ITPKB

Summary

ITPKB (inositol-trisphosphate 3-kinase B, HGNC:6179) is a protein-coding gene on chromosome 1q42.12, encoding Inositol-trisphosphate 3-kinase B (P27987). Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis.

The protein encoded by this protein regulates inositol phosphate metabolism by phosphorylation of second messenger inositol 1,4,5-trisphosphate to Ins(1,3,4,5)P4. The activity of this encoded protein is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling. Both calcium/calmodulin and protein phosphorylation mechanisms control its activity.

Source: NCBI Gene 3707 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ITPKB deficiency (Limited, ClinGen) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 158 total
• Druggable target: yes
• MANE Select transcript: NM_002221

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6179
Approved symbol	ITPKB
Name	inositol-trisphosphate 3-kinase B
Location	1q42.12
Locus type	gene with protein product
Status	Approved
Aliases	IP3KB, IP3-3KB
Ensembl gene	ENSG00000143772
Ensembl biotype	protein_coding
OMIM	147522
Entrez	3707

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000272117, ENST00000366784, ENST00000429204, ENST00000926664

RefSeq mRNA: 2 — MANE Select: NM_002221 NM_001388404, NM_002221

CCDS: CCDS1555, CCDS91167

Canonical transcript exons

ENST00000429204 — 8 exons

Exon	Start	End
ENSE00000961885	226648672	226648771
ENSE00000961886	226647167	226647380
ENSE00000961887	226641921	226642125
ENSE00000961888	226639557	226639658
ENSE00000961889	226637679	226637750
ENSE00001145367	226631690	226634886
ENSE00001442611	226735527	226737663
ENSE00001658024	226739041	226739282

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.3494 / max 846.7999, expressed in 1678 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17781	29.2221	1615
17782	3.2281	1209
17777	0.2833	112
17778	0.2500	73
17780	0.2187	107
17775	0.0538	34
17779	0.0521	34
17776	0.0413	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	99.09	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.06	gold quality
globus pallidus	UBERON:0001875	97.70	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.60	gold quality
medial globus pallidus	UBERON:0002477	97.42	gold quality
inferior olivary complex	UBERON:0002127	97.38	gold quality
substantia nigra pars compacta	UBERON:0001965	97.34	gold quality
subthalamic nucleus	UBERON:0001906	97.24	gold quality
ventral tegmental area	UBERON:0002691	97.07	gold quality
medulla oblongata	UBERON:0001896	97.01	gold quality
superior vestibular nucleus	UBERON:0007227	96.95	gold quality
middle frontal gyrus	UBERON:0002702	96.84	gold quality
inferior vagus X ganglion	UBERON:0005363	96.78	gold quality
midbrain	UBERON:0001891	96.51	gold quality
substantia nigra	UBERON:0002038	96.48	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.73	gold quality
cranial nerve II	UBERON:0000941	95.71	gold quality
spinal cord	UBERON:0002240	95.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.13	gold quality
amygdala	UBERON:0001876	94.90	gold quality
pons	UBERON:0000988	94.49	gold quality
putamen	UBERON:0001874	94.30	gold quality
hypothalamus	UBERON:0001898	94.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.60	gold quality
caudate nucleus	UBERON:0001873	93.59	gold quality
lower esophagus	UBERON:0013473	93.56	gold quality
CA1 field of hippocampus	UBERON:0003881	93.46	gold quality
thymus	UBERON:0002370	93.21	gold quality
temporal lobe	UBERON:0001871	92.98	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	256.42
E-CURD-119	yes	49.78
E-HCAD-35	yes	23.35
E-HCAD-25	yes	21.66
E-ANND-3	yes	8.30
E-MTAB-6058	no	14.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

138 targeting ITPKB, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606

Literature-anchored findings (GeneRIF, showing 15)

• results highlight the potential role of the three isoforms of InsP3 3-kinase as direct InsP3 metabolizing enzymes and direct regulators of Ca2+ responses to extracellular signals (PMID:12747803)
• We aim to summarize the existing information about functionally uncoupled IP(3)R and RyR channels, and to discuss the concept that those channels can participate in Ca(2+)-leak pathways. (PMID:16354157)
• In each of the three isoforms a nuclear export signal has evolved in the catalytic domain either de novo (IP3K-A) or as a substitute for an earlier evolved corresponding N-terminal signal (IP3K-B and IP3K-C). (PMID:16740130)
• IP3KB not only regulates cytoplasmic Ca(2+) signals by phosphorylation of subplasmalemmal and cytoplasmic Ins(1,4,5)P(3) but may also be involved in modulating nuclear Ca(2+) signals generated from these nuclear envelope invaginations. (PMID:21148483)
• a specific increase in inositol 1,4,5-trisphosphate 3-kinase A and B (ITPKA and ITPKB) was observed upon hESCs spontaneous differentiation. (PMID:22446005)
• ITPKB is increased in Alzheimer’s brain three-fold in the cerebral cortex of most patients with Alzheimer’s disease compared with control subjects and accumulates in dystrophic neurites associated with amyloid plaques. (PMID:24401760)
• The authors confirm downregulation of miR-132 and upregulation of ITPKB in three distinct human Alzheimer’s disease patient cohorts. (PMID:27485122)
• miR-140-5p regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (IP3k2). Therefore, the results of the present study demonstrated that miR-140-5p mediated drug-resistance in osteosarcoma cells by inducing autophagy. (PMID:27582507)
• ITPKB does not affect the cellular actin structure and does not suppress dissemination of human lung cancer cells in mice. (PMID:29871874)
• study also suggests a distinctive signaling function of IP4 that regulates NOX4. Furthermore, pharmaceutical inhibition of ITPKB displayed synergistic attenuation of tumor growth with cisplatin, suggesting ITPKB as a promising synthetic lethal target for cancer therapeutic intervention to overcome cisplatin resistance. (PMID:31081803)
• Severe combined immunodeficiency caused by inositol-trisphosphate 3-kinase B (ITPKB) deficiency. (PMID:31987846)
• Association of ITPKB, IL1R2 and COQ7 with Parkinson’s disease in Taiwan. (PMID:34244037)
• Increased Levels of the Parkinson’s Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of alpha-Synuclein, Independent of Mutation Status. (PMID:36768321)
• Genome-Wide Meta-Analysis Identifies Multiple Novel Rare Variants to Predict Common Human Infectious Diseases Risk. (PMID:37108169)
• Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis. (PMID:38438346)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	itpkb	ENSDARG00000010059
mus_musculus	Itpkb	ENSMUSG00000038855
rattus_norvegicus	Itpkb	ENSRNOG00000002969
drosophila_melanogaster	IP3K1	FBGN0032147
drosophila_melanogaster	Ip6k	FBGN0034644
caenorhabditis_elegans	lfe-2	WBGENE00002979
caenorhabditis_elegans	F30A10.3	WBGENE00009262

Paralogs (6): IP6K2 (ENSG00000068745), ITPKC (ENSG00000086544), ITPKA (ENSG00000137825), IPMK (ENSG00000151151), IP6K3 (ENSG00000161896), IP6K1 (ENSG00000176095)

Protein

Protein identifiers

Inositol-trisphosphate 3-kinase B — P27987 (reviewed: P27987)

Alternative names: Inositol 1,4,5-trisphosphate 3-kinase B

All UniProt accessions (1): P27987

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis.

Subunit / interactions. Interacts with DMTN.

Subcellular location. Cytoplasm. Cytoskeleton. Endoplasmic reticulum.

Activity regulation. IP3K is activated by calcium and calmodulin. Form B is much more sensitive to calcium/calmodulin than form A.

Similarity. Belongs to the inositol phosphokinase (IPK) family.

Isoforms (2)

UniProt ID	Names	Canonical?
P27987-1	1	yes
P27987-2	2

RefSeq proteins (2): NP_001375333, NP_002212* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005522	IPK	Family
IPR038286	IPK_sf	Homologous_superfamily

Pfam: PF03770

Enzyme classification (BRENDA):

• EC 2.7.1.127 — inositol-trisphosphate 3-kinase (BRENDA: 14 organisms, 87 substrates, 104 inhibitors, 42 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1D-MYO-INOSITOL 1,4,5-TRISPHOSPHATE	0.0002–0.011	21
ATP	0.033–2.5	13
1D-MYO-INOSITOL 2,4,5-TRISPHOSPHATE	0.0015–0.005	2
INSP3	0.0002–0.0017	2

Catalyzed reactions (Rhea), 1 shown:

• 1D-myo-inositol 1,4,5-trisphosphate + ATP = 1D-myo-inositol 1,3,4,5-tetrakisphosphate + ADP + H(+) (RHEA:11020)

UniProt features (36 total): binding site 10, region of interest 6, compositionally biased region 5, modified residue 5, sequence conflict 4, sequence variant 3, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27987-F1	56.58	0.25

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 (10): 679; 690; 730–732; 743; 745; 766; 793–800; 817; 897; 900

Post-translational modifications (5): 43, 49, 71, 204, 269

Mutagenesis-validated functional residues (1):

Position	Phenotype
897	loss of kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-1430728	Metabolism
R-HSA-1483249	Inositol phosphate metabolism

MSigDB gene sets: 359 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, HNF3ALPHA_Q6, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_THYMIC_T_CELL_SELECTION, CMYB_01, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_POLYOL_METABOLIC_PROCESS

GO Biological Process (16): MAPK cascade (GO:0000165), myeloid cell homeostasis (GO:0002262), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), inositol trisphosphate metabolic process (GO:0032957), inositol phosphate biosynthetic process (GO:0032958), negative regulation of neutrophil apoptotic process (GO:0033030), common myeloid progenitor cell proliferation (GO:0035726), positive thymic T cell selection (GO:0045059), negative regulation of myeloid cell differentiation (GO:0045638), positive regulation of Ras protein signal transduction (GO:0046579), positive regulation of alpha-beta T cell differentiation (GO:0046638), phosphatidylinositol phosphate biosynthetic process (GO:0046854), cellular response to calcium ion (GO:0071277), T cell differentiation (GO:0030217), thymic T cell selection (GO:0045061)

GO Molecular Function (8): inositol hexakisphosphate kinase activity (GO:0000828), calmodulin binding (GO:0005516), ATP binding (GO:0005524), inositol-1,4,5-trisphosphate 3-kinase activity (GO:0008440), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Inositol phosphate metabolism	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
inositol phosphate metabolic process	2
intracellular membrane-bounded organelle	2
cytoplasm	2
intracellular signaling cassette	1
immune system process	1
homeostasis of number of cells	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
polyol biosynthetic process	1
organophosphate biosynthetic process	1
neutrophil apoptotic process	1
regulation of neutrophil apoptotic process	1
negative regulation of myeloid cell apoptotic process	1
negative regulation of leukocyte apoptotic process	1
cell population proliferation	1
positive T cell selection	1
thymic T cell selection	1
myeloid cell differentiation	1
negative regulation of cell differentiation	1
regulation of myeloid cell differentiation	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
positive regulation of T cell differentiation	1
alpha-beta T cell differentiation	1
positive regulation of alpha-beta T cell activation	1
regulation of alpha-beta T cell differentiation	1
glycerophospholipid biosynthetic process	1
response to calcium ion	1
cellular response to metal ion	1
lymphocyte differentiation	1
T cell activation	1
T cell differentiation in thymus	1
T cell selection	1
phosphotransferase activity, phosphate group as acceptor	1

Protein interactions and networks

STRING

686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITPKB	IP6K1	Q92551	782
ITPKB	IP6K3	Q96PC2	761
ITPKB	IP6K2	Q9UHH9	670
ITPKB	IPMK	Q8NFU5	567
ITPKB	PLCG1	P19174	532
ITPKB	STAT6	P42226	520
ITPKB	AKT1	P31749	503
ITPKB	B2M	P01884	493
ITPKB	INPP5A	Q14642	489
ITPKB	LCP2	Q13094	474
ITPKB	CREBBP	Q92793	472
ITPKB	MFHAS1	Q9Y4C4	472
ITPKB	BCL6	P41182	471
ITPKB	EP300	Q09472	466
ITPKB	IPPK	Q9H8X2	465

IntAct

55 interactions, top by confidence:

