PARP4

Summary

PARP4 (poly(ADP-ribose) polymerase family member 4, HGNC:271) is a protein-coding gene on chromosome 13q12.12, encoding Protein mono-ADP-ribosyltransferase PARP4 (Q9UKK3). Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins.

This gene encodes poly(ADP-ribosyl)transferase-like 1 protein, which is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. Since this protein is not capable of binding DNA directly, its transferase activity may be activated by other factors such as protein-protein interaction mediated by the extensive carboxyl terminus.

Source: NCBI Gene 143 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 322 total
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• MANE Select transcript: NM_006437

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:271
Approved symbol	PARP4
Name	poly(ADP-ribose) polymerase family member 4
Location	13q12.12
Locus type	gene with protein product
Status	Approved
Aliases	VAULT3, p193, VPARP, VWA5C, ARTD4
Ensembl gene	ENSG00000102699
Ensembl biotype	protein_coding
OMIM	607519
Entrez	143

Gene structure

Transcript identifiers

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

ENST00000381989, ENST00000480576, ENST00000484989, ENST00000908086, ENST00000908087, ENST00000908088, ENST00000908089, ENST00000934617, ENST00000934618

RefSeq mRNA: 1 — MANE Select: NM_006437 NM_006437

CCDS: CCDS9307

Canonical transcript exons

ENST00000381989 — 34 exons

Exon	Start	End
ENSE00000679113	24426466	24426598
ENSE00000679115	24434395	24435474
ENSE00000679119	24446681	24446761
ENSE00000679120	24447016	24447186
ENSE00000679121	24449718	24449817
ENSE00000679122	24452406	24452593
ENSE00000679124	24455017	24455212
ENSE00000679125	24456341	24456478
ENSE00000679127	24459264	24459310
ENSE00000679128	24459972	24460136
ENSE00000679129	24469024	24469110
ENSE00000679131	24475472	24475596
ENSE00000679132	24477701	24477857
ENSE00000679133	24478093	24478276
ENSE00000679137	24490668	24490828
ENSE00000679142	24494573	24494722
ENSE00000679145	24500316	24500382
ENSE00000679146	24501633	24501834
ENSE00000876445	24493596	24493733
ENSE00000876446	24492421	24492594
ENSE00001428493	24512706	24512778
ENSE00001490516	24420931	24421314
ENSE00001490644	24503645	24503777
ENSE00001620244	24442590	24442685
ENSE00001625404	24469894	24470025
ENSE00001625973	24443650	24443730
ENSE00001645912	24431377	24431476
ENSE00001672511	24498116	24498229
ENSE00001687177	24486168	24486305
ENSE00001694368	24484653	24484748
ENSE00001739571	24441846	24441968
ENSE00001742432	24499301	24499376
ENSE00003614648	24459044	24459122
ENSE00003688713	24453587	24453654

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 93.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.7743 / max 349.8046, expressed in 1804 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136434	36.0771	1804
136435	0.6972	483

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	93.94	gold quality
duodenum	UBERON:0002114	93.54	gold quality
monocyte	CL:0000576	93.25	gold quality
leukocyte	CL:0000738	93.24	gold quality
gall bladder	UBERON:0002110	92.83	gold quality
bone marrow cell	CL:0002092	91.87	gold quality
blood	UBERON:0000178	91.59	gold quality
islet of Langerhans	UBERON:0000006	91.23	gold quality
transverse colon	UBERON:0001157	90.75	gold quality
adrenal tissue	UBERON:0018303	90.73	gold quality
calcaneal tendon	UBERON:0003701	90.68	gold quality
endometrium	UBERON:0001295	90.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.40	gold quality
small intestine	UBERON:0002108	90.37	gold quality
vermiform appendix	UBERON:0001154	90.27	gold quality
granulocyte	CL:0000094	90.00	gold quality
mucosa of transverse colon	UBERON:0004991	89.88	gold quality
right adrenal gland	UBERON:0001233	89.76	gold quality
right adrenal gland cortex	UBERON:0035827	89.59	gold quality
intestine	UBERON:0000160	89.44	gold quality
colonic epithelium	UBERON:0000397	89.30	gold quality
smooth muscle tissue	UBERON:0001135	89.20	gold quality
bone marrow	UBERON:0002371	89.16	gold quality
right uterine tube	UBERON:0001302	89.13	gold quality
left adrenal gland	UBERON:0001234	89.10	gold quality
adrenal gland	UBERON:0002369	89.05	gold quality
colon	UBERON:0001155	88.92	gold quality
urinary bladder	UBERON:0001255	88.61	gold quality
lymph node	UBERON:0000029	88.60	gold quality
left adrenal gland cortex	UBERON:0035825	88.48	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.11
E-CURD-112	no	2.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting PARP4, 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-4795-3P	100.00	74.62	4024
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
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
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-579-3P	99.86	71.66	3628

Literature-anchored findings (GeneRIF, showing 13)

• REVIEW:recent findings suggesting that PARP-1 participates in DNA damage signaling in cell death (PMID:12829019)
• the protein levels of MVP, TEP1 and vPARP are actually increased in the highergrade tumors suggesting existence of post-transcriptional regulation of vault component production. (PMID:23739867)
• PARP4 is a possible susceptibility gene of primary thyroid and breast cancer (PMID:26699384)
• Major vault protein is important in the drug resistance of cancer cells, but it requires the presence of vPARP for full activity (PMID:28551640)
• poly [ADPribose] polymerase(PARP)4 was identified as a novel cancer stemnessassociated gene in esophageal squamous cell carcinoma (ESCC) and its association with survival was validated in a cohort of 121 patients with ESCC (PMID:31002369)
• our results do not support that PARP4 functions as a cancer susceptibility gene. This study highlights the importance of performing functional analyses for candidate cancer predisposition genes. (PMID:31119570)
• Germline intronic PARP4 variants could be a risk factor for the development of TC. (PMID:31203137)
• Modification of PARP4, XRCC3, and RAD51 Gene Polymorphisms on the Relation between Bisphenol A Exposure and Liver Abnormality. (PMID:32316696)
• MVP Expression Facilitates Tumor Cell Proliferation and Migration Supporting the Metastasis of Colorectal Cancer Cells. (PMID:34829999)
• Modification Effect of PARP4 and ERCC1 Gene Polymorphisms on the Relationship between Particulate Matter Exposure and Fasting Glucose Level. (PMID:35627777)
• Identification of a novel PARP4 gene promoter CpG locus associated with cisplatin chemoresistance. (PMID:37013346)
• Structural and biochemical analysis of the PARP1-homology region of PARP4/vault PARP. (PMID:37971310)
• PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression. (PMID:39034402)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	parp4	ENSDARG00000069934
mus_musculus	Parp4	ENSMUSG00000054509
rattus_norvegicus	Mphosph8	ENSRNOG00000061152

Paralogs (11): ITIH4 (ENSG00000055955), ITIH1 (ENSG00000055957), ITIH6 (ENSG00000102313), VWA5A (ENSG00000110002), ITIH5 (ENSG00000123243), VWA5B2 (ENSG00000145198), ITIH2 (ENSG00000151655), VWA5B1 (ENSG00000158816), ITIH3 (ENSG00000162267), VWA3B (ENSG00000168658), VWA3A (ENSG00000175267)

Protein

Protein identifiers

Protein mono-ADP-ribosyltransferase PARP4 — Q9UKK3 (reviewed: Q9UKK3)

Alternative names: 193 kDa vault protein, ADP-ribosyltransferase diphtheria toxin-like 4, PARP-related/IalphaI-related H5/proline-rich, Poly [ADP-ribose] polymerase 4, Vault poly(ADP-ribose) polymerase

All UniProt accessions (1): Q9UKK3

UniProt curated annotations — full annotation on UniProt →

Function. Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins.

Subunit / interactions. Component of the vault ribonucleoprotein particle, at least composed of MVP, PARP4 and one or more vault RNAs (vRNAs). Interacts with TEP1.

Subcellular location. Cytoplasm. Nucleus. Cytoskeleton. Spindle.

Tissue specificity. Widely expressed; the highest levels are in the kidney; also detected in heart, placenta, lung, liver, skeletal muscle, spleen, leukocytes and pancreas.

Similarity. Belongs to the ARTD/PARP family.

RefSeq proteins (1): NP_006428* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001357	BRCT_dom	Domain
IPR002035	VWF_A	Domain
IPR004102	Poly(ADP-ribose)pol_reg_dom	Domain
IPR012317	Poly(ADP-ribose)pol_cat_dom	Domain
IPR013694	VIT	Domain
IPR031273	PARP4	Family
IPR036420	BRCT_dom_sf	Homologous_superfamily
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR036616	Poly(ADP-ribose)pol_reg_dom_sf	Homologous_superfamily
IPR058904	PARP4_MVP-ID	Domain
IPR058905	WGR-like_PARP4	Domain

Pfam: PF00092, PF00533, PF00644, PF08487, PF26156, PF26166

Enzyme classification (BRENDA):

• EC 2.4.2.30 — NAD+ ADP-ribosyltransferase (BRENDA: 32 organisms, 193 substrates, 306 inhibitors, 42 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NAD+	0.002–0.251	25
(ADP-D-RIBOSYL)N-ACTIN	0.011–0.037	7
(ADP-D-RIBOSYL)N-SOYBEAN-TRYPSIN-INHIBITOR	0.03–0.429	6
(ADP-D-RIBOSYL)N-RHOA PROTEIN	0.017	1
N6-ETHENO-NAD+	0.0225	1

Catalyzed reactions (Rhea), 2 shown:

• L-aspartyl-[protein] + NAD(+) = 4-O-(ADP-D-ribosyl)-L-aspartyl-[protein] + nicotinamide (RHEA:54424)
• L-glutamyl-[protein] + NAD(+) = 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + nicotinamide (RHEA:58224)

UniProt features (86 total): helix 23, strand 16, sequence conflict 15, sequence variant 11, modified residue 6, domain 5, turn 4, region of interest 3, short sequence motif 2, chain 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
9DEV	X-RAY DIFFRACTION	1.75
9DFO	X-RAY DIFFRACTION	1.9
9DFR	X-RAY DIFFRACTION	1.9
9DFP	X-RAY DIFFRACTION	1.92
9DFQ	X-RAY DIFFRACTION	2.1
8SWY	X-RAY DIFFRACTION	2.55
11JF	ELECTRON MICROSCOPY	2.85
9BW6	ELECTRON MICROSCOPY	2.9
9BW7	ELECTRON MICROSCOPY	2.9
8SX2	X-RAY DIFFRACTION	2.95
8SWZ	X-RAY DIFFRACTION	3
8SX1	X-RAY DIFFRACTION	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKK3-F1	69.73	0.24

Functional residue map

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

Post-translational modifications (6): 101, 333, 1236, 1335, 1476, 1504

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-196807	Nicotinate metabolism
R-HSA-9683610	Maturation of nucleoprotein
R-HSA-9694631	Maturation of nucleoprotein

MSigDB gene sets: 154 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, BROWNE_HCMV_INFECTION_6HR_DN, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, GOBP_INFLAMMATORY_RESPONSE, KAUFFMANN_DNA_REPAIR_GENES, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, BROWNE_HCMV_INFECTION_14HR_DN, DER_IFN_BETA_RESPONSE_UP, GOBP_DNA_DAMAGE_RESPONSE, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, GRUETZMANN_PANCREATIC_CANCER_UP, CUI_TCF21_TARGETS_2_DN, MODULE_568, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (5): DNA repair (GO:0006281), inflammatory response (GO:0006954), DNA damage response (GO:0006974), response to xenobiotic stimulus (GO:0009410), protein modification process (GO:0036211)

GO Molecular Function (10): DNA binding (GO:0003677), NAD+ poly-ADP-ribosyltransferase activity (GO:0003950), nucleotidyltransferase activity (GO:0016779), enzyme binding (GO:0019899), NAD+-protein-aspartate ADP-ribosyltransferase activity (GO:0140806), NAD+-protein-glutamate ADP-ribosyltransferase activity (GO:0140807), NAD+-protein mono-ADP-ribosyltransferase activity (GO:1990404), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), spindle microtubule (GO:0005876), membrane (GO:0016020), extracellular exosome (GO:0070062), ribonucleoprotein complex (GO:1990904), spindle (GO:0005819), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Translation of Structural Proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
pentosyltransferase activity	2
NAD+-protein mono-ADP-ribosyltransferase activity	2
intracellular membraneless organelle	2
DNA metabolic process	1
DNA damage response	1
defense response	1
cellular response to stress	1
response to chemical	1
protein metabolic process	1
macromolecule modification	1
nucleic acid binding	1
transferase activity, transferring phosphorus-containing groups	1
protein binding	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
transferase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
spindle	1
microtubule	1
extracellular vesicle	1
protein-containing complex	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

1098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PARP4	TEP1	Q99973	999
PARP4	MVP	Q14764	999
PARP4	PARP16	Q8N5Y8	780
PARP4	PARP15	Q460N3	745
PARP4	PARP6	Q2NL67	737
PARP4	PARP9	Q8IXQ6	719
PARP4	PARP10	Q53GL7	711
PARP4	ZMYM2	Q9UBW7	686
PARP4	PARP12	Q9H0J9	650
PARP4	PARP14	Q460N5	649
PARP4	PARP8	Q8N3A8	635
PARP4	PARP11	Q9NR21	619
PARP4	ZC3HAV1	Q7Z2W4	612
PARP4	PARG	Q86W56	596
PARP4	TIPARP	Q7Z3E1	550

IntAct

54 interactions, top by confidence:

A	B	Type	Score
ZKSCAN4	SCAND1	psi-mi:“MI:0914”(association)	0.870
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
ORF	PARP4	psi-mi:“MI:0915”(physical association)	0.560
MVP	GOPC	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
COP1	ETS2	psi-mi:“MI:0914”(association)	0.460
TPRX1	PARP4	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
PARP4		psi-mi:“MI:0915”(physical association)	0.370
PARP4	SMAD3	psi-mi:“MI:0915”(physical association)	0.370
	PARP4	psi-mi:“MI:0915”(physical association)	0.370
CLTC		psi-mi:“MI:0914”(association)	0.350
Lgals3bp	CS	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
MVP	HSPA8	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350
CCNL1	RPSA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-MS), PARP4 (Proximity Label-MS), PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-RNA), PARP4 (Affinity Capture-MS), MVP (Two-hybrid), MVP (Two-hybrid), PARP4 (Two-hybrid), PARP4 (Affinity Capture-MS), PARP4 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QP51, E9PYK3, E9Q4Z2, G1SPE9, O00763, O15228, O23617, P13676, P13798, P19205, P25154, P35574, P80227, P83006, P98192, Q10MJ1, Q2PQH8, Q338C0, Q496Z0, Q5EBA1, Q5IH13, Q5IH14, Q5R5S1, Q5U5V2, Q5ZIB9, Q641Y5, Q6V1X1, Q6YXW6, Q80YA7, Q80YD1, Q80ZK9, Q86TI2, Q8BVG4, Q8C0P5, Q8C5P5, Q8IYB8, Q8K4M9, Q8N5D0, Q8R146, Q8VZF3

Diamond homologs: E9PYK3, Q9UKK3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PARP4	“form complex”	“Vault ribonucleoprotein complex”	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — COADREAD, LUAD, PCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	221
Likely benign	16
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

5416 predictions. Top by Δscore:

Variant	Effect	Δscore
13:24431475:TC:T	acceptor_gain	1.0000
13:24431476:CC:C	acceptor_gain	1.0000
13:24432568:A:C	donor_gain	1.0000
13:24441841:TTTA:T	donor_loss	1.0000
13:24441842:TTACC:T	donor_loss	1.0000
13:24441843:TACC:T	donor_loss	1.0000
13:24441844:ACCT:A	donor_loss	1.0000
13:24441845:C:CG	donor_loss	1.0000
13:24441965:CATC:C	acceptor_gain	1.0000
13:24441967:TC:T	acceptor_gain	1.0000
13:24441968:CC:C	acceptor_gain	1.0000
13:24441969:C:CC	acceptor_gain	1.0000
13:24441974:T:TC	acceptor_gain	1.0000
13:24441980:C:CT	acceptor_gain	1.0000
13:24443645:CAAA:C	donor_loss	1.0000
13:24443646:AAAC:A	donor_loss	1.0000
13:24443647:AAC:A	donor_loss	1.0000
13:24443648:A:AG	donor_loss	1.0000
13:24443728:CAT:C	acceptor_gain	1.0000
13:24443729:ATCTG:A	acceptor_loss	1.0000
13:24443730:TCTG:T	acceptor_loss	1.0000
13:24443731:C:CC	acceptor_gain	1.0000
13:24443732:T:A	acceptor_loss	1.0000
13:24443733:G:C	acceptor_gain	1.0000
13:24443733:G:GC	acceptor_gain	1.0000
13:24443737:T:C	acceptor_gain	1.0000
13:24443737:T:TC	acceptor_gain	1.0000
13:24443742:C:CT	acceptor_gain	1.0000
13:24443743:A:T	acceptor_gain	1.0000
13:24443746:A:T	acceptor_gain	1.0000

AlphaMissense

11426 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:24447129:A:G	W1058R	0.998
13:24447129:A:T	W1058R	0.998
13:24447127:C:A	W1058C	0.996
13:24447127:C:G	W1058C	0.996
13:24456463:C:G	A814P	0.996
13:24442644:A:C	S1163R	0.995
13:24442644:A:T	S1163R	0.995
13:24442646:T:G	S1163R	0.995
13:24456373:A:G	W844R	0.995
13:24456373:A:T	W844R	0.995
13:24443706:C:G	A1131P	0.994
13:24459068:A:C	S800R	0.993
13:24459068:A:T	S800R	0.993
13:24459070:T:G	S800R	0.993
13:24443711:G:T	A1129D	0.992
13:24446761:C:G	A1096P	0.992
13:24455202:A:G	L858P	0.992
13:24455137:A:G	C880R	0.991
13:24478138:A:C	S529R	0.991
13:24478138:A:T	S529R	0.991
13:24478140:T:G	S529R	0.991
13:24447134:A:T	V1056D	0.990
13:24455202:A:T	L858H	0.990
13:24456371:C:A	W844C	0.990
13:24456371:C:G	W844C	0.990
13:24469043:A:G	L705P	0.990
13:24447128:C:G	W1058S	0.989
13:24455195:A:C	F860L	0.989
13:24455195:A:T	F860L	0.989
13:24455196:A:G	F860S	0.989

dbSNP variants (sampled 300 via entrez): RS1000030962 (13:24476802 G>A,T), RS1000083778 (13:24479566 C>T), RS1000160553 (13:24468328 G>A), RS1000205973 (13:24500987 A>C,G), RS1000331979 (13:24485357 T>A), RS1000415 (13:24457300 C>G,T), RS1000417418 (13:24422854 G>A,C), RS1000467762 (13:24469752 T>C), RS1000519756 (13:24469568 C>T), RS1000532541 (13:24462853 G>A,T), RS1000537822 (13:24440982 C>T), RS1000574397 (13:24430299 G>A), RS1000585044 (13:24463088 C>A), RS1000640894 (13:24428934 C>T), RS1000685640 (13:24504847 T>A,C)

Disease associations

OMIM: gene MIM:607519 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): primary ovarian failure (MONDO:0005387)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001099_28	Sudden cardiac arrest	7.000000e-07
GCST001762_363	Obesity-related traits	2.000000e-06
GCST005688_10	Idiopathic intracranial hypertension	1.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004278	sudden cardiac arrest
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6142 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 37,681 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1094636	NIRAPARIB	4	6,433
CHEMBL1173055	RUCAPARIB	4	7,009
CHEMBL3137320	TALAZOPARIB	4	5,534
CHEMBL521686	OLAPARIB	4	13,038
CHEMBL506871	VELIPARIB	3	5,421
CHEMBL5095043	ATAMPARIB	1	246

