THAP4

Summary

THAP4 (THAP domain containing 4, HGNC:23187) is a protein-coding gene on chromosome 2q37.3, encoding Peroxynitrite isomerase THAP4 (Q8WY91). Heme-binding protein able to scavenge peroxynitrite and to protect free L-tyrosine against peroxynitrite-mediated nitration, by acting as a peroxynitrite isomerase that converts peroxynitrite to nitrate.

Enables several functions, including heme binding activity; nitric oxide binding activity; and peroxynitrite isomerase activity. Involved in nitrate metabolic process and tyrosine metabolic process. Located in cytosol and nucleoplasm.

Source: NCBI Gene 51078 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 106 total — 1 pathogenic
• MANE Select transcript: NM_015963

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23187
Approved symbol	THAP4
Name	THAP domain containing 4
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	CGI-36, Nb(III)
Ensembl gene	ENSG00000176946
Ensembl biotype	protein_coding
OMIM	612533
Entrez	51078

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000321679, ENST00000402136, ENST00000402545, ENST00000407315, ENST00000497486, ENST00000863245, ENST00000863246, ENST00000863247, ENST00000863248

RefSeq mRNA: 2 — MANE Select: NM_015963 NM_001164356, NM_015963

CCDS: CCDS2551, CCDS54440

Canonical transcript exons

ENST00000407315 — 6 exons

Exon	Start	End
ENSE00001554858	241636941	241637158
ENSE00001561536	241584405	241584725
ENSE00001673370	241602970	241603079
ENSE00001723868	241606314	241606473
ENSE00001776546	241632917	241634079
ENSE00003594678	241601896	241601999

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4056 / max 107.2680, expressed in 1803 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34931	12.4729	1787
34932	3.2059	1529
34930	1.3608	982
34933	1.0339	691
34926	0.7857	342
34927	0.5463	281

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.62	gold quality
mucosa of transverse colon	UBERON:0004991	96.21	gold quality
right atrium auricular region	UBERON:0006631	96.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.16	gold quality
heart left ventricle	UBERON:0002084	96.03	gold quality
gastrocnemius	UBERON:0001388	96.01	gold quality
cardiac ventricle	UBERON:0002082	95.85	gold quality
cardiac atrium	UBERON:0002081	95.58	gold quality
metanephros cortex	UBERON:0010533	95.45	gold quality
muscle of leg	UBERON:0001383	95.44	gold quality
adult mammalian kidney	UBERON:0000082	95.19	gold quality
lower esophagus mucosa	UBERON:0035834	95.13	gold quality
heart	UBERON:0000948	94.86	gold quality
muscle organ	UBERON:0001630	94.57	gold quality
renal medulla	UBERON:0000362	94.43	gold quality
putamen	UBERON:0001874	94.12	gold quality
transverse colon	UBERON:0001157	94.09	gold quality
caudate nucleus	UBERON:0001873	93.90	gold quality
body of stomach	UBERON:0001161	93.88	gold quality
nucleus accumbens	UBERON:0001882	93.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.72	gold quality
right frontal lobe	UBERON:0002810	93.63	gold quality
triceps brachii	UBERON:0001509	93.54	gold quality
anterior cingulate cortex	UBERON:0009835	93.51	gold quality
cingulate cortex	UBERON:0003027	93.50	gold quality
prefrontal cortex	UBERON:0000451	93.47	gold quality
amygdala	UBERON:0001876	93.13	gold quality
skin of leg	UBERON:0001511	93.07	gold quality
skeletal muscle tissue	UBERON:0001134	93.04	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting THAP4, 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-3120-5P	100.00	65.56	965
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-4638-3P	97.90	65.75	905

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	thap4	ENSDARG00000077323
mus_musculus	Thap4	ENSMUSG00000026279
rattus_norvegicus	Thap4	ENSRNOG00000018351
caenorhabditis_elegans		WBGENE00008993

Protein

Protein identifiers

Peroxynitrite isomerase THAP4 — Q8WY91 (reviewed: Q8WY91)

Alternative names: Ferric Homo sapiens nitrobindin, THAP domain-containing protein 4

All UniProt accessions (2): Q8WY91, B5MCC0

UniProt curated annotations — full annotation on UniProt →

Function. Heme-binding protein able to scavenge peroxynitrite and to protect free L-tyrosine against peroxynitrite-mediated nitration, by acting as a peroxynitrite isomerase that converts peroxynitrite to nitrate. Therefore, this protein likely plays a role in peroxynitrite sensing and in the detoxification of reactive nitrogen and oxygen species (RNS and ROS, respectively). Is able to bind nitric oxide (NO) in vitro, but may act as a sensor of peroxynitrite levels in vivo, possibly modulating the transcriptional activity residing in the N-terminal region.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Nucleus.

Cofactor. Binds 1 heme b group per subunit, that coordinates a highly solvent-exposed Fe(III) atom.

Domain organisation. The C-terminal nitrobindin region coordinates a heme and bears the isomerase activity. The N-terminal zinc finger domain likely binds DNA and may be involved in transcriptional regulation.

Pathway. Nitrogen metabolism.

Similarity. In the C-terminal section; belongs to the nitrobindin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WY91-1	1	yes
Q8WY91-2	2

RefSeq proteins (2): NP_001157828, NP_057047* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006612	THAP_Znf	Domain
IPR012674	Calycin	Homologous_superfamily
IPR014878	THAP4-like_heme-bd	Domain
IPR038441	THAP_Znf_sf	Homologous_superfamily
IPR045165	Nitrobindin	Family

Pfam: PF05485, PF08768

Catalyzed reactions (Rhea), 1 shown:

• peroxynitrite = nitrate (RHEA:63116)

UniProt features (31 total): strand 11, region of interest 3, compositionally biased region 3, binding site 2, modified residue 2, splice variant 2, turn 2, chain 1, zinc finger region 1, sequence variant 1, sequence conflict 1, helix 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3IA8	X-RAY DIFFRACTION	1.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WY91-F1	68.26	0.35

Functional residue map

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

Ligand- & substrate-binding residues (2): 567 (axial binding residue); 444

Post-translational modifications (2): 163, 239

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 102 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GARY_CD5_TARGETS_UP, STEIN_ESRRA_TARGETS_UP, GOMF_TETRAPYRROLE_BINDING, GAZDA_DIAMOND_BLACKFAN_ANEMIA_ERYTHROID_DN, GOMF_ISOMERASE_ACTIVITY, KRIGE_RESPONSE_TO_TOSEDOSTAT_6HR_DN, CEBPZ_TARGET_GENES, CIITA_TARGET_GENES, DROSHA_TARGET_GENES, E2F5_TARGET_GENES

GO Biological Process (2): obsolete tyrosine metabolic process (GO:0006570), nitrate metabolic process (GO:0042126)

GO Molecular Function (9): DNA binding (GO:0003677), zinc ion binding (GO:0008270), heme binding (GO:0020037), identical protein binding (GO:0042802), peroxynitrite isomerase activity (GO:0062213), nitric oxide binding (GO:0070026), protein binding (GO:0005515), isomerase activity (GO:0016853), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
oxoacid metabolic process	1
reactive nitrogen species metabolic process	1
nucleic acid binding	1
transition metal ion binding	1
tetrapyrrole binding	1
protein binding	1
isomerase activity	1
small molecule binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

632 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THAP4	THAP11	Q96EK4	905
THAP4	THAP12	O43422	904
THAP4	THAP7	Q9BT49	584
THAP4	THAP3	Q8WTV1	574
THAP4	THAP10	Q9P2Z0	571
THAP4	ANKMY1	Q9P2S6	562
THAP4	MYO1F	O00160	526
THAP4	STK25	O00506	509
THAP4	PAWR	Q96IZ0	491
THAP4	FARP2	O94887	487
THAP4	HCFC1	P51610	480
THAP4	SPINT3	P49223	479
THAP4	DTYMK	P23919	462
THAP4	RRM1	P23921	440
THAP4	GLYATL3	Q5SZD4	394

IntAct

140 interactions, top by confidence:

A	B	Type	Score
TRADD	TNF	psi-mi:“MI:0914”(association)	0.790
THAP4	CPNE2	psi-mi:“MI:0915”(physical association)	0.670
CMTM7	THAP4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	MAL2	psi-mi:“MI:0915”(physical association)	0.560
AGTRAP	THAP4	psi-mi:“MI:0915”(physical association)	0.560
TPD52	THAP4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
SCAMP1	THAP4	psi-mi:“MI:0915”(physical association)	0.560
AMD1	THAP4	psi-mi:“MI:0915”(physical association)	0.560
DGAT2L6	THAP4	psi-mi:“MI:0915”(physical association)	0.560
TMEM86B	THAP4	psi-mi:“MI:0915”(physical association)	0.560
LAT	THAP4	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	THAP4	psi-mi:“MI:0915”(physical association)	0.560
CACNG1	THAP4	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	THAP4	psi-mi:“MI:0915”(physical association)	0.560
TMEM86A	THAP4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	NDRG4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	RMDN2	psi-mi:“MI:0915”(physical association)	0.560
ANKRD46	THAP4	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	THAP4	psi-mi:“MI:0915”(physical association)	0.560
GIMAP1	THAP4	psi-mi:“MI:0915”(physical association)	0.560
PPGB	THAP4	psi-mi:“MI:0915”(physical association)	0.560
RTP2	THAP4	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	THAP4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	CMTM7	psi-mi:“MI:0915”(physical association)	0.560
THAP4	THAP4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
PLP2	THAP4	psi-mi:“MI:0915”(physical association)	0.560
THAP4	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (83): CORO2A (Affinity Capture-MS), THAP4 (Reconstituted Complex), AIFM1 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS), GFER (Affinity Capture-MS), ACTB (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), THAP4 (Affinity Capture-RNA), THAP4 (Affinity Capture-RNA), THAP4 (Affinity Capture-MS), THAP4 (Affinity Capture-MS), THAP4 (Affinity Capture-MS), THAP4 (Two-hybrid), THAP4 (Two-hybrid)

ESM2 similar proteins: A0A1L8HTT5, A0JPQ7, A4FV61, A4IFK0, O75151, O88974, P35689, P49140, P55265, P55266, P97432, Q02040, Q0VEE6, Q14202, Q14596, Q15047, Q15554, Q501R9, Q53GL0, Q5EAN7, Q5F3F2, Q5HYC2, Q5R6F3, Q5RC94, Q5RF77, Q5SYB0, Q642B6, Q69Z66, Q69Z99, Q6P3Z3, Q76CY8, Q810L3, Q86XL3, Q8C4S8, Q8ND82, Q8NE31, Q8WY91, Q91VL8, Q95JV5, Q96EP1

Diamond homologs: A0PT73, A0QIQ0, A0R6J8, A1KM55, A1R8X8, A1SPL4, A1T297, A3PTJ4, A4FQE4, A4T0W5, A4X1P5, A5CTZ4, A5U669, A6W6D1, A8LDK0, A8LZD6, B0RAV9, B1VQH0, B1VS45, B2GIH3, B2HLY1, B8HD40, C5CC85, O64527, P9WFG6, P9WFG7, Q0RS51, Q0S4V4, Q0S749, Q1BEZ2, Q2JFV4, Q2TBI2, Q47KW7, Q4JXD1, Q5YS78, Q5Z2A5, Q642B6, Q6AAW4, Q6NFH6, Q6P3Z3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of MAPK cascade	6	10.1×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	79
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1340707	GRCh37/hg19 2q37.3(chr2:239436367-242783384)x1	Pathogenic

SpliceAI

1586 predictions. Top by Δscore:

Variant	Effect	Δscore
2:241601890:GCTCA:G	donor_loss	1.0000
2:241601891:CTCA:C	donor_loss	1.0000
2:241601892:TCACC:T	donor_loss	1.0000
2:241601893:CA:C	donor_loss	1.0000
2:241601894:A:C	donor_loss	1.0000
2:241601895:C:CG	donor_loss	1.0000
2:241601895:CCTG:C	donor_gain	1.0000
2:241601995:CACGC:C	acceptor_gain	1.0000
2:241601996:ACGCC:A	acceptor_loss	1.0000
2:241601997:CGC:C	acceptor_gain	1.0000
2:241601997:CGCCT:C	acceptor_loss	1.0000
2:241601998:GCCTG:G	acceptor_loss	1.0000
2:241601999:CCTGC:C	acceptor_loss	1.0000
2:241602000:C:CA	acceptor_loss	1.0000
2:241602000:C:CC	acceptor_gain	1.0000
2:241602001:T:A	acceptor_loss	1.0000
2:241602965:CTCAC:C	donor_loss	1.0000
2:241602966:TCA:T	donor_loss	1.0000
2:241603077:AACC:A	acceptor_loss	1.0000
2:241603081:T:G	acceptor_loss	1.0000
2:241606307:AACTT:A	donor_loss	1.0000
2:241606308:ACTTA:A	donor_loss	1.0000
2:241606309:CTT:C	donor_loss	1.0000
2:241606310:TTACG:T	donor_loss	1.0000
2:241606311:TACGA:T	donor_loss	1.0000
2:241606312:A:AC	donor_gain	1.0000
2:241606313:C:CA	donor_gain	1.0000
2:241606313:CG:C	donor_gain	1.0000
2:241606313:CGA:C	donor_gain	1.0000
2:241606313:CGAG:C	donor_gain	1.0000

AlphaMissense

3768 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:241633978:A:G	F60S	1.000
2:241634045:A:G	W38R	1.000
2:241634045:A:T	W38R	1.000
2:241584712:A:G	F543S	0.999
2:241603026:A:G	F485S	0.999
2:241606420:A:G	W432R	0.999
2:241606420:A:T	W432R	0.999
2:241633977:G:C	F60L	0.999
2:241633977:G:T	F60L	0.999
2:241633979:A:G	F60L	0.999
2:241633989:A:C	C56W	0.999
2:241633991:A:G	C56R	0.999
2:241633995:A:C	F54L	0.999
2:241633995:A:T	F54L	0.999
2:241633997:A:G	F54L	0.999
2:241634043:C:A	W38C	0.999
2:241634043:C:G	W38C	0.999
2:241634076:G:C	F27L	0.999
2:241634076:G:T	F27L	0.999
2:241634077:A:G	F27S	0.999
2:241634078:A:G	F27L	0.999
2:241636946:G:C	F24L	0.999
2:241636946:G:T	F24L	0.999
2:241636948:A:G	F24L	0.999
2:241637003:A:C	C5W	0.999
2:241637005:A:G	C5R	0.999
2:241584718:C:G	R541P	0.998
2:241603025:G:C	F485L	0.998
2:241603025:G:T	F485L	0.998
2:241603027:A:G	F485L	0.998

dbSNP variants (sampled 300 via entrez): RS1000003762 (2:241638313 A>G), RS1000016200 (2:241595918 G>T), RS1000061220 (2:241595663 A>G), RS1000071605 (2:241584367 C>T), RS1000113830 (2:241638565 C>A), RS1000171341 (2:241628301 C>A,G), RS1000195789 (2:241617614 A>G), RS1000237695 (2:241616322 A>G), RS1000241416 (2:241623349 C>G), RS1000276343 (2:241638430 C>G,T), RS1000327678 (2:241628859 G>A), RS1000406964 (2:241601679 CA>C,CAA), RS1000511012 (2:241592109 A>G), RS1000578258 (2:241634866 A>T), RS1000620179 (2:241597409 G>C)

Disease associations

OMIM: gene MIM:612533 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000597_2	Brain structure	6.000000e-07
GCST001942_6	Prostate cancer	5.000000e-09
GCST010653_8	Thyroid stimulating hormone levels	1.000000e-11
GCST012490_359	Femur bone mineral density x serum urate levels interaction	2.000000e-12
GCST90002402_296	Platelet count	2.000000e-12
GCST90020028_766	Hip circumference adjusted for BMI	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004309	platelet count
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	increases methylation	2
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
coumarin	decreases phosphorylation	1
ICG 001	increases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
Sodium Selenite	increases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1

Clinical trials (associated diseases)

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