PIP4K2A

Summary

PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase type 2 alpha, HGNC:8997) is a protein-coding gene on chromosome 10p12.2, encoding Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (P48426). Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).

Phosphatidylinositol-5,4-bisphosphate, the precursor to second messengers of the phosphoinositide signal transduction pathways, is thought to be involved in the regulation of secretion, cell proliferation, differentiation, and motility. The protein encoded by this gene is one of a family of enzymes capable of catalyzing the phosphorylation of phosphatidylinositol-5-phosphate on the fourth hydroxyl of the myo-inositol ring to form phosphatidylinositol-5,4-bisphosphate. The amino acid sequence of this enzyme does not show homology to other kinases, but the recombinant protein does exhibit kinase activity. This gene is a member of the phosphatidylinositol-5-phosphate 4-kinase family.

Source: NCBI Gene 5305 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 74 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005028

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8997
Approved symbol	PIP4K2A
Name	phosphatidylinositol-5-phosphate 4-kinase type 2 alpha
Location	10p12.2
Locus type	gene with protein product
Status	Approved
Aliases	PIP5KIIA, PIP5KIIalpha
Ensembl gene	ENSG00000150867
Ensembl biotype	protein_coding
OMIM	603140
Entrez	5305

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000323883, ENST00000376573, ENST00000422321, ENST00000432610, ENST00000474335, ENST00000545335, ENST00000604912, ENST00000605011, ENST00000899822, ENST00000928212

RefSeq mRNA: 2 — MANE Select: NM_005028 NM_001330062, NM_005028

CCDS: CCDS7141, CCDS81443

Canonical transcript exons

ENST00000376573 — 10 exons

Exon	Start	End
ENSE00000996549	22541804	22542047
ENSE00000996555	22539971	22540074
ENSE00000996557	22550659	22550772
ENSE00001834756	22534854	22537281
ENSE00001913313	22714183	22714578
ENSE00003513932	22609620	22609717
ENSE00003527510	22567851	22567889
ENSE00003531156	22607927	22608023
ENSE00003585290	22573311	22573457
ENSE00003688885	22591629	22591781

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.1544 / max 18507.4862, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108672	39.6952	1813
108648	34.7079	1741
108671	4.2974	1153
108670	0.7466	320
108649	0.7074	166

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	99.52	gold quality
medial globus pallidus	UBERON:0002477	99.42	gold quality
globus pallidus	UBERON:0001875	99.41	gold quality
inferior vagus X ganglion	UBERON:0005363	99.35	gold quality
lateral globus pallidus	UBERON:0002476	99.34	gold quality
corpus callosum	UBERON:0002336	99.33	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.03	gold quality
subthalamic nucleus	UBERON:0001906	98.99	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.99	gold quality
spinal cord	UBERON:0002240	98.82	gold quality
CA1 field of hippocampus	UBERON:0003881	98.68	gold quality
medulla oblongata	UBERON:0001896	98.66	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.64	gold quality
substantia nigra pars compacta	UBERON:0001965	98.46	gold quality
substantia nigra	UBERON:0002038	98.46	gold quality
midbrain	UBERON:0001891	98.45	gold quality
trabecular bone tissue	UBERON:0002483	98.35	gold quality
ventral tegmental area	UBERON:0002691	98.21	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.17	gold quality
superior vestibular nucleus	UBERON:0007227	98.16	gold quality
pons	UBERON:0000988	98.10	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.01	gold quality
cranial nerve II	UBERON:0000941	97.88	gold quality
putamen	UBERON:0001874	97.88	gold quality
postcentral gyrus	UBERON:0002581	97.76	gold quality
parietal lobe	UBERON:0001872	97.55	gold quality
Ammon’s horn	UBERON:0001954	97.46	gold quality
monocyte	CL:0000576	97.38	gold quality
leukocyte	CL:0000738	97.04	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	3674.70
E-HCAD-30	yes	2660.98
E-HCAD-25	yes	2605.37
E-CURD-119	yes	27.21
E-MTAB-6678	yes	25.47
E-HCAD-9	yes	17.47
E-CURD-46	yes	13.14
E-GEOD-84465	yes	13.13
E-GEOD-180759	no	3923.98
E-CURD-89	no	834.88
E-ENAD-20	no	454.79
E-GEOD-109979	no	424.51
E-MTAB-7037	no	272.69
E-MTAB-5061	no	3.68
E-HCAD-10	no	1.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

132 targeting PIP4K2A, 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-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777

Literature-anchored findings (GeneRIF, showing 40)

• translocation by protein kinase C is required for platelet alpha-granule secretion (PMID:12509423)
• Single nucleotide polymorphism is associated with schizophfenia. (PMID:16801950)
• The strongest evidence for schizophrenia association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes. This SNP leads to a change in protein composition. (PMID:17410640)
• PIP5K2A gene is implicated in schizophrenia in Chinese population (PMID:17555944)
• rs11013052 was significantly associated with schizophrenia in this Indonesian family sample (PMID:18314871)
• unlike PtdIns5P production enhanced by cell stress, we show that this pool of PtdIns5P is specifically regulated by the inositol lipid kinase PIP4K2a (PMID:18364242)
• We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular correlate of neuronal M channels. (PMID:18545987)
• study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population (PMID:19475563)
• PIP5K2A is a novel signaling element in the regulation of EAAT3 activity (PMID:19644675)
• PIP4KIIA may be one of the factors related to the regulation of the beta-globin gene expression and the different levels of Hb H in alpha-thalassemic patients (PMID:19656170)
• A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. (PMID:19937977)
• PIP4Kbeta interacts with and modulates nuclear localization of the PIP4Kalpha. (PMID:20583997)
• Studies indicate that the gene PIP5K2A was significantly elevated in stroma cells in distant metastasis group, compared to stroma in no distant metastasis group. (PMID:21124964)
• The present study demonstrated that expression of PIP4K2A mRNA is significantly increased in LCL derived from patients with schizophrenia (PMID:21377334)
• PIP5K2A variant influences susceptibility to schizophrenia in the Russian population of Siberia. Authors studied 355 patients with schizophrenic disorders from the Russian population of Siberia. (PMID:23739505)
• Variation at 10p12.2 (PIP4K2A) and 10p14 (GATA3) influences risk of acute lymphoblastic anemia and tumor subtype. (Meta-analysis) (PMID:23996088)
• The data suggest that PI5P4Ka N251S does not significantly differ in activity from the wild-type enzyme, throwing a new light on its association with schizophrenia. (PMID:24081551)
• Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. (PMID:24086693)
• Knocking down PI5P4Kalpha and beta in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K beta and deficient for p53 impaired growth on plastic and in xenografts. (PMID:24209622)
• PIP4K2A to be essential for the clonogenic and leukemia-initiating potential of human AML cells, and for the clonogenic potential of murine MLL-AF9 AML cells. (PMID:24681948)
• We also showed that PIPKIIalpha silencing can induce alpha and gamma globin expression and decrease cell proliferation in K562 cells. (PMID:24788727)
• The diplotype ATTGCT/ATTGCT of the PIP4K2A gene confers approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. (PMID:25025909)
• PIP5K2A is possibly involved in a mechanism protecting against tardive dyskinesia-inducing neurotoxicity. (PMID:25548108)
• meta-analysis of association of SNPs rs7088318 and rs4748793 and acute lymphoblastic leukemia susceptibility (PMID:27149463)
• the rs7088318 (PIP4K2A) and rs2239633 (CEBPE) polymorphisms were not associated with ALL risk. (PMID:28476190)
• The PIP4K2A plays a critical role in intracellular cholesterol transport by upregulating PI(4,5)P2 levels in the peroxisomal membrane. (PMID:29353240)
• Recombinant PIP4K2A has the RNA binding activity and can associate specifically with Plasmodium 3’UTR RNAs. (PMID:29518392)
• Fine-mapping at chromosome 10p12 identified rs4748812 variant in PIP4K2A which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. This variant was found associated with childhood acute lymphoblastic leukemia. (PMID:29923177)
• PIP4K2A competes with PTEN for physical interaction with p85 and induces proteasome-mediated degradation, thus, demonstrating an essential tumor suppressive role in glioblastoma. (PMID:30898893)
• the loss of PIP4Ks (PIP4K2A, PIP4K2B, and PIP4K2C) in vitro results in a paradoxical increase in PI(4,5)P2 and a concomitant increase in insulin-stimulated production of PI(3,4,5)P3. (PMID:31091439)
• study provides additional evidence of the involvement of members of the PIP4K2 family, in particular PIP4K2A and PIP4K2C, in AML (PMID:31109595)
• Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase. (PMID:32218783)
• Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain. (PMID:32449185)
• Genetic polymorphisms of PIP5K2A and course of schizophrenia. (PMID:33092542)
• PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay. (PMID:33984270)
• Pharmacological inhibition of PI5P4Kalpha/beta disrupts cell energy metabolism and selectively kills p53-null tumor cells. (PMID:34001596)
• Thermal proteome profiling identifies PIP4K2A and ZADH2 as off-targets of Polo-like kinase 1 inhibitor volasertib. (PMID:34143546)
• Association of PIP4K2A Polymorphisms with Alcohol Use Disorder. (PMID:34681036)
• Contributions of ARID5B, IKZF1, PIP4K2A, and GATA3 Gene Polymorphisms to Childhood Acute Lymphoblastic Leukemia in a Chinese Population. (PMID:36952466)
• Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis. (PMID:38059827)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pip4k2aa	ENSDARG00000003776
danio_rerio	pip4k2ab	ENSDARG00000063544
mus_musculus	Pip4k2a	ENSMUSG00000026737
rattus_norvegicus	AABR07028769.1	ENSRNOG00000016670
drosophila_melanogaster	PIP4K	FBGN0039924
caenorhabditis_elegans		WBGENE00004088

Paralogs (6): PIP5K1B (ENSG00000107242), PIP5K1A (ENSG00000143398), PIP4K2C (ENSG00000166908), PIP5KL1 (ENSG00000167103), PIP5K1C (ENSG00000186111), PIP4K2B (ENSG00000276293)

Protein

Protein identifiers

Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha — P48426 (reviewed: P48426)

Alternative names: 1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha, Diphosphoinositide kinase 2-alpha, PIP5KIII, Phosphatidylinositol 5-Phosphate 4-Kinase, Phosphatidylinositol 5-phosphate 4-kinase type II alpha, PtdIns(4)P-5-kinase B isoform, PtdIns(4)P-5-kinase C isoform, PtdIns(5)P-4-kinase isoform 2-alpha

All UniProt accessions (3): P48426, H7BXS3, S4R320

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Has both ATP- and GTP-dependent kinase activities. May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. Required for lysosome-peroxisome membrane contacts and intracellular cholesterol transport through modulating peroxisomal PtdIns(4,5)P2 level. In collaboration with PIP4K2B, has a role in mediating autophagy in times of nutrient stress. Required for autophagosome-lysosome fusion and the regulation of cellular lipid metabolism. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size. Negatively regulates insulin signaling through a catalytic-independent mechanism. PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3.

Subunit / interactions. Homodimer. Interacts with PIP4K2B; the interaction may regulate localization to the nucleus. Probably interacts with PIP5K1A; the interaction inhibits PIP5K1A kinase activity.

Subcellular location. Cell membrane. Nucleus. Lysosome. Cytoplasm. Photoreceptor inner segment. Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. Expressed ubiquitously, with high levels in the brain. Present in most tissues, except notably skeletal muscle and small intestine.

Post-translational modifications. Phosphorylated in tyrosines. Phosphorylation is induced by light and increases kinase activity.

Activity regulation. In rod outer segments, activated by light. Inhibited by I-OMe tyrphostin AG-538 (I-OMe-AG-538), acting as an ATP-competitive inhibitor.

Isoforms (2)

UniProt ID	Names	Canonical?
P48426-1	1	yes
P48426-2	2

RefSeq proteins (2): NP_001316991, NP_005019* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002498	PInositol-4-P-4/5-kinase_core	Domain
IPR023610	PInositol-4/5-P-5/4-kinase	Family
IPR027483	PInositol-4-P-4/5-kinase_C_sf	Homologous_superfamily
IPR027484	PInositol-4-P-5-kinase_N	Homologous_superfamily

Pfam: PF01504

Enzyme classification (BRENDA):

• EC 2.7.1.149 — 1-phosphatidylinositol-5-phosphate 4-kinase (BRENDA: 9 organisms, 17 substrates, 83 inhibitors, 6 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0039–0.0942	6

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ADP + H(+) (RHEA:12280)
• 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + GTP = 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + GDP + H(+) (RHEA:55964)
• 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + ATP = 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ADP + H(+) (RHEA:55992)

UniProt features (52 total): strand 16, helix 11, modified residue 5, sequence conflict 5, mutagenesis site 3, turn 3, sequence variant 2, region of interest 2, initiator methionine 1, chain 1, splice variant 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
6UX9	X-RAY DIFFRACTION	1.71
6YM4	X-RAY DIFFRACTION	1.95
7N7K	X-RAY DIFFRACTION	2
6YM3	X-RAY DIFFRACTION	2.05
8C8C	X-RAY DIFFRACTION	2.1
7N7J	X-RAY DIFFRACTION	2.1
7N6Z	X-RAY DIFFRACTION	2.2
6OSP	X-RAY DIFFRACTION	2.21
7N7N	X-RAY DIFFRACTION	2.3
9OLE	X-RAY DIFFRACTION	2.4
6YM5	X-RAY DIFFRACTION	2.5
7N71	X-RAY DIFFRACTION	2.5
9L5Q	X-RAY DIFFRACTION	2.5
2YBX	X-RAY DIFFRACTION	2.56
7N7M	X-RAY DIFFRACTION	2.6
7N7L	X-RAY DIFFRACTION	2.7
7N7O	X-RAY DIFFRACTION	2.7
11AD	X-RAY DIFFRACTION	2.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48426-F1	86.87	0.72

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 (5): 145, 2, 3, 14, 89

Mutagenesis-validated functional residues (3):

Position	Phenotype
131	abolishes catalytic activity; when associated with f-138.
138	abolishes catalytic activity; when associated with l-131.
273	loss of kinase activity. increases accumulation of lysosomal cholesterol.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-6811555	PI5P Regulates TP53 Acetylation
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847453	Synthesis of PIPs in the nucleus

MSigDB gene sets: 401 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, MYOGENIN_Q6, GOBP_VACUOLE_ORGANIZATION, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_VESICLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_MEMBRANE_FUSION, MORI_IMMATURE_B_LYMPHOCYTE_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (11): regulation of autophagy (GO:0010506), megakaryocyte development (GO:0035855), negative regulation of insulin receptor signaling pathway (GO:0046627), phosphatidylinositol phosphate biosynthetic process (GO:0046854), autophagosome-lysosome fusion (GO:0061909), vesicle-mediated cholesterol transport (GO:0090119), 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate biosynthetic process (GO:1902635), positive regulation of autophagosome assembly (GO:2000786), lipid metabolic process (GO:0006629), regulation of signal transduction (GO:0009966), phosphatidylinositol metabolic process (GO:0046488)

GO Molecular Function (9): ATP binding (GO:0005524), 1-phosphatidylinositol-4-phosphate 5-kinase activity (GO:0016308), 1-phosphatidylinositol-5-phosphate 4-kinase activity (GO:0016309), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphatidylinositol kinase activity (GO:0052742)

GO Cellular Component (11): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), nucleoplasm (GO:0005654), lysosome (GO:0005764), autophagosome (GO:0005776), cytosol (GO:0005829), plasma membrane (GO:0005886), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
PI Metabolism	2
Regulation of TP53 Activity through Acetylation	1
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
phosphatidylinositol kinase activity	2
autophagy	1
regulation of catabolic process	1
megakaryocyte differentiation	1
myeloid cell development	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
glycerophospholipid biosynthetic process	1
vesicle fusion	1
macroautophagy	1
vesicle-mediated transport	1
cytosolic transport	1
intracellular cholesterol transport	1
phosphatidylinositol phosphate biosynthetic process	1
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate metabolic process	1
autophagosome assembly	1
positive regulation of macroautophagy	1
positive regulation of vacuole organization	1
positive regulation of organelle assembly	1
regulation of autophagosome assembly	1
primary metabolic process	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
phosphorus metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
lipid kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1

Protein interactions and networks

STRING

1692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIP4K2A	TUT1	Q9H6E5	822
PIP4K2A	PAPOLA	P51003	798
PIP4K2A	GLE1	Q53GS7	775
PIP4K2A	AP2M1	P20172	724
PIP4K2A	TLN2	Q9Y4G6	708
PIP4K2A	ARID5B	Q14865	694
PIP4K2A	TLN1	Q9Y490	692
PIP4K2A	PAPOLG	Q9BWT3	691
PIP4K2A	CEBPE	Q15744	670
PIP4K2A	SON	P18583	639
PIP4K2A	PI4K2A	Q9BTU6	639
PIP4K2A	PAPOLB	Q9NRJ5	637
PIP4K2A	PTF1A	Q7RTS3	613
PIP4K2A	LHPP	Q9H008	576
PIP4K2A	CACNB2	Q08289	562
PIP4K2A	PTEN	P60484	562

IntAct

103 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
EAF1	ELL2	psi-mi:“MI:0914”(association)	0.840
STK11	HSP90AA1	psi-mi:“MI:0914”(association)	0.740
PIP4K2A	AHCYL1	psi-mi:“MI:0914”(association)	0.730
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
FAM90A1	KPNA3	psi-mi:“MI:0914”(association)	0.670
NEMP1	RGPD8	psi-mi:“MI:0914”(association)	0.640
ZRANB2	PIP4K2A	psi-mi:“MI:0914”(association)	0.610
PIP4K2A	MEIS3	psi-mi:“MI:0915”(physical association)	0.560
RAC1	PIP4K2A	psi-mi:“MI:0915”(physical association)	0.540
RAC1	PIP4K2A	psi-mi:“MI:0407”(direct interaction)	0.540
SUN2	POTEF	psi-mi:“MI:0914”(association)	0.530
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
PRICKLE3	SIAH2	psi-mi:“MI:0914”(association)	0.530
PIP4K2B	AHCYL1	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ZNF428	PIP4K2A	psi-mi:“MI:0914”(association)	0.530
HDGFL2	CDC7	psi-mi:“MI:0914”(association)	0.530
GPBP1L1	CNOT1	psi-mi:“MI:0914”(association)	0.530
SUN2	PIP4K2A	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
env	PGRMC1	psi-mi:“MI:0914”(association)	0.460

BioGRID (422): PIP4K2A (Affinity Capture-MS), PIP4K2A (Affinity Capture-MS), PIP4K2A (Affinity Capture-MS), PIP4K2A (Affinity Capture-MS), PIP4K2A (Co-fractionation), PIP4K2A (Co-fractionation), PIP4K2A (Co-fractionation), PIP4K2A (Co-fractionation), PIP4K2A (Co-fractionation), SKP1 (Co-fractionation), PIP4K2A (Synthetic Lethality), PIP4K2A (Affinity Capture-MS), PIP4K2A (Affinity Capture-MS), PIP4K2A (Affinity Capture-MS), PIP4K2A (Biochemical Activity)

ESM2 similar proteins: A7MBL8, B3EX61, G3V7Q0, O00763, O02810, O13010, O60942, O70172, O88370, O88377, O94806, P10687, P10894, P48426, P69341, P78356, P97789, Q0P5F7, Q13613, Q15139, Q15147, Q5F356, Q5PQ01, Q5R488, Q6DIX1, Q6GL14, Q6IQ26, Q6IQE1, Q6PAL8, Q7TT16, Q80V72, Q80XI4, Q8BKC8, Q8BPM2, Q8BWW9, Q8IZH2, Q8K1Y2, Q8NFU5, Q8TBX8, Q91XU3

Diamond homologs: O13010, O13853, O70161, O70172, O88370, O88377, O96838, P38994, P48426, P78356, Q0P5F7, Q55GN6, Q5F356, Q5I6B8, Q5PQ01, Q5R488, Q6GL14, Q6IQE1, Q80XI4, Q8L850, Q8RY89, Q8TBX8, Q91XU3, Q9R0I8, Q9SLG9, A2A3N6, D3ZSI8, O14986, O48709, O60331, P70181, P70182, Q56YP2, Q5CZZ9, Q5ZJ58, Q6EX42, Q8I239, Q8L796, Q99755, Q9M149

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PRKD1	down-regulates	PIP4K2A	phosphorylation
PIP4K2A	“up-regulates quantity”	“1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)”	“chemical modification”
PIP4K2A	“down-regulates quantity”	“1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)”	“chemical modification”
CSNK2A1	up-regulates	PIP4K2A	phosphorylation
ARF6	“up-regulates activity”	PIP4K2A

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	0
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3703 predictions. Top by Δscore:

Variant	Effect	Δscore
10:22541802:A:AC	donor_gain	1.0000
10:22541803:C:CC	donor_gain	1.0000
10:22541803:CTTT:C	donor_gain	1.0000
10:22541806:T:A	donor_gain	1.0000
10:22541817:A:AC	donor_gain	1.0000
10:22541817:AATT:A	donor_gain	1.0000
10:22542048:C:CC	acceptor_gain	1.0000
10:22550653:TCTTA:T	donor_loss	1.0000
10:22550654:CTTA:C	donor_loss	1.0000
10:22550655:TTAC:T	donor_loss	1.0000
10:22550656:TAC:T	donor_loss	1.0000
10:22550657:A:T	donor_loss	1.0000
10:22550769:TGGC:T	acceptor_gain	1.0000
10:22550771:GCC:G	acceptor_loss	1.0000
10:22550773:C:CC	acceptor_gain	1.0000
10:22550773:C:CG	acceptor_loss	1.0000
10:22573462:A:C	acceptor_gain	1.0000
10:22589082:A:C	donor_gain	1.0000
10:22591624:ATTAC:A	donor_loss	1.0000
10:22591625:TTA:T	donor_loss	1.0000
10:22591626:TACCT:T	donor_loss	1.0000
10:22591627:ACCTG:A	donor_loss	1.0000
10:22591786:CCGGG:C	acceptor_gain	1.0000
10:22591787:C:T	acceptor_gain	1.0000
10:22591787:CGGG:C	acceptor_gain	1.0000
10:22591788:G:T	acceptor_gain	1.0000
10:22591790:G:GC	acceptor_gain	1.0000
10:22591795:G:C	acceptor_gain	1.0000
10:22591795:G:GC	acceptor_gain	1.0000
10:22607922:CTCA:C	donor_loss	1.0000

AlphaMissense

2733 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:22537222:A:C	F400L	1.000
10:22537222:A:T	F400L	1.000
10:22537224:A:G	F400L	1.000
10:22537235:C:G	R396P	1.000
10:22537236:G:T	R396S	1.000
10:22537245:A:G	Y393H	1.000
10:22539977:T:A	K378N	1.000
10:22539977:T:G	K378N	1.000
10:22539981:A:T	V377D	1.000
10:22539986:T:A	K375N	1.000
10:22539986:T:G	K375N	1.000
10:22539993:G:T	A373D	1.000
10:22540002:G:T	A370D	1.000
10:22542004:C:T	G279E	1.000
10:22542005:C:G	G279R	1.000
10:22542005:C:T	G279R	1.000
10:22542010:A:G	L277P	1.000
10:22542013:A:G	L276P	1.000
10:22542015:A:C	S275R	1.000
10:22542015:A:T	S275R	1.000
10:22542017:T:G	S275R	1.000
10:22542022:T:A	D273V	1.000
10:22542043:A:G	L266P	1.000
10:22550675:A:G	L259P	1.000
10:22550738:A:G	F238S	1.000
10:22550747:T:A	D235V	1.000
10:22550747:T:G	D235A	1.000
10:22550748:C:G	D235H	1.000
10:22550749:T:A	K234N	1.000
10:22550749:T:G	K234N	1.000

dbSNP variants (sampled 300 via entrez): RS1000001944 (10:22707876 G>A,C), RS1000003633 (10:22669827 A>G), RS1000018222 (10:22658088 A>G), RS1000020510 (10:22596163 C>T), RS1000026760 (10:22566672 T>A), RS1000056955 (10:22705552 C>T), RS1000069575 (10:22622575 G>A), RS1000077603 (10:22567057 C>G,T), RS1000091012 (10:22632410 T>A,C), RS1000101582 (10:22714010 A>G), RS1000133856 (10:22693314 A>C,G), RS1000139263 (10:22627125 C>T), RS1000157514 (10:22701925 T>C), RS1000198471 (10:22626872 C>G), RS1000217022 (10:22550930 G>A)

Disease associations

OMIM: gene MIM:603140 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001762_423	Obesity-related traits	9.000000e-06
GCST002158_1	Acute lymphoblastic leukemia (B-cell precursor)	2.000000e-09
GCST003123_23	Severe influenza A (H1N1) infection	9.000000e-14
GCST005315_6	Acute lymphoblastic leukemia (childhood)	3.000000e-20
GCST005832_8	Acute lymphoblastic leukemia in childhood (B cell precursor)	2.000000e-10
GCST007624_6	Positive urgency	8.000000e-07
GCST008839_472	Height	6.000000e-14
GCST009638_6	B-cell acute lymphoblastic leukaemia	3.000000e-15
GCST90002389_438	Lymphocyte percentage of white cells	9.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003940	physical activity
EFO:1001488	influenza A (H1N1)
EFO:0006946	behavioural disinhibition measurement
EFO:0007993	lymphocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795194 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 15,748 (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
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL2104863	IMANIXIL	2	1,142
CHEMBL230011	TG100-115	2	1,504

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol phosphate kinases

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
BAY-091	Inhibition	8.89	pIC50
BAY-297	Inhibition	8.89	pIC50

ChEMBL bioactivities

262 potent at pChembl≥5 of 284 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	BAY-091
8.89	IC50	1.3	nM	BAY-091
8.70	IC50	2	nM	CHEMBL5280127
8.59	IC50	2.6	nM	BAY-091
8.52	IC50	3	nM	BAY-091
8.52	IC50	3	nM	CHEMBL5280127
8.30	IC50	5	nM	CHEMBL5276719
8.26	IC50	5.5	nM	CHEMBL5276719
8.15	IC50	7	nM	CHEMBL5270765
8.10	IC50	8	nM	BAY-091
8.07	IC50	8.5	nM	BAY-091
8.05	IC50	9	nM	BAY-091
8.00	IC50	10	nM	CHEMBL5288342
7.89	IC50	13	nM	CHEMBL5290005
7.85	IC50	14	nM	CHEMBL5271652
7.85	IC50	14	nM	CHEMBL5280127
7.80	IC50	16	nM	BAY-091
7.79	IC50	16.4	nM	BAY-091
7.72	IC50	19	nM	CHEMBL5277824
7.70	IC50	20	nM	CHEMBL5270765
7.70	IC50	19.95	nM	CHEMBL5277633
7.68	IC50	21	nM	BAY-091
7.57	IC50	27	nM	CHEMBL5276719
7.54	IC50	29	nM	CHEMBL5280127
7.52	IC50	30	nM	CHEMBL5288492
7.52	IC50	30	nM	CHEMBL5270765
7.43	IC50	37	nM	CHEMBL5282226
7.40	IC50	40	nM	CHEMBL5284796
7.40	IC50	40	nM	CHEMBL5271804
7.40	IC50	39.81	nM	CHEMBL5275392
7.38	IC50	42	nM	CHEMBL5273876
7.33	IC50	47	nM	CHEMBL5272762
7.30	IC50	50.12	nM	CHEMBL5420914
7.29	IC50	51	nM	CHEMBL5271652
7.23	IC50	59	nM	CHEMBL5276719
7.21	IC50	61	nM	CHEMBL5265849
7.20	IC50	63.1	nM	CHEMBL5287672
7.18	IC50	66	nM	CHEMBL5274835
7.16	IC50	69	nM	CHEMBL5290005
7.15	IC50	71	nM	CHEMBL5277824
7.13	IC50	74	nM	CHEMBL5275703
7.10	IC50	79.43	nM	CHEMBL5269721
7.10	IC50	79.43	nM	CHEMBL5410949
7.06	IC50	88	nM	CHEMBL5288989
7.05	IC50	89	nM	CHEMBL5273777
7.02	Kd	95.1	nM	CHEMBL3752910
7.00	IC50	100	nM	CHEMBL5285486
7.00	IC50	100	nM	CHEMBL5438658
7.00	IC50	100	nM	CHEMBL5412191
7.00	IC50	100	nM	CHEMBL5394000

PubChem BioAssay actives

2 with measured affinity, of 6100 total; 2 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
N-(3-chloro-4-methoxyphenyl)-1-phenylpyrazolo[3,4-d]pyrimidin-4-amine	1956677: Inhibition of recombinant PI5P4Kalpha (unknown origin) expressed in Escherichia coli BL21(DE3) by ADP-Glo reagent based assay	ic50	1.2589	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	1425113: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	7.0170	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
mercuric bromide	decreases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
decabromobiphenyl ether	decreases expression	1
terbufos	decreases methylation	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Air Pollutants, Occupational	affects expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects methylation	1

ChEMBL screening assays

136 unique, capped per target: 134 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1837980	Binding	Inhibition of human PIP5K2alpha in HL60 cells lysate at 10 uM using post probe-labeling by LC-MS/MS analysis relative to control	Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β. — Bioorg Med Chem Lett
CHEMBL2354223	Functional	PubChem BioAssay. qHTS for Inhibitors of phosphatidylinositol 5-phosphate 4-kinase (PI5P4K). (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2AT	Abcam HeLa PIP4K2A KO	Cancer cell line	Female
CVCL_D7XH	Ubigene A-549 PIP4K2A KO	Cancer cell line	Male
CVCL_D8SY	Ubigene HCT 116 PIP4K2A KO	Cancer cell line	Male
CVCL_D9NF	Ubigene HEK293 PIP4K2A KO	Transformed cell line	Female
CVCL_E0KS	Ubigene HeLa PIP4K2A KO	Cancer cell line	Female
CVCL_TD87	HAP1 PIP4K2A (-) 1	Cancer cell line	Male
CVCL_TD88	HAP1 PIP4K2A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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