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

ChEMBL bioactivities

32 potent at pChembl≥5 of 41 total, top 32 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	Kd	0.7	nM	TALAZOPARIB
9.00	IC50	1	nM	CHEMBL5402698
7.87	IC50	13.5	nM	OLAPARIB
6.98	Kd	105	nM	VELIPARIB
6.85	Kd	141	nM	OLAPARIB
6.64	IC50	229.1	nM	CHEMBL6170252
6.59	IC50	254	nM	CHEMBL3764816
6.59	IC50	257	nM	CHEMBL3764816
6.57	Kd	272	nM	NIRAPARIB
6.48	IC50	330	nM	NIRAPARIB
6.39	IC50	410	nM	OLAPARIB
6.39	IC50	407.4	nM	OLAPARIB
6.36	IC50	440	nM	CHEMBL595018
6.35	IC50	446	nM	NIRAPARIB
6.35	IC50	446.7	nM	NIRAPARIB
6.30	IC50	500	nM	CHEMBL5198711
6.30	Kd	503	nM	RUCAPARIB
6.18	IC50	660	nM	CHEMBL609002
6.12	IC50	758.6	nM	PJ34
6.10	IC50	800	nM	CHEMBL5181770
6.10	IC50	800	nM	CHEMBL5200299
6.08	IC50	839	nM	RUCAPARIB
6.08	IC50	831.8	nM	RUCAPARIB
5.72	IC50	1900	nM	CHEMBL5176271
5.57	IC50	2700	nM	CHEMBL5184065
5.46	IC50	3500	nM	VELIPARIB
5.46	IC50	3467	nM	VELIPARIB
5.36	IC50	4390	nM	CHEMBL1086580
5.36	IC50	4365	nM	CHEMBL1086580
5.22	IC50	6000	nM	CHEMBL5406267
5.04	IC50	9200	nM	ATAMPARIB
5.00	IC50	1e+04	nM	CHEMBL5431108

PubChem BioAssay actives

31 with measured affinity, of 77 total; 19 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Talazoparib	1895780: Binding affinity to PARP4 (unknown origin) assessed as apparent dissociation constant	kd	0.0007	uM
4-[[3-[3-(5-bromofuran-2-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one	2012697: Inhibition of PARP4 (unknown origin) using biotinylated NAD+ as substrate by luminescence assay	ic50	0.0010	uM
Olaparib	2012697: Inhibition of PARP4 (unknown origin) using biotinylated NAD+ as substrate by luminescence assay	ic50	0.0135	uM
2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide	1895780: Binding affinity to PARP4 (unknown origin) assessed as apparent dissociation constant	kd	0.1050	uM
(11R,12S)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one	1428390: Inhibition of recombinant human His6-tagged PARP4 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay	ic50	0.2540	uM
Niraparib	1895780: Binding affinity to PARP4 (unknown origin) assessed as apparent dissociation constant	kd	0.2720	uM
2-(2-pyridin-3-ylacetyl)-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-10-one	455970: Inhibition of VPARP	ic50	0.4400	uM
6,8-dimethyl-2-(pyrimidin-2-ylsulfanylmethyl)-3H-quinazolin-4-one	1853426: Inhibition of N-terminal His-tagged recombinant human PARP4 brct-catalytic domain (369 to 573 residues) expressed in Escherichia coli BL21 (DE3) preincubated with 6-a-NAD+ for 5 to 10 mins followed by enzyme addition and measured after 60 mins using NAD+ as substrate byHRP based chemiluminescence assay	ic50	0.5000	uM
Rucaparib	1895780: Binding affinity to PARP4 (unknown origin) assessed as apparent dissociation constant	kd	0.5030	uM
2-(3-pyrazin-2-ylpropanoyl)-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-10-one	455970: Inhibition of VPARP	ic50	0.6600	uM
2-(dimethylamino)-N-(6-oxo-5H-phenanthridin-2-yl)acetamide	1428390: Inhibition of recombinant human His6-tagged PARP4 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay	ic50	0.7586	uM
6-bromo-8-methyl-2-(pyrimidin-2-ylsulfanylmethyl)-3H-quinazolin-4-one	1853426: Inhibition of N-terminal His-tagged recombinant human PARP4 brct-catalytic domain (369 to 573 residues) expressed in Escherichia coli BL21 (DE3) preincubated with 6-a-NAD+ for 5 to 10 mins followed by enzyme addition and measured after 60 mins using NAD+ as substrate byHRP based chemiluminescence assay	ic50	0.8000	uM
4-[(6-iodo-8-methyl-4-oxo-3H-quinazolin-2-yl)methylsulfanyl]benzoic acid	1853426: Inhibition of N-terminal His-tagged recombinant human PARP4 brct-catalytic domain (369 to 573 residues) expressed in Escherichia coli BL21 (DE3) preincubated with 6-a-NAD+ for 5 to 10 mins followed by enzyme addition and measured after 60 mins using NAD+ as substrate byHRP based chemiluminescence assay	ic50	0.8000	uM
4-[(6-bromo-8-methyl-4-oxo-3H-quinazolin-2-yl)methylsulfanyl]benzoic acid	1853426: Inhibition of N-terminal His-tagged recombinant human PARP4 brct-catalytic domain (369 to 573 residues) expressed in Escherichia coli BL21 (DE3) preincubated with 6-a-NAD+ for 5 to 10 mins followed by enzyme addition and measured after 60 mins using NAD+ as substrate byHRP based chemiluminescence assay	ic50	1.9000	uM
6-iodo-8-methyl-2-(pyrimidin-2-ylsulfanylmethyl)-3H-quinazolin-4-one	1853426: Inhibition of N-terminal His-tagged recombinant human PARP4 brct-catalytic domain (369 to 573 residues) expressed in Escherichia coli BL21 (DE3) preincubated with 6-a-NAD+ for 5 to 10 mins followed by enzyme addition and measured after 60 mins using NAD+ as substrate byHRP based chemiluminescence assay	ic50	2.7000	uM
2-[4-(trifluoromethyl)phenyl]-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidin-4-one	1428390: Inhibition of recombinant human His6-tagged PARP4 ADP-ribosyltransferase domain expressed in Escherichia coli BL21(DE3) preincubated for 15 mins followed by biotinylated NAD+ addition by chemiluminescence assay	ic50	4.3652	uM
[1,2,4]triazolo[3,4-b][1,3]benzothiazol-6-ol	1965923: Inhibition of N-terminal MBP tagged/C-terminal PARP4 (unknown origin) expressed in Escherichia coli in presence of NAD+	ic50	6.0000	uM
4-[[(2S)-1-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy]propan-2-yl]amino]-5-(trifluoromethyl)-1H-pyridazin-6-one	1869188: Inhibition of PARP4 (unknown origin)	ic50	9.2000	uM
6-methyl-[1,2,4]triazolo[3,4-b][1,3]benzothiazol-1-amine	1965923: Inhibition of N-terminal MBP tagged/C-terminal PARP4 (unknown origin) expressed in Escherichia coli in presence of NAD+	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
arsenite	decreases reaction, decreases methylation, affects binding	2
tanshinone	increases expression	2
Acetaminophen	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
uranyl acetate	increases expression	1
lead acetate	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric oxide	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	decreases expression	1
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride	affects binding	1
ICG 001	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Chelating Agents	affects binding, increases expression	1
Copper	increases expression, affects binding	1
Doxorubicin	decreases expression	1
Estradiol	affects expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lithium	increases expression	1
Nickel	decreases expression	1

ChEMBL screening assays

22 unique, capped per target: 22 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1060808	Binding	Inhibition of human vPARP catalytic domain expressed in Escherichia coli up to 500 nM	Identification of aminoethyl pyrrolo dihydroisoquinolinones as novel poly(ADP-ribose) polymerase-1 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TC19	HAP1 PARP4 (-) 1	Cancer cell line	Male
CVCL_TC20	HAP1 PARP4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists