ITPA

Summary

ITPA (inosine triphosphatase, HGNC:6176) is a protein-coding gene on chromosome 20p13, encoding Inosine triphosphate pyrophosphatase (Q9BY32). Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2’-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5’-triphosphate (XTP) to their respective monophosphate derivatives.

This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 3704 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 347 total — 23 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• MANE Select transcript: NM_033453

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6176
Approved symbol	ITPA
Name	inosine triphosphatase
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	HLC14-06-P, dJ794I6.3
Ensembl gene	ENSG00000125877
Ensembl biotype	protein_coding
OMIM	147520
Entrez	3704

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 6 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000380113, ENST00000399838, ENST00000455664, ENST00000460550, ENST00000460676, ENST00000461029, ENST00000472295, ENST00000483354, ENST00000490838, ENST00000609835, ENST00000900242, ENST00000900243, ENST00000900244, ENST00000900245, ENST00000932180, ENST00000932181, ENST00000932182, ENST00000932183, ENST00000932184, ENST00000932185, ENST00000932186

RefSeq mRNA: 10 — MANE Select: NM_033453 NM_001267623, NM_001324236, NM_001324237, NM_001324238, NM_001324240, NM_001351739, NM_001424408, NM_001424409, NM_033453, NM_181493

CCDS: CCDS13051, CCDS46576, CCDS58762

Canonical transcript exons

ENST00000380113 — 8 exons

Exon	Start	End
ENSE00000858732	3213319	3213383
ENSE00001483921	3209498	3209617
ENSE00003490728	3213169	3213226
ENSE00003502300	3218517	3218632
ENSE00003546728	3221841	3221917
ENSE00003597114	3213985	3214058
ENSE00003603648	3215281	3215312
ENSE00003850431	3223366	3223860

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 96.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.6005 / max 177.2784, expressed in 1816 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183206	25.2334	1816
183205	0.3671	175

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	96.22	gold quality
left lobe of thyroid gland	UBERON:0001120	96.02	gold quality
metanephros cortex	UBERON:0010533	95.89	gold quality
mucosa of transverse colon	UBERON:0004991	95.68	gold quality
right adrenal gland cortex	UBERON:0035827	95.40	gold quality
right adrenal gland	UBERON:0001233	95.39	gold quality
thyroid gland	UBERON:0002046	95.29	gold quality
right uterine tube	UBERON:0001302	95.27	gold quality
left adrenal gland	UBERON:0001234	95.03	gold quality
left adrenal gland cortex	UBERON:0035825	95.02	gold quality
esophagus mucosa	UBERON:0002469	94.81	gold quality
adrenal cortex	UBERON:0001235	94.72	gold quality
lower esophagus mucosa	UBERON:0035834	94.70	gold quality
granulocyte	CL:0000094	94.65	gold quality
skin of leg	UBERON:0001511	94.64	gold quality
skin of abdomen	UBERON:0001416	94.49	gold quality
minor salivary gland	UBERON:0001830	94.45	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.36	gold quality
spleen	UBERON:0002106	94.25	gold quality
adrenal gland	UBERON:0002369	94.06	gold quality
body of stomach	UBERON:0001161	94.05	gold quality
monocyte	CL:0000576	93.98	gold quality
mononuclear cell	CL:0000842	93.86	gold quality
mouth mucosa	UBERON:0003729	93.84	gold quality
body of pancreas	UBERON:0001150	93.75	gold quality
zone of skin	UBERON:0000014	93.71	gold quality
leukocyte	CL:0000738	93.69	gold quality
apex of heart	UBERON:0002098	93.64	gold quality
right lobe of liver	UBERON:0001114	93.46	gold quality
transverse colon	UBERON:0001157	93.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

17 targeting ITPA, 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-9902	99.89	69.15	2250
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-6732-3P	98.17	67.52	802
HSA-MIR-6870-3P	98.08	65.10	692
HSA-MIR-6783-5P	97.67	67.21	1528

Literature-anchored findings (GeneRIF, showing 40)

• Sequencing of the genomic DNA from a subject with complete ITP-ase deficiency revealed homozygosity for missense mutation 198C>A. (PMID:12436200)
• ITPA 94C>A deficiency-associated allele has a role in response to azathioprine in inflammatory bowel disease to (PMID:15571265)
• analysis of blood samples reveals ITPase gene polymorphisms in a Japanese population (PMID:15571266)
• TPMT, ITPA, and MTHFR genotypes do not predict adverse drug reactions, including bone marrow suppression, in liver transplant patients. (PMID:15973722)
• cocrystallization of ITPA with a molar ratio of XTP appears to have improved the crystals by eliminating twinning and resulted in an orthorhombic space group. (PMID:17077483)
• The ITPA c.94C>A allelic variant destroys an exonic splicing silencing (ESS) element in exon 2 causing activation of two nearby upstream 5’ splice sites and missplicing of exons 2 and 3 cassette causing structural changes contributing to ITPase deficiency (PMID:17113761)
• ITPA deficiency mutation P32T leads to a shift of this loop that results in a disturbed affinity for nucleotides and/or a reduced catalytic activity in both monomers of the physiological dimer. (PMID:17138556)
• distribution of ITPA activity, types & frequencies of gene variants associated with lower enzyme activity were determined in a Bulgarian population; a novel frameshift mutation 359_366dupTCAGCACC in exon 6 found in a subject with reduced enzyme activity (PMID:17304144)
• There was no evidence for functional promoter SNPs, and it is suggested that only SNPs within the very proximal promoter region (approximately 200 bp) have the potential to be functionally significant. (PMID:18223458)
• Genetic polymorphism of inosine triphosphate pyrophosphatase (ITPA) is a significant determinant of mercaptopurine metabolism and neutropenia in acute lymphoblastic leukemia patients. (PMID:18685564)
• It is suggested that the ITPA gene mutation is closely related to adverse reactions of AZA/6-MP in Japanese patients, and screening for the mutant allele is useful for predicting the most serious adverse reactions (PMID:19214663)
• Adverse reactions to thiopurines in IBD may be predisposed by thiopurine methyltransferase (TPMT) or inosine triphosphate pyrophosphatase (ITPA) gene mutations. 87T>C and IVS2+53C>T were novel single nucleotide polymorphisms of the ITPA gene. (PMID:19579612)
• Data suggest that the P32T mutation of triphosphate pyrophosphatase exerts its effect in certain human tissues by cumulative effects of destabilization of transcripts, protein stability, and availability. (PMID:19631656)
• The present study is the first to reveal the bimodal distribution of ITPA activity in Chinese patients with renal transplantation and 94C>A polymorphism. (PMID:19682085)
• Amino acid substituted ITPase is a functional protein, with a reduced rate of NTP pyrophosphohydrolase activity and protein stability. (PMID:19914375)
• ITPA variants may have a role in the clinical course of pulmonary Langerhans’ cell histiocytosis (PMID:20930204)
• Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy. (PMID:21246582)
• The inosine triphosphatase genotype appear to be strongly associated with differental risk of rivabirin-induced HA and, consequently, of ribavirin dose reduction. (PMID:21612542)
• variants could protect against hemolytic anemia + RBV dose reuctn, assoc w/ high rate response if TT genotype @ rs8099917 of IL28b (PMID:21817190)
• There were no significant differences in virological responses of HCV-RNA between patients with the ITPA major allele and those with the minor allele. (PMID:22052220)
• The study shows the effect of ITPA polymorphisms on the handling of inosine triphosphate and thioinosine triphosphate. (PMID:22060550)
• Relative to HCV infection,ITPA is a gene on chromosome 20, coding for inosine triphosphatase, and polymorphisms on this gene have been associated with ribavirin-induced hemolytic anemia [review] (PMID:22189977)
• This study provides the first analysis of ITPA mutant allele frequency in individuals of Tunisian origin (PMID:22225964)
• Results suggest that long-term effects of HIV-infection altering ITPase protein expression or stability. (PMID:22272297)
• inosine triphosphate pyrophosphatase has a pivotal role in maintaining genome stability and the prevention of apoptosis in human cells (PMID:22384212)
• Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients. (PMID:22430973)
• an association was found between ITPA SNP genotype and treatment-induced anemia during a 4-week course of ribavirin monotherapy in patients with chronic hepatitis C (PMID:22460221)
• patients with the ITPA-CC genotype showed a smaller decrease in platelet counts during natural interferon-beta/ribavirin combination therapy. (PMID:22554247)
• We have confirmed a strong association between functional ITPA variants and Ribavirin-induced hemolysis and showed protection from RBV dose reduction. (PMID:22584257)
• ITPA deficiency was associated with slower hemoglobin decline early in treatment (week 4, P = 0.020) and rapid virologic response (RVR) at week 4 (P = 0.017) in patients coinfected with HIV and hepatitis C virus. (PMID:22585729)
• ITPase C94A has been recognized in about 15% of Japanese bur recent studies on its relationship with thiopurine toxicity has not been clarified. (PMID:23126166)
• ITPA SNPs influence ribavirin-induced anemia in chronic hepatitis C. (PMID:23139603)
• association between ribavirin (RBV) serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response (PMID:23195617)
• IL-28B polymorphisms and ITPA variants influence outcome of treatment for chronic hepatitis C with Peg-Interferon and ribavirin. (PMID:23301546)
• We propose that the dimer of P32T variant subunit with wild-type subunit is degraded in cells similarly to the P32T homodimer explaining the level of loss of ITPA activity in heterozygotes. (PMID:23528839)
• Rs1127354 ITPA polymorphism plays a decisive role in protecting against treatment-induced anemia and the need for ribavirin dose reduction in Egyptian hepatitis C patients. (PMID:23538996)
• Study supports recent studies which point towards an important role for ITPase in cellular surveillance of rogue nucleotides.in hematologic malignancy. (PMID:23547827)
• ITPA polymorphisms influenced the degree of anaemia but not thrombocytopenia during therapy of chronic hepatitis C genotype 6 infection. (PMID:23730840)
• role of conserved residues in substrate specificity (PMID:23770441)
• Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia. (PMID:23850877)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	itpa	ENSDARG00000057529
mus_musculus	Itpa	ENSMUSG00000074797
rattus_norvegicus	Itpa	ENSRNOG00000021233
drosophila_melanogaster	CG8891	FBGN0031663
caenorhabditis_elegans		WBGENE00001823

Protein

Protein identifiers

Inosine triphosphate pyrophosphatase — Q9BY32 (reviewed: Q9BY32)

Alternative names: Non-canonical purine NTP pyrophosphatase, Non-standard purine NTP pyrophosphatase, Nucleoside-triphosphate diphosphatase, Nucleoside-triphosphate pyrophosphatase, Putative oncogene protein hlc14-06-p, XTP/dITP diphosphatase

All UniProt accessions (3): Q9BY32, A0A0S2Z3W7, A0A0S2Z423

UniProt curated annotations — full annotation on UniProt →

Function. Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2’-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5’-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitous. Highly expressed in heart, liver, sex glands, thyroid and adrenal gland.

Disease relevance. Inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:613850] A common inherited condition characterized by the abnormal accumulation of inosine triphosphate in erythrocytes. It might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. The disease is caused by variants affecting the gene represented in this entry. Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme. Developmental and epileptic encephalopathy 35 (DEE35) [MIM:616647] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE35 is characterized by onset of seizures in the first months of life associated with essentially no normal development. Many patients die in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Similarity. Belongs to the HAM1 NTPase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BY32-1	1	yes
Q9BY32-2	2
Q9BY32-3	3

RefSeq proteins (10): NP_001254552, NP_001311165, NP_001311166, NP_001311167, NP_001311169, NP_001338668, NP_001411337, NP_001411338, NP_258412, NP_852470 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002637	RdgB/HAM1	Family
IPR027502	ITPase	Family
IPR029001	ITPase-like_fam	Homologous_superfamily

Pfam: PF01725

Enzyme classification (BRENDA):

• EC 3.6.1.66 — XTP/dITP diphosphatase (BRENDA: 12 organisms, 31 substrates, 4 inhibitors, 23 Km, 22 kcat entries)
• EC 3.6.1.9 — nucleotide diphosphatase (BRENDA: 33 organisms, 282 substrates, 447 inhibitors, 181 Km, 58 kcat entries)

Substrate kinetics (BRENDA)

81 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0062–78	14
NAD+	0.004–31.2	12
ITP	0.0071–0.51	11
FAD	0.005–1.8	10
UDP-GLUCOSE	0.62–50	8
NADH	0.042–20	7
THYMIDINE 5’-MONOPHOSPHATE P-NITROPHENYL ESTER	0.066–20	7
UTP	0.0566–33	7
DITP	0.0017–0.45	5
XTP	0.027–1.69	5
4-NITROPHENYL-5’-THYMIDINE MONOPHOSPHATE	0.0618–0.222	5
4-NITROPHENYL-5’-TMP	0.027–0.1185	4
AP3A	0.0051–0.0495	4
ADENOSINE 5’-PHOSPHOSULFATE	0.5–3	3
ADP	0.18–4.3	3

Catalyzed reactions (Rhea), 4 shown:

• dITP + H2O = dIMP + diphosphate + H(+) (RHEA:28342)
• XTP + H2O = XMP + diphosphate + H(+) (RHEA:28610)
• ITP + H2O = IMP + diphosphate + H(+) (RHEA:29399)
• N(6)-hydroxy-dATP + H2O = N(6)-hydroxy-dAMP + diphosphate + H(+) (RHEA:83971)

UniProt features (35 total): helix 8, strand 8, binding site 8, splice variant 2, sequence variant 2, sequence conflict 2, turn 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2CAR	X-RAY DIFFRACTION	1.09
2I5D	X-RAY DIFFRACTION	1.63
4F95	X-RAY DIFFRACTION	2.07
2J4E	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BY32-F1	95.37	0.92

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 (8): 14–19; 44; 56; 72–73; 89; 149–152; 172; 177–178

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-74259	Purine catabolism
R-HSA-9755088	Ribavirin ADME
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-8956319	Nucleotide catabolism
R-HSA-9748784	Drug ADME

MSigDB gene sets: 165 (showing top): GOBP_CHROMOSOME_ORGANIZATION, MODULE_52, MATTIOLI_MGUS_VS_PCL, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, KEGG_PURINE_METABOLISM, GOBP_NUCLEOSIDE_PHOSPHATE_CATABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_CATABOLIC_PROCESS

GO Biological Process (5): ITP catabolic process (GO:0006193), nucleoside triphosphate catabolic process (GO:0009143), deoxyribonucleoside triphosphate catabolic process (GO:0009204), chromosome organization (GO:0051276), nucleotide metabolic process (GO:0009117)

GO Molecular Function (8): nucleotide binding (GO:0000166), dITP diphosphatase activity (GO:0035870), ITP diphosphatase activity (GO:0036220), XTP diphosphatase activity (GO:0036222), identical protein binding (GO:0042802), metal ion binding (GO:0046872), nucleoside triphosphate diphosphatase activity (GO:0047429), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Nucleotide catabolism	1
Drug ADME	1
Metabolism	1
Metabolism of nucleotides	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleoside triphosphate diphosphatase activity	3
cellular anatomical structure	3
purine ribonucleotide catabolic process	1
purine ribonucleoside triphosphate catabolic process	1
ITP metabolic process	1
nucleoside triphosphate metabolic process	1
nucleoside phosphate catabolic process	1
nucleotide catabolic process	1
deoxyribonucleoside triphosphate metabolic process	1
deoxyribose phosphate catabolic process	1
organelle organization	1
nucleoside phosphate metabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
protein binding	1
cation binding	1
pyrophosphatase activity	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITPA	IFNL3	Q8IZI9	835
ITPA	NUDT15	Q9NV35	823
ITPA	TPMT	P51580	822
ITPA	ADA	P00813	777
ITPA	ATIC	P31939	728
ITPA	AHCY	P23526	704
ITPA	IMPDH2	P12268	657
ITPA	AMPD1	P23109	654
ITPA	GMPS	P49915	648
ITPA	ENDOV	Q8N8Q3	613
ITPA	TYMS	P04818	608
ITPA	GART	P22102	594
ITPA	ADSS2	P30520	579
ITPA	ABCC4	O15439	564
ITPA	IFNA13	P01562	560

IntAct

51 interactions, top by confidence:

A	B	Type	Score
LAMTOR5	LAMTOR4	psi-mi:“MI:0914”(association)	0.960
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ITPA	ITPA	psi-mi:“MI:0915”(physical association)	0.670
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
VPS4B	BIRC2	psi-mi:“MI:0914”(association)	0.530
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
FAM3B	LRP5	psi-mi:“MI:0914”(association)	0.530
WNT4	TOMM40	psi-mi:“MI:0914”(association)	0.530
LRRK2		psi-mi:“MI:0914”(association)	0.350
FERMT1	TARSL2	psi-mi:“MI:0914”(association)	0.350
TSHR	POTEF	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
P2RX5	NOP56	psi-mi:“MI:0914”(association)	0.350
CCL22	HSPA12A	psi-mi:“MI:0914”(association)	0.350
SERPINB11	CPE	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
FERMT1	TARS3	psi-mi:“MI:0914”(association)	0.350
FGB	KIF2A	psi-mi:“MI:0914”(association)	0.350
HHIPL1	CDC7	psi-mi:“MI:0914”(association)	0.350
DEFB136	MANBA	psi-mi:“MI:0914”(association)	0.350
SLURP1	MANBA	psi-mi:“MI:0914”(association)	0.350
ADAMTS4	RAD51B	psi-mi:“MI:0914”(association)	0.350

BioGRID (119): ITPA (Two-hybrid), ITPA (Affinity Capture-RNA), ITPA (Affinity Capture-RNA), ITPA (Affinity Capture-RNA), ITPA (Affinity Capture-MS), ITPA (Affinity Capture-MS), ITPA (Affinity Capture-MS), ITPA (Affinity Capture-MS), ITPA (Affinity Capture-MS), ECHS1 (Co-fractionation), ITPA (Co-fractionation), ITPA (Co-fractionation), ITPA (Co-fractionation), ITPA (Co-fractionation), ITPA (Co-fractionation)

ESM2 similar proteins: A3LVK6, A4R1J6, A5WVX0, A7RWC9, A8BKZ6, A8NZ80, A8XZP2, A9VE54, B2B5Q3, B6TNW8, B8BH95, C0NE84, C4YRQ5, C5WZH0, C7YTE3, C8V9B7, D3ZW55, D5GCI8, E0VVF6, E3KAB5, E3QBC5, F1NLH9, F4P9L8, F6HS55, F6Y089, P47119, Q0UFP3, Q16YB3, Q1K4R6, Q2GW61, Q2KIC5, Q2NLA8, Q2TX99, Q4DBX5, Q4DRX4, Q4PD06, Q4WTN9, Q54LQ6, Q59N80, Q5KPF3

Diamond homologs: A0LG38, A0M0C9, A1W4I7, A2BJY7, A4J7Y6, A4R1J6, A5FH89, A6LGA4, A7RWC9, A8A8W1, A8XZP2, A9VE54, B0K3T5, B0KBM4, B0XL39, B1L6T7, B1ZXD5, B2V8P5, B4U8R9, B5YHP2, B6IVK5, B8BH95, B9L638, B9MEJ9, C0NE84, C1CXX6, C1FI13, C4L4I7, C5WZH0, C8V9B7, D0MY11, D3ZW55, D5GCI8, D9PYS9, E0VVF6, F1NLH9, F6HS55, F6Y089, O28046, O59580

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	13
Uncertain significance	118
Likely benign	136
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072785	NM_033453.4(ITPA):c.410C>A (p.Ser137Ter)	Pathogenic
1471894	NM_033453.4(ITPA):c.264-2A>G	Pathogenic
1723392	NC_000020.10:g.(3194705_3195926)_(3195959_3199162)del	Pathogenic
2031686	NM_033453.4(ITPA):c.90dup (p.Phe31fs)	Pathogenic
2045104	NM_033453.4(ITPA):c.519del (p.Asn173fs)	Pathogenic
218088	NM_033453.4(ITPA):c.264-607_295+1267del	Pathogenic
218089	NM_033453.4(ITPA):c.452G>A (p.Trp151Ter)	Pathogenic
2427135	NC_000020.10:g.(?3195907)(3195978_?)del	Pathogenic
2444404	NM_033453.4(ITPA):c.142G>T (p.Glu48Ter)	Pathogenic
2808287	NM_033453.4(ITPA):c.284del (p.Lys94_Leu95insTer)	Pathogenic
2867319	NM_033453.4(ITPA):c.73C>T (p.Gln25Ter)	Pathogenic
3017430	NM_033453.4(ITPA):c.252del (p.Gly85fs)	Pathogenic
3775566	NM_033453.4(ITPA):c.41del (p.Thr14fs)	Pathogenic
4292748	NM_033453.4(ITPA):c.189+1G>A	Pathogenic
464831	NM_033453.4(ITPA):c.304C>T (p.Gln102Ter)	Pathogenic
4823917	NM_033453.4(ITPA):c.359_365del (p.Leu120fs)	Pathogenic
4823918	NM_033453.4(ITPA):c.484C>T (p.Gln162Ter)	Pathogenic
533413	NM_033453.4(ITPA):c.270del (p.Trp90fs)	Pathogenic
533428	NC_000020.11:g.(?3209532)(3209637_?)del	Pathogenic
580951	NM_033453.4(ITPA):c.70dup (p.Val24fs)	Pathogenic
804162	NM_033453.4(ITPA):c.124+2T>C	Pathogenic
804289	NM_033453.4(ITPA):c.263+583_295+1203del	Pathogenic
940510	NM_033453.4(ITPA):c.264-1G>C	Pathogenic
1066265	NM_033453.4(ITPA):c.49_66+4del	Likely pathogenic
1490678	NM_033453.4(ITPA):c.190-2A>T	Likely pathogenic
2069676	NM_033453.4(ITPA):c.296-2A>C	Likely pathogenic
2113025	NM_033453.4(ITPA):c.67-2A>G	Likely pathogenic
2446383	GRCh37/hg19 20p13-12.3(chr20:3034557-5524417)x1	Likely pathogenic
2582696	NM_033453.4(ITPA):c.137del (p.Gln46fs)	Likely pathogenic
3148970	NM_033453.4(ITPA):c.489-1G>T	Likely pathogenic

SpliceAI

1971 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3209488:G:GT	donor_gain	1.0000
20:3209532:C:G	donor_gain	1.0000
20:3209605:G:GT	donor_gain	1.0000
20:3209615:G:GT	donor_gain	1.0000
20:3215275:TTGCA:T	acceptor_loss	1.0000
20:3215278:CA:C	acceptor_loss	1.0000
20:3215279:A:AG	acceptor_gain	1.0000
20:3215279:AG:A	acceptor_loss	1.0000
20:3215280:G:GC	acceptor_loss	1.0000
20:3215280:G:GG	acceptor_gain	1.0000
20:3215280:GAAA:G	acceptor_gain	1.0000
20:3215310:AAGGT:A	donor_loss	1.0000
20:3215312:GG:G	donor_loss	1.0000
20:3215313:G:C	donor_loss	1.0000
20:3215314:T:G	donor_loss	1.0000
20:3218514:CA:C	acceptor_loss	1.0000
20:3218515:A:AG	acceptor_gain	1.0000
20:3218515:A:C	acceptor_loss	1.0000
20:3218516:G:GG	acceptor_gain	1.0000
20:3221914:AGACG:A	donor_loss	1.0000
20:3221915:GAC:G	donor_gain	1.0000
20:3221917:CG:C	donor_loss	1.0000
20:3221918:G:C	donor_loss	1.0000
20:3221918:G:GG	donor_gain	1.0000
20:3209513:G:GT	donor_gain	0.9900
20:3209514:G:GT	donor_gain	0.9900
20:3209531:GCTGG:G	donor_gain	0.9900
20:3209612:G:GT	donor_gain	0.9900
20:3209615:G:T	donor_gain	0.9900
20:3213317:A:G	acceptor_gain	0.9900

AlphaMissense

1252 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3221893:T:C	F155S	0.997
20:3214010:A:C	D72A	0.996
20:3221880:T:A	W151R	0.996
20:3221880:T:C	W151R	0.996
20:3214009:G:C	D72H	0.995
20:3218569:C:G	C116W	0.995
20:3221874:T:C	F149L	0.995
20:3221876:T:A	F149L	0.995
20:3221876:T:G	F149L	0.995
20:3221882:G:C	W151C	0.995
20:3221882:G:T	W151C	0.995
20:3214010:A:T	D72V	0.994
20:3214011:C:A	D72E	0.993
20:3214011:C:G	D72E	0.993
20:3215288:T:C	F91L	0.993
20:3215290:T:A	F91L	0.993
20:3215290:T:G	F91L	0.993
20:3221892:T:C	F155L	0.993
20:3221894:T:A	F155L	0.993
20:3221894:T:G	F155L	0.993
20:3213365:T:G	C57W	0.992
20:3213362:A:C	K56N	0.991
20:3213362:A:T	K56N	0.991
20:3213363:T:C	C57R	0.990
20:3213372:G:C	A60P	0.990
20:3214007:A:T	E71V	0.990
20:3214010:A:G	D72G	0.990
20:3218568:G:A	C116Y	0.990
20:3209589:T:A	V13E	0.989
20:3214004:T:A	V70D	0.989

dbSNP variants (sampled 300 via entrez): RS1000098592 (20:3219066 C>T), RS1000166523 (20:3213459 A>G), RS1000380729 (20:3224159 T>C), RS1000428801 (20:3206881 G>A), RS1000557664 (20:3203394 A>G), RS1000764935 (20:3208266 T>G), RS1000918253 (20:3219819 G>T), RS1000973553 (20:3219515 C>T), RS1000978016 (20:3202859 G>C), RS1001139500 (20:3225030 C>A,T), RS1001255791 (20:3203759 G>A), RS1001771008 (20:3220410 T>G), RS1001821948 (20:3220196 T>G), RS1001831810 (20:3203041 G>A), RS1001934914 (20:3226549 C>G)

Disease associations

OMIM: gene MIM:147520 | disease phenotypes: MIM:613850, MIM:616647, MIM:106600

GenCC curated gene-disease

Disease	Classification	Inheritance
inosine triphosphatase deficiency	Strong	Autosomal recessive
developmental and epileptic encephalopathy, 35	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AR

Mondo (6): inosine triphosphatase deficiency (MONDO:0013461), developmental and epileptic encephalopathy, 35 (MONDO:0014719), infantile epileptic-dyskinetic encephalopathy (MONDO:0018226), developmental and epileptic encephalopathy (MONDO:0100620), tooth agenesis (MONDO:0005486), corneal dystrophy (MONDO:0018102)

Orphanet (6): ITPA-related lethal infantile neurological disorder with cataract and cardiac involvement (Orphanet:457375), Infantile epileptic-dyskinetic encephalopathy (Orphanet:364063), Oligodontia (Orphanet:99798), Corneal dystrophy (Orphanet:34533), NON RARE IN EUROPE: Inosine triphosphate pyrophosphatase deficiency (Orphanet:319684), NON RARE IN EUROPE: Hypodontia (Orphanet:2227)

HPO phenotypes

21 total (22 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000518	Cataract
HP:0000737	Irritability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001620	Abnormally high-pitched voice
HP:0001638	Cardiomyopathy
HP:0002059	Cerebral atrophy
HP:0002133	Status epilepticus
HP:0002188	Delayed CNS myelination
HP:0003593	Infantile onset
HP:0006829	Severe muscular hypotonia
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0200085	Limb tremor
HP:6000510	Elevated erythrocyte inosine triphosphate concentration
HP:6000511	Reduced erythrocyte inosine triphosphatase activity
HP:0001131	Corneal dystrophy

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000604_1	Chronic hepatitis C infection	9.000000e-76
GCST000604_2	Chronic hepatitis C infection	2.000000e-58
GCST000729_1	Ribavirin-induced anemia	4.000000e-44
GCST001076_1	IFN-related cytopenia	1.000000e-09
GCST001094_2	Response to hepatitis C treatment	1.000000e-15
GCST001094_4	Response to hepatitis C treatment	2.000000e-25
GCST003542_168	Night sleep phenotypes	9.000000e-06
GCST007325_233	General risk tolerance (MTAG)	4.000000e-09
GCST009613_3	HDL cholesterol levels x loop diuretics use interaction	3.000000e-07
GCST010002_59	Refractive error	6.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004272	anemia (phenotype)
EFO:0008579	risk-taking behaviour
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003317	Corneal Dystrophies, Hereditary	C11.204.236; C11.270.162; C16.320.290.162
C567924	Infantile Epileptic-Dyskinetic Encephalopathy (supp.)
C564127	Inosine Triphosphatase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105788 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

11 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1127354	Efficacy	3	azathioprine	Inflammatory Bowel Diseases
rs1127354	Toxicity	2B	peginterferon alfa-2b;ribavirin	Anemia;Chronic hepatitis C virus infection
rs1127354	Efficacy,Toxicity	3	methotrexate	Acute lymphoblastic leukemia;Rheumatoid arthritis
rs1127354	Dosage	3	interferon alfa-2b;recombinant;ribavirin	Chronic hepatitis C virus infection
rs1127354	Efficacy	3	azathioprine	Liver transplantation;Transplant rejection
rs1127354	Efficacy	3	azathioprine;purine analogues	Systemic lupus erythematosus
rs1127354	Toxicity	4	mercaptopurine	Acute lymphoblastic leukemia;Myelosuppression
rs6051702	Toxicity	3	peginterferon alfa-2a;ribavirin	Hepatitis C virus infection
rs7270101	Toxicity	2B	peginterferon alfa-2b;ribavirin	Anemia;Chronic hepatitis C virus infection
rs7270101	Dosage,Toxicity	3	mercaptopurine;methotrexate	Acute lymphoblastic leukemia;Leukopenia;Neutropenia
rs7270101	Toxicity	4	azathioprine	Inflammatory Bowel Diseases

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1127354	DDRGK1, ITPA	2B	23.50	7	methotrexate;azathioprine;purine analogues;azathioprine;interferon alfa-2b;recombinant;ribavirin;mercaptopurine;peginterferon alfa-2b;ribavirin
rs6051702	DNAAF9, ITPA	3	3.00	1	peginterferon alfa-2a;ribavirin
rs7270101	ITPA	2B	8.00	3	mercaptopurine;methotrexate;azathioprine;peginterferon alfa-2b;ribavirin

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	Kd	6.286	nM	CHEMBL5653589
8.14	ED50	7.166	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 9 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148613: Binding affinity to human ITPA incubated for 45 mins by Kinobead based pull down assay	kd	0.0063	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Azathioprine	affects response to substance	7
sodium arsenite	affects cotreatment, decreases expression	3
Particulate Matter	decreases expression, decreases reaction, increases abundance	3
bisphenol A	decreases expression, increases expression	2
Methotrexate	affects response to substance	2
2,4,6-tribromophenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4008391	Binding	Inhibition of human His-tagged ITPase expressed in bacterial expression system after 1 hr by malachite green reagent based assay	Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2ZG	Abcam HEK293T ITPA KO	Transformed cell line	Female
CVCL_IN47	GM01619	Transformed cell line	Female
CVCL_IN55	GM01617	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT05279157	PHASE2	COMPLETED	Autologous Adipose-Derived Adult Stem Cell Implantation for Corneal Diseases (ADASCs-CT-CD)
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT05538936	Not specified	COMPLETED	The Effect of Spa and Massage on Babies on Colic Symptoms
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06266234	Not specified	RECRUITING	Characterization by Automated System on Infantile Spasmes
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07413211	Not specified	RECRUITING	Genetic Developmental and Epileptic Encephalopathy Natural History Study for Clinical Trial Readiness
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT01470235	Not specified	UNKNOWN	Hypodontia and Ovarian Cancer
NCT03445026	Not specified	UNKNOWN	Frequency of Hypodontia After Chemotherapy in Childhood Cancer Survivors Study
NCT05771246	Not specified	COMPLETED	Craniofacial Morphology And Sella Turcica Bridging Associated With Third Molar Agenesis.
NCT04484402	PHASE1/PHASE2	COMPLETED	Treatment of Patients With Inflammatory-dystrophic Diseases of the Cornea Using Autologous Stem Cells
NCT02932852	EARLY_PHASE1	UNKNOWN	Autologous Adipose-Derived Adult Stem Cell Transplantation for Corneal Diseases
NCT01084850	Not specified	UNKNOWN	Corneal Endothelium Morphology and Central Thickness in Type II Diabetes Mellitus and Normal Subjects
NCT02173847	Not specified	COMPLETED	Laser Assisted Procedures in Penetrating Keratoplasty
NCT02736877	Not specified	UNKNOWN	Corneal Transplantation Guided by OCT RESCAN
NCT02746055	Not specified	UNKNOWN	Study of the Prevalence of TGFBI Corneal Dystrophies
NCT03461991	Not specified	COMPLETED	Correlation Between In-vivo Anatomy of Corneal Dystrophies as Assessed by High- Resolution Optical Coherence Tomography (OCT) Measurement and Histological Examination
NCT03504800	Not specified	RECRUITING	OCT in Diagnosis of Irregular Corneas
NCT04129021	Not specified	RECRUITING	High Resolution, High-speed Multimodal Ophthalmic Imaging
NCT04164407	Not specified	UNKNOWN	Keratoconus, Corneal Diseases and Transplant Registry
NCT04384094	Not specified	UNKNOWN	Defining the Operating Parameters for a Rebound-esthesiometer
NCT04424550	Not specified	COMPLETED	Comparative Results After DSAEK, UT-DSAEK and DMEK for Fuchs Endothelial Corneal Dystophy
NCT05742321	Not specified	RECRUITING	Analysis of the Genotype/Phenotype Relationship in the Fuchs’ Corneal Endothelial Dystrophy in France
NCT05891106	Not specified	COMPLETED	AONDA Therapeutic Indication Study I