A	B	Type	Score
ITPKB	GOLGA2	psi-mi:“MI:0915”(physical association)	0.670
GOLGA2	ITPKB	psi-mi:“MI:0915”(physical association)	0.670
BRAF	MEN1	psi-mi:“MI:0914”(association)	0.600
ITPKB	BRAF	psi-mi:“MI:0915”(physical association)	0.600
ITPKB	BRAF	psi-mi:“MI:2364”(proximity)	0.600
ITPKB	SCAI	psi-mi:“MI:0915”(physical association)	0.560
ITPKB	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
ITPKB	CTDSP1	psi-mi:“MI:0915”(physical association)	0.560
KRT34	ITPKB	psi-mi:“MI:0915”(physical association)	0.560
ITPKB	CEP70	psi-mi:“MI:0915”(physical association)	0.560
ITPKB	IFT88	psi-mi:“MI:0915”(physical association)	0.560
ITPKB	TRIM54	psi-mi:“MI:0915”(physical association)	0.560
ITPKB	PPP3CA	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
ITPKB	PSME3	psi-mi:“MI:0915”(physical association)	0.370
ITPKB	PDE4A	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
AKT1	ITPKB	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	ITPKB	psi-mi:“MI:2364”(proximity)	0.270
SPOP	ITPKB	psi-mi:“MI:2364”(proximity)	0.270
ITPKB	SPOP	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (27): ITPKB (Two-hybrid), PSME3 (Two-hybrid), ITPKB (Two-hybrid), PDE4A (Affinity Capture-MS), PDE4D (Affinity Capture-MS), PIBF1 (Affinity Capture-MS), ADNP2 (Affinity Capture-MS), ESF1 (Affinity Capture-MS), ITPKB (Affinity Capture-RNA), ITPKB (Affinity Capture-MS), ITPKB (Affinity Capture-RNA), ITPKB (Two-hybrid), ITPKB (Two-hybrid), ITPKB (Two-hybrid), ITPKB (Two-hybrid)

ESM2 similar proteins: A0A1B0GVZ6, A2A7Y5, A2VE02, A3KGF9, A5D7K1, A6NDZ8, A6NE82, A6NGG8, A6NJ08, A6QP24, A7MB40, B1ASB6, B2RQL2, D3ZUE1, M3WHG5, O94850, P27987, P97609, Q13796, Q4R2Z8, Q4R736, Q5RCJ6, Q5SSG4, Q5SX79, Q5VZ46, Q5XIK6, Q68A65, Q6GQX2, Q6NS69, Q6PAC4, Q6ZUT6, Q7Z591, Q80VW7, Q8BHW6, Q8BZW2, Q8CGM2, Q8IWN7, Q8IXJ9, Q8IY92, Q8IYF1

Diamond homologs: P17105, P23677, P27987, P42335, Q7TS72, Q80ZG2, Q8R071, Q95Q62, Q96DU7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKCA	“down-regulates activity”	ITPKB
PRKACA	“down-regulates activity”	ITPKB	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TP53 Regulates Metabolic Genes	5	28.2×	9e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	114
Likely benign	15
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

2268 predictions. Top by Δscore:

Variant	Effect	Δscore
1:226634883:TGAC:T	acceptor_gain	1.0000
1:226634887:C:CC	acceptor_gain	1.0000
1:226634888:T:G	acceptor_loss	1.0000
1:226637674:TCTA:T	donor_loss	1.0000
1:226637675:CTACC:C	donor_loss	1.0000
1:226637676:TACCT:T	donor_loss	1.0000
1:226637677:ACC:A	donor_loss	1.0000
1:226637678:CCT:C	donor_gain	1.0000
1:226637707:T:TA	donor_gain	1.0000
1:226637747:CGAT:C	acceptor_gain	1.0000
1:226637750:TC:T	acceptor_loss	1.0000
1:226637751:C:CC	acceptor_gain	1.0000
1:226637751:C:CG	acceptor_loss	1.0000
1:226637752:T:C	acceptor_loss	1.0000
1:226637757:A:AC	acceptor_gain	1.0000
1:226639552:CTCA:C	donor_loss	1.0000
1:226639553:TCA:T	donor_loss	1.0000
1:226639554:CAC:C	donor_loss	1.0000
1:226639555:A:AC	donor_gain	1.0000
1:226639556:C:CC	donor_gain	1.0000
1:226639556:C:CG	donor_loss	1.0000
1:226639556:CCAGG:C	donor_gain	1.0000
1:226639572:T:TA	donor_gain	1.0000
1:226639655:CTTT:C	acceptor_gain	1.0000
1:226639656:TTTCT:T	acceptor_loss	1.0000
1:226639658:TCTGA:T	acceptor_loss	1.0000
1:226639659:C:CC	acceptor_gain	1.0000
1:226639659:CTGAG:C	acceptor_loss	1.0000
1:226641915:CCTCA:C	donor_loss	1.0000
1:226641916:CTCA:C	donor_loss	1.0000

AlphaMissense

6164 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:226634821:G:C	D897E	1.000
1:226634821:G:T	D897E	1.000
1:226634822:T:A	D897V	1.000
1:226634822:T:C	D897G	1.000
1:226634822:T:G	D897A	1.000
1:226634823:C:G	D897H	1.000
1:226634864:A:G	F883S	1.000
1:226634867:A:G	L882P	1.000
1:226634870:A:G	L881P	1.000
1:226634875:G:C	S879R	1.000
1:226634875:G:T	S879R	1.000
1:226634877:T:G	S879R	1.000
1:226641929:C:G	G815R	1.000
1:226641929:C:T	G815R	1.000
1:226641937:C:A	R812M	1.000
1:226641973:C:G	R800P	1.000
1:226641975:C:A	W799C	1.000
1:226641975:C:G	W799C	1.000
1:226641977:A:G	W799R	1.000
1:226641977:A:T	W799R	1.000
1:226647174:C:G	G747R	1.000
1:226647174:C:T	G747R	1.000
1:226647185:T:A	D743V	1.000
1:226647186:C:G	D743H	1.000
1:226647343:C:A	K690N	1.000
1:226647343:C:G	K690N	1.000
1:226647347:A:G	L689P	1.000
1:226647374:A:G	F680S	1.000
1:226648686:A:G	L673P	1.000
1:226648696:A:G	W670R	1.000

dbSNP variants (sampled 300 via entrez): RS1000044709 (1:226641759 G>A), RS1000052759 (1:226740488 C>T), RS1000066237 (1:226668116 T>C), RS1000079343 (1:226702345 C>A,T), RS1000085783 (1:226740911 T>C), RS1000117835 (1:226703443 G>A), RS1000143885 (1:226669578 A>G), RS1000151943 (1:226703562 G>A), RS1000169594 (1:226661470 G>A), RS1000170875 (1:226703611 A>C), RS1000209313 (1:226688503 G>T), RS1000257321 (1:226636838 C>T), RS1000335211 (1:226631904 G>A,C), RS1000340065 (1:226735326 G>A), RS1000341108 (1:226713073 T>A,C)

Disease associations

OMIM: gene MIM:147522 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
severe combined immunodeficiency	Limited	Autosomal recessive
Tourette syndrome	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ITPKB deficiency	Limited	AR

Mondo (3): myeloproliferative neoplasm, unclassifiable (MONDO:0019452), Tourette syndrome (MONDO:0007661), severe combined immunodeficiency (MONDO:0015974)

Orphanet (1): Chronic myeloproliferative disease, unclassifiable (Orphanet:86830)

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001521_29	Subcutaneous adipose tissue	6.000000e-06
GCST004902_15	Parkinson’s disease	2.000000e-11
GCST005038_15	Allergic disease (asthma, hay fever or eczema)	2.000000e-09
GCST008295_15	Number of decayed, missing and filled tooth surfaces or use of dentures	3.000000e-08
GCST008306_25	Dentures	1.000000e-08
GCST009325_84	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-15
GCST010002_355	Refractive error	1.000000e-12
GCST010042_108	Asthma	2.000000e-09
GCST010043_93	Asthma	2.000000e-10
GCST010049_4	Parkinson’s disease	8.000000e-10
GCST010991_26	Parkinson’s disease	6.000000e-08
GCST012490_162	Femur bone mineral density x serum urate levels interaction	4.000000e-11
GCST90002382_28	Eosinophil percentage of white cells	4.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010078	dentures
EFO:0004531	urate measurement
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5165 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Inositol 1,4,5-trisphosphate 3-kinases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
GNF362	Inhibition	8.05	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	3
Valproic Acid	affects expression, decreases expression	3
bisphenol A	decreases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
trichostatin A	affects cotreatment, increases expression	1
ochratoxin A	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	decreases expression, increases abundance, affects cotreatment	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Methapyrilene	increases methylation	1
Ozone	increases abundance, affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3721023	Binding	Inhibition of ITPKb in human Jurkat cells assessed as reduction in conversion of IP3 to IP4 using [3H]-myo-inositol incubated for 5 mins by beta-RAM radio-HPLC method	Compounds and compositions as ITPKB inhibitors

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7ST	Ubigene A-549 ITPKB KO	Cancer cell line	Male
CVCL_D8NK	Ubigene HCT 116 ITPKB KO	Cancer cell line	Male
CVCL_D9HK	Ubigene HEK293 ITPKB KO	Transformed cell line	Female
CVCL_E0FP	Ubigene HeLa ITPKB KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00322101	PHASE3	COMPLETED	Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia
NCT00799461	PHASE3	COMPLETED	Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome