PI4K2A

Summary

PI4K2A (phosphatidylinositol 4-kinase type 2 alpha, HGNC:30031) is a protein-coding gene on chromosome 10q24.2, encoding Phosphatidylinositol 4-kinase type 2-alpha (Q9BTU6). Membrane-bound phosphatidylinositol-4 kinase (PI4-kinase) that catalyzes the phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P), a lipid that plays important roles in endocytosis, Golgi function, protein sorting and membrane trafficking and i….

Phosphatidylinositolpolyphosphates (PtdInsPs) are centrally involved in many biologic processes, ranging from cell growth and organization of the actin cytoskeleton to endo- and exocytosis. PI4KII phosphorylates PtdIns at the D-4 position, an essential step in the biosynthesis of PtdInsPs (Barylko et al., 2001 [PubMed 11244087]).

Source: NCBI Gene 55361 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities (Strong, GenCC)
• Clinical variants (ClinVar): 41 total — 1 pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_018425

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30031
Approved symbol	PI4K2A
Name	phosphatidylinositol 4-kinase type 2 alpha
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	PI4KII, DKFZP761G1923, PIK42A
Ensembl gene	ENSG00000155252
Ensembl biotype	protein_coding
OMIM	609763
Entrez	55361

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000370631, ENST00000880057, ENST00000880058, ENST00000880059, ENST00000880060, ENST00000880061, ENST00000931595, ENST00000931596, ENST00000931597, ENST00000941613, ENST00000941614

RefSeq mRNA: 1 — MANE Select: NM_018425 NM_018425

CCDS: CCDS7469

Canonical transcript exons

ENST00000370631 — 9 exons

Exon	Start	End
ENSE00001453188	97673581	97676434
ENSE00003529686	97667061	97667120
ENSE00003552455	97666438	97666571
ENSE00003558325	97664885	97664984
ENSE00003569936	97656821	97656974
ENSE00003622102	97650941	97651141
ENSE00003625782	97662907	97662968
ENSE00003650300	97656285	97656416
ENSE00003978209	97640671	97641177

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 92.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9396 / max 138.0397, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106453	20.8978	1805
106454	1.6969	1007
106452	1.3450	873

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	92.56	gold quality
right adrenal gland cortex	UBERON:0035827	88.81	gold quality
right adrenal gland	UBERON:0001233	88.12	gold quality
left adrenal gland	UBERON:0001234	88.08	gold quality
decidua	UBERON:0002450	87.96	gold quality
stromal cell of endometrium	CL:0002255	87.92	gold quality
left adrenal gland cortex	UBERON:0035825	87.88	gold quality
adrenal cortex	UBERON:0001235	87.70	gold quality
adrenal gland	UBERON:0002369	87.02	gold quality
right frontal lobe	UBERON:0002810	86.59	gold quality
pigmented layer of retina	UBERON:0001782	86.00	gold quality
prefrontal cortex	UBERON:0000451	85.97	gold quality
amniotic fluid	UBERON:0000173	85.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.24	gold quality
islet of Langerhans	UBERON:0000006	85.00	gold quality
pons	UBERON:0000988	84.86	gold quality
ileal mucosa	UBERON:0000331	84.64	gold quality
esophagus mucosa	UBERON:0002469	84.64	gold quality
mucosa of stomach	UBERON:0001199	84.55	gold quality
hypothalamus	UBERON:0001898	84.51	gold quality
adenohypophysis	UBERON:0002196	84.44	gold quality
nucleus accumbens	UBERON:0001882	84.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.30	gold quality
gall bladder	UBERON:0002110	84.24	gold quality
skin of leg	UBERON:0001511	83.96	gold quality
substantia nigra pars compacta	UBERON:0001965	83.93	gold quality
frontal cortex	UBERON:0001870	83.91	gold quality
dorsal root ganglion	UBERON:0000044	83.74	gold quality
esophagus	UBERON:0001043	83.53	gold quality
neocortex	UBERON:0001950	83.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting PI4K2A, 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-9-5P	100.00	72.28	2361
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-3202	99.66	67.70	2737

Literature-anchored findings (GeneRIF, showing 28)

• Association of T cell antigen CD7 with type II phosphatidylinositol-4 kinase, a key component in pathways of inositol phosphate turnover. (PMID:12594831)
• The active site of this enzyme occurs in a p97/valosin-containing-protein-rich fraction of the endoplasmic reticulum (PMID:12650639)
• propose that PI4KIIalpha establishes the Golgi’s unique lipid-defined organelle identity by generating PI(4)P-rich domains that specify the docking of the AP-1 coat machinery (PMID:12914695)
• The linkage of CD63 with PI 4-kinase type II may result in the recruitment of this signaling enzyme to specific membrane locations in the platelet where it influences phosphoinositide-dependent signaling and platelet spreading. (PMID:15711748)
• changes in membrane environment can regulate PI4KIIalpha activity. (PMID:16249177)
• phosphatidylinositol 4-kinase IIalpha is necessary for the correct endocytic traffic and downregulation of activated epidermal growth factor receptor. (PMID:16443754)
• both the kinase activity and the sorting signal present in PI4KIIalpha are necessary to rescue endosomal PI4KIIalpha siRNA-induced mutant phenotypes (PMID:18256276)
• AP-3 and BLOC-1 act, either in concert or sequentially, to specify sorting of PI4KIIalpha along the endocytic route. (PMID:19010779)
• Dvl directly interacted with and activated PI4KII alpha by increasing its V(max) for ATP and PtdIns. In addition, Dvl regulated PI4KII alpha and PIP5KI via different domains. (PMID:19561074)
• PI4KIIalpha is a novel regulator of tumor growth by its action on angiogenesis and HIF-1alpha regulation. (PMID:20154717)
• Results suggest that the phosphatidylinositol 4-kinase 2-alpha gene may not be a cause of autosomal recessive hereditary spastic paraplegia in humans. (PMID:21190509)
• Knockdown of PI4KIIalpha inhibits EGF-stimulated Akt phosphorylation. (PMID:21218173)
• The Hermansky-Pudlak syndrome complex BLOC-1 and its cargo PI4KIIalpha interact with regulators of the actin cytoskeleton. (PMID:23676666)
• The palmitoylation insertion contributes to the phosphatidylinositol-binding pocket and anchors PI4KIIalpha to the membrane. (PMID:24675427)
• structure and phylogenetic analysis (PMID:24752359)
• phosphatidylinositol 4-kinase IIalpha knockdown inhibited vesicle-associated membrane protein 3 trafficking to perinuclear membranes and impaired the rate of VAMP3-mediated recycling of the transferrin receptor (PMID:25002402)
• PI4K2A is a novel regulator of vesicular trafficking and neurotransmission in the brain. (PMID:25083612)
• PI4KIIalpha is a specific downstream effector of GABARAP and it generates PI4P, which has a key role in the final stage of autophagy. (PMID:26038556)
• Here two crystal structures are presented: the structure of human PIK42A and the structure of PIK42B containing a nucleoside analogue. (PMID:26143926)
• PtdIns4KIIalpha regulates receptor sorting at early endosomes through a PtdIns(4)P-dependent pathway and contributes substrate for the synthesis of endosomal PtdIns(4,5)P2. (PMID:26823017)
• RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIa and PI4KIIa in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. (PMID:27068535)
• Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIbeta mRNA are associated with human cancers. This finding supports the cell data and suggests that PI4KIIbeta may be a clinically significant suppressor of invasion. (PMID:27798239)
• PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KIIalpha, the use of which will facilitate evaluations of PI4KIIalpha as a cancer therapeutic target. (PMID:28827373)
• These results indicate that GABARAP and PI4K2A interact tightly. Although lipidation of GABARAP is essential for its role in autophagy, here we show that its lipidation is not required for the interaction of GABARAP and PI4K2A. (PMID:29792687)
• both integrin alpha3beta1 and PI4KIIalpha co-localized to the trans-Golgi network, where they physically interacted with each other, and PI4KIIalpha specifically associated with integrin alpha3 but not alpha5 (PMID:30659093)
• Therapeutic targeting of the PI4K2A/PKR lysosome network is critical for misfolded protein clearance and survival in cancer cells. (PMID:31554935)
• High expression of PI4K2A predicted poor prognosis of colon adenocarcinoma (COAD) and correlated with immunity. (PMID:35634680)
• PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy. (PMID:35880319)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pi4k2a	ENSDARG00000033666
mus_musculus	Pi4k2a	ENSMUSG00000025178
rattus_norvegicus	Pi4k2a	ENSRNOG00000014675
drosophila_melanogaster	Pi4KIIalpha	FBGN0037339
caenorhabditis_elegans		WBGENE00022501

Paralogs (1): PI4K2B (ENSG00000038210)

Protein

Protein identifiers

Phosphatidylinositol 4-kinase type 2-alpha — Q9BTU6 (reviewed: Q9BTU6)

Alternative names: Phosphatidylinositol 4-kinase type II-alpha

All UniProt accessions (1): Q9BTU6

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-bound phosphatidylinositol-4 kinase (PI4-kinase) that catalyzes the phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P), a lipid that plays important roles in endocytosis, Golgi function, protein sorting and membrane trafficking and is required for prolonged survival of neurons. Besides, phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P) is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3).

Subunit / interactions. Associates with the BLOC-1 and the AP-3 complexes; the BLOC-1 complex is required for optimal binding of PI4K2A to the AP-3 complex. Interacts with BLOC1S5 and DTNBP1. Interacts with FOS; this interaction may enhance phosphatidylinositol phosphorylation activity. Interacts with ITCH. Interacts with ATG9A.

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Membrane raft. Cell projection. Dendrite. Presynaptic cell membrane. Synapse. Synaptosome. Mitochondrion. Endosome. Endosome membrane. Cytoplasmic vesicle. Membrane. Cell membrane. Perikaryon. Neuron projection.

Tissue specificity. Widely expressed. Highest expression is observed in kidney, brain, heart, skeletal muscle, and placenta and lowest expression is observed in colon, thymus, and small intestine.

Post-translational modifications. Palmitoylated by ZDHHC3 and ZDHHC7 in the CCPCC motif. Palmitoylation is cholesterol-dependent, and required for TGN localization. Ubiquitinated by ITCH; this does not lead to proteasomal degradation.

Disease relevance. Neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities (NEDMSB) [MIM:620732] An autosomal recessive disorder characterized by failure to thrive, global developmental delay with intellectual disability and absent speech, seizures, hypotonia, inability to walk, orofacial dyskinesia, involuntary movements, and structural brain abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the PI3/PI4-kinase family. Type II PI4K subfamily.

RefSeq proteins (1): NP_060895* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000403	PI3/4_kinase_cat_dom	Domain
IPR039756	Lsb6/PI4K2	Family

Pfam: PF00454

Enzyme classification (BRENDA):

• EC 2.7.1.67 — 1-phosphatidylinositol 4-kinase (BRENDA: 26 organisms, 60 substrates, 371 inhibitors, 71 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.018–1.7	43
PHOSPHATIDYLINOSITOL	0.017–1	18
1-PHOSPHATIDYL-1D-MYO-INOSITOL	0.016–0.1	2
GTP	0.62	1

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ADP + H(+) (RHEA:19877)

UniProt features (81 total): mutagenesis site 24, helix 15, strand 10, region of interest 8, modified residue 7, binding site 4, lipid moiety-binding region 4, sequence variant 3, compositionally biased region 2, turn 2, chain 1, domain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5I0N	X-RAY DIFFRACTION	2.28
4YC4	X-RAY DIFFRACTION	2.58
4PLA	X-RAY DIFFRACTION	2.77
5EUT	X-RAY DIFFRACTION	2.8
4HNE	X-RAY DIFFRACTION	2.95
4HND	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTU6-F1	80.05	0.57

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 (4): 131–137; 152; 261–264; 346

Post-translational modifications (11): 1, 5, 9, 44, 47, 51, 462, 174, 175, 177, 178

Mutagenesis-validated functional residues (24):

Position	Phenotype
129	reduces enzyme activity, probably due to impaired membrane-association; when associated with e-275 and e-276.
152	abolishes enzyme activity.
157–159	abolishes enzyme activity.
163	reduces enzyme activity.
165–172	abolishes enzyme activity.
165	abolishes enzyme activity; when associated with a-168 and a-172.
166	reduces enzyme activity.
168	abolishes enzyme activity; when associated with a-165 and a-172.
172	abolishes enzyme activity; when associated with a-165 and a-168.
174–178	no effect on membrane-association.
174–178	abolishes palmitoylation and impairs membrane-association.
184	abolishes enzyme activity; when associated with a-349.
263	abolishes enzyme activity; when associated with a-345.
269	reduces enzyme activity by half.
275	reduces enzyme activity.
275	reduces enzyme activity, probably due to impaired membrane-association; when associated with e-129 and e-276.
276	reduces enzyme activity, probably due to impaired membrane-association; when associated with e-129 and e-275.
308	abolishes enzyme activity.
345	abolishes enzyme activity; when associated with a-263.
349	abolishes enzyme activity; when associated with a-184.
359	strongly reduced enzyme activity, probably due to impaired membrane-association. abolishes enzyme activity; when associa
365	reduces enzyme activity, probably due to impaired membrane-association. abolishes enzyme activity; when associated with
368	reduces enzyme activity, probably due to impaired membrane-association. abolishes enzyme activity; when associated with
445	reduces enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane

MSigDB gene sets: 350 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_ENDOSOME_ORGANIZATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOCC_TRANS_GOLGI_NETWORK, BLALOCK_ALZHEIMERS_DISEASE_UP, SASSON_RESPONSE_TO_FORSKOLIN_DN, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (5): phosphatidylinositol biosynthetic process (GO:0006661), Golgi organization (GO:0007030), endosome organization (GO:0007032), phosphatidylinositol phosphate biosynthetic process (GO:0046854), lipid metabolic process (GO:0006629)

GO Molecular Function (8): magnesium ion binding (GO:0000287), 1-phosphatidylinositol 4-kinase activity (GO:0004430), ATP binding (GO:0005524), AP-3 adaptor complex binding (GO:0035651), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (24): Golgi membrane (GO:0000139), mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), endosome (GO:0005768), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), dendrite (GO:0030425), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), growing cell tip (GO:0035838), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perikaryon (GO:0043204), membrane raft (GO:0045121), presynaptic active zone (GO:0048786), glutamatergic synapse (GO:0098978), Golgi apparatus (GO:0005794), BLOC-1 complex (GO:0031083), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
endomembrane system organization	2
bounding membrane of organelle	2
presynapse	2
biosynthetic process	1
phosphatidylinositol metabolic process	1
organelle organization	1
vesicle organization	1
glycerophospholipid biosynthetic process	1
primary metabolic process	1
metal ion binding	1
phosphatidylinositol kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
Golgi apparatus	1
intracellular membrane-bounded organelle	1
lysosome	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
Golgi apparatus subcompartment	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
neuron projection	1
dendritic tree	1
intracellular vesicle	1
early endosome	1
endosome membrane	1
site of polarized growth	1
cell tip	1
synaptic membrane	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PI4K2A	PI4KB	P78405	783
PI4K2A	PI4KA	P42356	761
PI4K2A	LRP6	O75581	702
PI4K2A	PIP4K2A	P48426	639
PI4K2A	PAPOLG	Q9BWT3	632
PI4K2A	WNT3A	P56704	622
PI4K2A	PIP5K1A	Q99755	605
PI4K2A	TUT1	Q9H6E5	586
PI4K2A	GABARAP	O95166	563
PI4K2A	PIP5K1C	O60331	551
PI4K2A	PAPOLA	P51003	549
PI4K2A	PAPOLB	Q9NRJ5	548
PI4K2A	OSBP	P22059	544
PI4K2A	EEA1	Q15075	519
PI4K2A	ANTXR1	Q9H6X2	516

IntAct

70 interactions, top by confidence:

A	B	Type	Score
GABARAP	IPO5	psi-mi:“MI:0914”(association)	0.590
ITCH	PI4K2A	psi-mi:“MI:0915”(physical association)	0.570
PI4K2A	ITCH	psi-mi:“MI:0915”(physical association)	0.570
PI4K2A	ITCH	psi-mi:“MI:0407”(direct interaction)	0.570
ITCH	PI4K2A	psi-mi:“MI:0403”(colocalization)	0.570
TSPAN3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
P2RX1	ATE1	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
PI4K2A	GABARAP	psi-mi:“MI:0914”(association)	0.530
IRGC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.530
TTC7A	PI4K2A	psi-mi:“MI:0915”(physical association)	0.400
ALDH1A1	PI4K2A	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
PI4K2A	NOS3	psi-mi:“MI:0915”(physical association)	0.370
RAD23A	PI4K2A	psi-mi:“MI:0915”(physical association)	0.370
CNOT1	IBTK	psi-mi:“MI:0914”(association)	0.350
PHF8	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
KIF3A	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
TPCN2	DDX11L8	psi-mi:“MI:0914”(association)	0.350
PACC1	DEGS1	psi-mi:“MI:0914”(association)	0.350
PVR	QSOX1	psi-mi:“MI:0914”(association)	0.350
TMEM231	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
FANCE	GNPAT	psi-mi:“MI:0914”(association)	0.350
MBLAC2	STAT3	psi-mi:“MI:0914”(association)	0.350
IRGC	RPS6KA3	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (113): PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), CLTB (Co-fractionation), PI4K2A (Co-fractionation), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), PI4K2A (Affinity Capture-MS)

ESM2 similar proteins: A2XFP3, A2ZI32, A4VCL2, B4JW99, B4LCX4, B8AIZ4, F4J2C8, O22775, O75063, O75072, P14599, P45895, P54360, P86275, Q0KHV6, Q10MQ0, Q2QXP0, Q2TBE6, Q5K027, Q5MJS3, Q5RH51, Q5SP46, Q5XIL2, Q5ZEQ8, Q5ZIK0, Q6DCQ8, Q6GX83, Q6H765, Q6PE18, Q701R1, Q701R2, Q86BJ3, Q8CBQ5, Q8CID3, Q8IXL6, Q8R507, Q8RXE1, Q8T5G8, Q8VCS3, Q93ZX7

Diamond homologs: P42951, Q08B31, Q28G26, Q2TBE6, Q49GP5, Q505I0, Q5XIL2, Q5ZIK0, Q6DCQ8, Q6PE18, Q8CBQ5, Q8TCG2, Q99M64, Q9BTU6, Q9UT42, Q6K881, Q9C671, Q9SI52

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ATR	down-regulates	PI4K2A
PI4K2A	down-regulates	CLSPN	phosphorylation
adenosine	“down-regulates activity”	PI4K2A	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	35
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3024432	NM_018425.4(PI4K2A):c.925C>T (p.Arg309Ter)	Pathogenic

SpliceAI

1552 predictions. Top by Δscore:

Variant	Effect	Δscore
10:97641173:AGGGG:A	donor_gain	1.0000
10:97641174:GGGG:G	donor_gain	1.0000
10:97641174:GGGGG:G	donor_gain	1.0000
10:97641175:G:GT	donor_gain	1.0000
10:97641175:GGG:G	donor_gain	1.0000
10:97641175:GGGG:G	donor_gain	1.0000
10:97641176:GG:G	donor_gain	1.0000
10:97641176:GGG:G	donor_gain	1.0000
10:97641176:GGGT:G	donor_loss	1.0000
10:97641177:GG:G	donor_gain	1.0000
10:97641177:GGTG:G	donor_loss	1.0000
10:97641179:T:G	donor_loss	1.0000
10:97650929:T:TA	acceptor_gain	1.0000
10:97650938:TA:T	acceptor_loss	1.0000
10:97650939:A:AG	acceptor_gain	1.0000
10:97650939:A:AT	acceptor_loss	1.0000
10:97650939:A:C	acceptor_loss	1.0000
10:97650939:AGAG:A	acceptor_gain	1.0000
10:97650940:G:GA	acceptor_gain	1.0000
10:97650940:GA:G	acceptor_gain	1.0000
10:97650940:GAGG:G	acceptor_gain	1.0000
10:97650940:GAGGA:G	acceptor_gain	1.0000
10:97653266:GACT:G	donor_gain	1.0000
10:97656278:A:AG	acceptor_gain	1.0000
10:97656278:ACT:A	acceptor_gain	1.0000
10:97656280:T:A	acceptor_gain	1.0000
10:97656283:A:G	acceptor_loss	1.0000
10:97656284:GGT:G	acceptor_gain	1.0000
10:97656284:GGTA:G	acceptor_gain	1.0000
10:97656412:CAAAG:C	donor_loss	1.0000

AlphaMissense

3123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:97641139:G:C	G133R	1.000
10:97641148:G:A	G136R	1.000
10:97641148:G:C	G136R	1.000
10:97641149:G:A	G136E	1.000
10:97650954:T:A	V150D	1.000
10:97650959:A:G	K152E	1.000
10:97650961:A:C	K152N	1.000
10:97650961:A:T	K152N	1.000
10:97650963:C:A	P153H	1.000
10:97650972:A:T	E156V	1.000
10:97650973:A:C	E156D	1.000
10:97650973:A:T	E156D	1.000
10:97650978:C:A	P158H	1.000
10:97650994:T:A	N163K	1.000
10:97650994:T:G	N163K	1.000
10:97651001:T:A	W166R	1.000
10:97651001:T:C	W166R	1.000
10:97651007:A:G	K168E	1.000
10:97651040:T:C	F179L	1.000
10:97651042:T:A	F179L	1.000
10:97651042:T:G	F179L	1.000
10:97651044:G:A	G180D	1.000
10:97651046:C:A	R181S	1.000
10:97651052:T:C	C183R	1.000
10:97651056:T:A	L184H	1.000
10:97651056:T:C	L184P	1.000
10:97651070:G:C	G189R	1.000
10:97651083:A:T	E193V	1.000
10:97651088:G:T	G195W	1.000
10:97651089:G:A	G195E	1.000

dbSNP variants (sampled 300 via entrez): RS1000042700 (10:97664432 C>A,T), RS1000245510 (10:97659291 C>T), RS1000346482 (10:97638916 T>C), RS1000458921 (10:97665908 T>C), RS1000465506 (10:97648906 A>G), RS1000511743 (10:97663873 G>A), RS1000557092 (10:97672999 T>G), RS1000590494 (10:97652475 A>G,T), RS1000690856 (10:97643550 G>A,C,T), RS1000795552 (10:97649349 G>A), RS1000834546 (10:97666212 A>G), RS1000879914 (10:97640448 G>C), RS1000880837 (10:97671696 A>G), RS1001005040 (10:97646465 C>A), RS1001202715 (10:97650724 A>T)

Disease associations

OMIM: gene MIM:609763 | disease phenotypes: MIM:620732

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities (MONDO:0958240)

Orphanet (0):

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000411	Protruding ear
HP:0000601	Hypotelorism
HP:0000737	Irritability
HP:0000763	Sensory neuropathy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001348	Brisk reflexes
HP:0001508	Failure to thrive
HP:0001761	Pes cavus
HP:0002046	Heat intolerance
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002179	Opisthotonus
HP:0002197	Generalized-onset seizure
HP:0002280	Enlarged cisterna magna
HP:0002310	Orofacial dyskinesia
HP:0002365	Hypoplasia of the brainstem
HP:0002509	Limb hypertonia
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0002719	Recurrent infections
HP:0003202	Skeletal muscle atrophy
HP:0003593	Infantile onset
HP:0008936	Axial hypotonia

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096619 (PROTEIN FAMILY), CHEMBL2251 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 222,014 (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
CHEMBL477	ADENOSINE	4	222,014

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol kinases

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

Ligand	Action	Affinity	Parameter
adenosine	Inhibition	5.0	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL293027	IC50	6000 nM

ChEMBL bioactivities

16 potent at pChembl≥5 of 89 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.84	IC50	1460	nM	CHEMBL5220205
5.43	Ki	3700	nM	CHEMBL63783
5.39	Ki	4100	nM	CHEMBL293027
5.30	Ki	5000	nM	CHEMBL413106
5.30	Ki	5000	nM	CHEMBL62835
5.22	IC50	6000	nM	CHEMBL293027
5.22	Ki	6000	nM	CHEMBL294590
5.22	IC50	6000	nM	CHEMBL63783
5.16	Ki	6900	nM	CHEMBL306444
5.15	IC50	7100	nM	2-AMINOPYRIDINE
5.14	IC50	7200	nM	CHEMBL413106
5.14	IC50	7200	nM	CHEMBL62835
5.08	Ki	8300	nM	CHEMBL291377
5.08	Ki	8400	nM	CHEMBL1321883
5.06	IC50	8700	nM	CHEMBL294590
5.05	Ki	9000	nM	CHEMBL304265

PubChem BioAssay actives

16 with measured affinity, of 208 total; 11 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
(2S)-2-[[2-(4-butyl-2-oxochromen-7-yl)oxyacetyl]amino]-3-(5-hydroxy-1H-indol-3-yl)propanoic acid	1917567: Inhibition of PI4K2A catalytic domain (unknown origin) assessed as enzyme residual activity incubated for 60 mins using ATP as substrate by ATP-Glo luminescent assay	ic50	1.4600	uM
9-cyclohexylpurin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	3.7000	uM
9-(1-adamantyl)purin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	4.1000	uM
9-cycloheptylpurin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	5.0000	uM
9-(1-methylcyclohexyl)purin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	5.0000	uM
9-cyclopentylpurin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	6.0000	uM
9-tert-butylpurin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	6.9000	uM
pyridin-2-amine	155650: Inhibitory activity (IC50) against human phosphatidylinositol 4-kinase at the ATP binding site	ic50	7.1000	uM
9-(2-fluorophenyl)purin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	8.3000	uM
[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	8.4000	uM
9-(2,2-dimethylpropyl)purin-6-amine	155653: Binding affinity (Ki) against human phosphatidylinositol 4-kinase	ki	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
cobaltous chloride	increases expression	2
Valproic Acid	affects expression, increases expression	2
Aflatoxin B1	increases methylation, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
afuresertib	increases expression	1
FR900359	affects phosphorylation	1
uranyl acetate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
aflatoxin B2	increases methylation	1
avobenzone	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases palmitoylation, decreases reaction	1
Caffeine	affects phosphorylation	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Oxygen	decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1

ChEMBL screening assays

29 unique, capped per target: 27 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL758625	Binding	Inhibition of Phosphatidylinositol 4-kinase of human epidermoid carcinoma A431 cells	Synthesis of echiguanine analogs and their ribofuranosyl glycosides that inhibit phosphatidylinositol 4-kinase — Bioorg Med Chem Lett
CHEMBL760329	Functional	Rate of phosphorylation was determined with that of mammalian PI using human erythrocyte PI 4-kinase at 200 uM substrate	Total synthesis of the four stereoisomers of dihexadecanoyl phosphatidylinositol and the substrate stereospecificity of human erythrocyte membrane phosphatidylinositol 4-kinase. — J Med Chem

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_B2AN	Abcam HeLa PI4K2A KO	Cancer cell line	Female
CVCL_D7X0	Ubigene A-549 PI4K2A KO	Cancer cell line	Male
CVCL_D8SD	Ubigene HCT 116 PI4K2A KO	Cancer cell line	Male
CVCL_D9MV	Ubigene HEK293 PI4K2A KO	Transformed cell line	Female
CVCL_E0K8	Ubigene HeLa PI4K2A KO	Cancer cell line	Female
CVCL_TD36	HAP1 PI4K2A (-) 1	Cancer cell line	Male
CVCL_TD37	HAP1 PI4K2A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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