 10 induced pluripotent stem cell, 4 cancer cell line, 3 embryonic stem cell, 1 finite cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7K5	SEES3-1V human THAP1, clone1	Embryonic stem cell	Male
CVCL_A7K6	SEES3-1V human THAP1, clone2	Embryonic stem cell	Male
CVCL_A7K7	SEES3-1V human THAP1, clone3	Embryonic stem cell	Male
CVCL_E5VB	SK-N-AS THAP1 clone 10	Cancer cell line	Female
CVCL_E5VC	SK-N-AS THAP1 F81L clone 35	Cancer cell line	Female
CVCL_E5VD	SK-N-AS THAP1 L180S clone 8	Cancer cell line	Female
CVCL_E5VE	SK-N-AS THAP1 S21T clone 9	Cancer cell line	Female
CVCL_EZ51	ND40075	Finite cell line	Male
CVCL_UG30	LUEi001-A	Induced pluripotent stem cell	Male
CVCL_UG31	LUEi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

172 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT07267065	PHASE1	NOT_YET_RECRUITING	AAV2-hAADC for Parkinson’s Disease (PDCS-01)
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT03428009	Not specified	RECRUITING	Dystonia Genotype-Phenotype Correlation
NCT04033393	Not specified	UNKNOWN	Dual-task Performance in Young-onset PD
NCT04722198	Not specified	UNKNOWN	Effects of Lactobacillus Plantarum PS128 on Symptoms of Early-onset Parkinson’s Disease: a Pilot Study
NCT00004421	PHASE2/PHASE3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT00608231	PHASE2/PHASE3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT04277247	PHASE2/PHASE3	UNKNOWN	Botulinum Toxin Type A for Foot Dystonia-associated Pain in Parkinson’s Disease
NCT02015039	PHASE1/PHASE2	COMPLETED	Pilot Trial of Botulinum Toxin and Occupational Therapy for Writer’s Cramp
NCT02911103	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Deep Brain Stimulation Surgery for Focal Hand Dystonia
NCT04727177	EARLY_PHASE1	UNKNOWN	Precision-targeted Transcranial Magnetic Stimulation in the Treatment of Primary Dystonia
NCT00006336	Not specified	COMPLETED	Sensory Training to Treat Focal Dystonia
NCT00017875	Not specified	COMPLETED	Transcranial Magnetic Stimulation (TMS) Studies of Dystonia
NCT00029601	Not specified	COMPLETED	Surround Inhibition in Patients With Dystonia
NCT00031369	Not specified	TERMINATED	Brain Anatomy in Dystonia
NCT00047957	Not specified	COMPLETED	Brain Inhibition of Muscle Movement in Normal Volunteers
NCT00050024	Not specified	COMPLETED	Transcranial Magnetic Stimulation and Electrical Stimulation of Nerves to Study Focal Dystonia
NCT00072956	Not specified	COMPLETED	The Physiology of Tricks