PPIP5K2

Summary

PPIP5K2 (diphosphoinositol pentakisphosphate kinase 2, HGNC:29035) is a protein-coding gene on chromosome 5q21.1, encoding Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2 (O43314). Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4.

This gene encodes a member of the histidine acid phosphatase family of proteins. Despite containing a histidine acid phosphatase domain, the encoded protein functions as an inositol pyrophosphate kinase, and is thought to lack phosphatase activity. This kinase activity is the mechanism by which the encoded protein synthesizes high-energy inositol pyrophosphates, which act as signaling molecules that regulate cellular homeostasis and other processes. This gene may be associated with autism spectrum disorder in human patients.

Source: NCBI Gene 23262 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive 100 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 162 total
• Phenotypes (HPO): 5
• Druggable target: yes
• MANE Select transcript: NM_001276277

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29035
Approved symbol	PPIP5K2
Name	diphosphoinositol pentakisphosphate kinase 2
Location	5q21.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0433, VIP2, CFAP160
Ensembl gene	ENSG00000145725
Ensembl biotype	protein_coding
OMIM	611648
Entrez	23262

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 30 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000321521, ENST00000358359, ENST00000414217, ENST00000502481, ENST00000504083, ENST00000504275, ENST00000507310, ENST00000507921, ENST00000508935, ENST00000509597, ENST00000510672, ENST00000511022, ENST00000511724, ENST00000515845, ENST00000613674, ENST00000613907, ENST00000627916, ENST00000698750, ENST00000881489, ENST00000881490, ENST00000881491, ENST00000881492, ENST00000881493, ENST00000881494, ENST00000881495, ENST00000881496, ENST00000881497, ENST00000881498, ENST00000881499, ENST00000927929, ENST00000927930, ENST00000927931, ENST00000927932, ENST00000960518, ENST00000960519

RefSeq mRNA: 11 — MANE Select: NM_001276277 NM_001276277, NM_001281471, NM_001345871, NM_001345872, NM_001345873, NM_001345874, NM_001345875, NM_001345876, NM_001345877, NM_001345878, NM_015216

CCDS: CCDS34207, CCDS64212, CCDS75283, CCDS93758

Canonical transcript exons

ENST00000358359 — 31 exons

Exon	Start	End
ENSE00001551365	103120301	103120488
ENSE00002045150	103201522	103212799
ENSE00003462227	103149152	103149313
ENSE00003464438	103173858	103173972
ENSE00003470325	103173155	103173282
ENSE00003479790	103186320	103186439
ENSE00003482766	103158188	103158313
ENSE00003492532	103152648	103152749
ENSE00003499572	103168072	103168295
ENSE00003514615	103133453	103133648
ENSE00003520319	103155909	103155994
ENSE00003538425	103167179	103167320
ENSE00003552981	103147931	103148032
ENSE00003554174	103158452	103158573
ENSE00003568526	103159146	103159328
ENSE00003573053	103154834	103154943
ENSE00003593521	103146527	103146681
ENSE00003593771	103194900	103195025
ENSE00003594470	103177667	103177774
ENSE00003598622	103183234	103183407
ENSE00003618177	103184672	103184744
ENSE00003621210	103180021	103180188
ENSE00003664095	103151253	103151374
ENSE00003666740	103153848	103153934
ENSE00003674058	103136732	103136822
ENSE00003676084	103129306	103129703
ENSE00003678170	103177864	103177980
ENSE00003684551	103190842	103190982
ENSE00003685364	103154670	103154745
ENSE00003690020	103138384	103138469
ENSE00003974641	103187314	103187376

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.3424 / max 572.5707, expressed in 1810 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57838	22.2109	1785
57837	17.9955	1755
57839	3.4304	1323
57836	0.7034	377
203642	0.0022	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.26	gold quality
calcaneal tendon	UBERON:0003701	97.22	gold quality
cortical plate	UBERON:0005343	95.15	gold quality
blood vessel layer	UBERON:0004797	95.12	gold quality
ganglionic eminence	UBERON:0004023	95.10	gold quality
sural nerve	UBERON:0015488	94.33	gold quality
bone marrow cell	CL:0002092	94.08	gold quality
tibia	UBERON:0000979	93.81	gold quality
monocyte	CL:0000576	93.46	gold quality
bone marrow	UBERON:0002371	93.39	gold quality
mononuclear cell	CL:0000842	93.37	gold quality
rectum	UBERON:0001052	93.30	gold quality
leukocyte	CL:0000738	93.16	gold quality
ventricular zone	UBERON:0003053	93.16	gold quality
descending thoracic aorta	UBERON:0002345	93.15	gold quality
left ovary	UBERON:0002119	92.52	gold quality
body of pancreas	UBERON:0001150	92.40	gold quality
tibial nerve	UBERON:0001323	92.38	gold quality
left coronary artery	UBERON:0001626	92.32	gold quality
germinal epithelium of ovary	UBERON:0001304	92.24	gold quality
right coronary artery	UBERON:0001625	92.21	gold quality
right ovary	UBERON:0002118	92.15	gold quality
gall bladder	UBERON:0002110	92.12	gold quality
thoracic aorta	UBERON:0001515	91.99	gold quality
ascending aorta	UBERON:0001496	91.88	gold quality
mucosa of stomach	UBERON:0001199	91.71	gold quality
embryo	UBERON:0000922	91.65	gold quality
ovary	UBERON:0000992	91.58	gold quality
coronary artery	UBERON:0001621	91.41	gold quality
endometrium	UBERON:0001295	91.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

120 targeting PPIP5K2, 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-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 9)

• describe the PPIP5K2’s conformational dynamics, its unprecedented topological presentation of nucleotide and inositol phosphate, and the charge balance that facilitates partly associative in-line phosphoryl transfer (PMID:22119861)
• the specificity constants for PPIP5K2 revise upwards by one-to-two orders of magnitude the inherent catalytic activities of this enzyme, and we show its equilibrium point favours 80-90% depletion of InsP/-InsP. (PMID:23240582)
• The degree of nuclear localization of hPPIP5K2 was increased when S1006 was rendered non-phosphorylatable by its mutation to Ala. (PMID:26084399)
• SEZ6L, HISPPD1, FEZF1, SAMD11 gene variants may be associated with autism spectrum disorder. (PMID:26204995)
• This study characterized kinetic properties of the bifunctional inositol pyrophosphate 5-diphosphoinositol 1,2,3,4,6-pentakisphosphatekinase/inositol pyrophosphate, 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate phosphatase activities of full-length diphosphoinositol pentakisphosphate kinase 1 and 2. (PMID:28126903)
• demonstration that PPIP5K2 has a role in hearing in humans indicates that PP-IP signaling is important to hair cell maintenance and function within inner ear (PMID:29590114)
• Data suggest that the enzyme-substrate forces are predictive of the various diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) catalytic activities. (PMID:30956131)
• PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus. (PMID:31852976)
• PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair. (PMID:34645979)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppip5k2	ENSDARG00000078441
mus_musculus	Ppip5k2	ENSMUSG00000040648
rattus_norvegicus	Ppip5k2	ENSRNOG00000011613
drosophila_melanogaster	l(1)G0196	FBGN0027279
caenorhabditis_elegans	F46F11.1	WBGENE00018508

Paralogs (1): PPIP5K1 (ENSG00000168781)

Protein

Protein identifiers

Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2 — O43314 (reviewed: O43314)

Alternative names: Diphosphoinositol pentakisphosphate kinase 2, Histidine acid phosphatase domain-containing protein 1, InsP6 and PP-IP5 kinase 2, VIP1 homolog 2

All UniProt accessions (11): A0A087WWN8, A0A087WZV0, A0A8V8TMN4, D6RBU4, D6RFG4, O43314, H0Y9M0, H0Y9S9, K7EJG8, K7ENU7, K7EPT7

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at position 1 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates PP-InsP5 at position 1, produced by IP6Ks from InsP6, to produce (PP)2-InsP4. Required for normal hearing.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Deafness, autosomal recessive, 100 (DFNB100) [MIM:618422] A form of non-syndromic, sensorineural deafness characterized by prelingual hearing impairment. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal acid phosphatase-like domain binds PtdIns(3,4,5)P3 and InsP6. Despite its similarity with the phosphatase domain of histidine acid phosphatases, it has no phosphatase activity.

Similarity. Belongs to the histidine acid phosphatase family. VIP1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O43314-1	1	yes
O43314-2	2

RefSeq proteins (11): NP_001263206, NP_001268400, NP_001332800, NP_001332801, NP_001332802, NP_001332803, NP_001332804, NP_001332805, NP_001332806, NP_001332807, NP_056031 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000560	His_Pase_clade-2	Family
IPR029033	His_PPase_superfam	Homologous_superfamily
IPR033379	Acid_Pase_AS	Active_site
IPR037446	His_Pase_VIP1	Family
IPR040557	VIP1_N	Domain

Pfam: PF00328, PF18086

Enzyme classification (BRENDA):

• EC 2.7.4.21 — inositol-hexakisphosphate 5-kinase (BRENDA: 10 organisms, 35 substrates, 31 inhibitors, 11 Km, 1 kcat entries)
• EC 2.7.4.24 — diphosphoinositol-pentakisphosphate 1-kinase (BRENDA: 5 organisms, 22 substrates, 20 inhibitors, 12 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.037–1.4	4
INOSITOL HEXAKISPHOSPHATE	0.0007–0.0061	3
ADP	0.0052–1.39	3
1D-MYO-INOSITOL 5-DIPHOSPHATE PENTAKISPHOSPHATE	0.0001–0.0002	2
ATP	0.022–1.89	2
1D-MYO-INOSITOL HEXAKISPHOSPHATE	0.0004	1
5-DIPHOSPHO-1D-MYO-INOSITOL (1,2,3,4,6)PENTAKISP	0.002	1
ADP	1.57	1
D-MYO-INOSITOL-1,3,4,5,6-PENTAKISPHOSPHATE	0.0055	1
1,5-BIS-DIPHOSPHO-1D-MYO-INOSITOL 2,3,4,6-TETRAK	—	1
1-DIPHOSPHO-1D-MYO-INOSITOL 2,3,4,5,6-PENTAKISPH	0.0001	1
1D-MYO-INOSITOL 1,5-BIS(DIPHOSPHATE) 2,3,4,6-TET	1.94	1
5-DIPHOSPHO-1D-MYO-INOSITOL 1,2,3,4,6-PENTAKISPH	0.0001	1
DIPHOSPHOINOSITOL PENTAKISPHOSPHATE	0.7	1

Catalyzed reactions (Rhea), 2 shown:

• 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate + ATP + H(+) = 1,5-bis(diphospho)-1D-myo-inositol 2,3,4,6-tetrakisphosphate + ADP (RHEA:10276)
• 1D-myo-inositol hexakisphosphate + ATP = 1-diphospho-1D-myo-inositol 2,3,4,5,6-pentakisphosphate + ADP (RHEA:37459)

UniProt features (75 total): strand 20, binding site 14, modified residue 11, helix 11, sequence variant 6, region of interest 4, compositionally biased region 4, mutagenesis site 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
3T7A	X-RAY DIFFRACTION	1.7
4NZN	X-RAY DIFFRACTION	1.75
8G9E	X-RAY DIFFRACTION	1.75
3T9A	X-RAY DIFFRACTION	1.8
3T9B	X-RAY DIFFRACTION	1.85
3T9D	X-RAY DIFFRACTION	1.85
4Q4D	X-RAY DIFFRACTION	1.85
5DGI	X-RAY DIFFRACTION	1.85
3T54	X-RAY DIFFRACTION	1.9
3T9C	X-RAY DIFFRACTION	1.9
3T9E	X-RAY DIFFRACTION	1.9
4HN2	X-RAY DIFFRACTION	1.9
4NZO	X-RAY DIFFRACTION	1.9
4Q4C	X-RAY DIFFRACTION	1.9
5BYA	X-RAY DIFFRACTION	1.9
6N5C	X-RAY DIFFRACTION	1.95
3T9F	X-RAY DIFFRACTION	2
4NZM	X-RAY DIFFRACTION	2
3T99	X-RAY DIFFRACTION	2.1
5DGH	X-RAY DIFFRACTION	2.1
5BYB	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43314-F1	70.73	0.37

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 (14): 134; 187; 194; 213–214; 213; 237–240; 246–248; 248; 262; 264; 309; 321–323 …

Post-translational modifications (11): 38, 223, 1006, 1016, 1074, 1091, 1165, 1172, 1180, 1220, 1221

Mutagenesis-validated functional residues (3):

Position	Phenotype
213	reduces enzyme activity by about 99%.
248	loss of enzyme activity.
262	reduces enzyme activity by about 99%.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1855167	Synthesis of pyrophosphates in the cytosol

MSigDB gene sets: 168 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, GOBP_INOSITOL_METABOLIC_PROCESS, SCHLOSSER_SERUM_RESPONSE_DN, MODULE_284, GOBP_SENSORY_PERCEPTION, ZHANG_BREAST_CANCER_PROGENITORS_UP, CUI_TCF21_TARGETS_2_DN, chr5q21, XU_GH1_AUTOCRINE_TARGETS_DN

GO Biological Process (4): inositol metabolic process (GO:0006020), sensory perception of sound (GO:0007605), inositol phosphate biosynthetic process (GO:0032958), inositol phosphate metabolic process (GO:0043647)

GO Molecular Function (11): inositol-1,3,4,5,6-pentakisphosphate kinase activity (GO:0000827), inositol hexakisphosphate kinase activity (GO:0000828), diphosphoinositol pentakisphosphate kinase activity (GO:0000829), inositol hexakisphosphate 5-kinase activity (GO:0000832), ATP binding (GO:0005524), 5-diphosphoinositol pentakisphosphate 1-kinase activity (GO:0033857), inositol hexakisphosphate 1-kinase activity (GO:0052723), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Inositol phosphate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphotransferase activity, phosphate group as acceptor	3
inositol phosphate kinase activity	3
polyol metabolic process	2
inositol hexakisphosphate kinase activity	2
cellular anatomical structure	2
sensory perception of mechanical stimulus	1
inositol phosphate metabolic process	1
polyol biosynthetic process	1
organophosphate biosynthetic process	1
organophosphate metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
diphosphoinositol pentakisphosphate kinase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1204 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPIP5K2	IP6K3	Q96PC2	914
PPIP5K2	IP6K1	Q92551	910
PPIP5K2	IP6K2	Q9UHH9	879
PPIP5K2	VIPR2	P41587	845
PPIP5K2	VIP	P01282	815
PPIP5K2	ADCYAP1	P18509	789
PPIP5K2	ADCYAP1R1	P41586	613
PPIP5K2	NHLRC3	Q5JS37	573
PPIP5K2	PRR14L	Q5THK1	541
PPIP5K2	RPP25L	Q8N5L8	486
PPIP5K2	VIPR1	P32241	467
PPIP5K2	IPPK	Q9H8X2	442
PPIP5K2	KIAA0319L	Q8IZA0	433
PPIP5K2	MYC	P01106	432
PPIP5K2	NUDT12	Q9BQG2	422

IntAct

64 interactions, top by confidence:

A	B	Type	Score
ANKRD28	PPP6C	psi-mi:“MI:0914”(association)	0.870
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CELA3A	POTEF	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
MAD2L1	PPIP5K2	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
PPIP5K2	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.400
PPIP5K2	MANF	psi-mi:“MI:0915”(physical association)	0.400
PPIP5K2	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
SFN	PPIP5K2	psi-mi:“MI:0915”(physical association)	0.400
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
DNMBP	RASGRF2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
COPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPE	ESYT2	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
SPANXN2	ZNF320	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), LUZP1 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS), PPIP5K2 (Affinity Capture-MS)

ESM2 similar proteins: A2APC3, A4Q9E4, A8X9V4, A9X4T1, B2GUB3, B2RR83, H2KZM9, O16102, O43314, O95922, P08487, P10686, P16259, P16885, P19174, P20807, P23678, P24135, P43368, P49619, P49620, P49621, P51186, Q09639, Q09647, Q0VC71, Q14562, Q14BI7, Q22070, Q23SI8, Q3SXZ7, Q3SZH6, Q564U4, Q5PPI9, Q5R746, Q5REW0, Q62077, Q641W7, Q64691, Q6NS52

Diamond homologs: A2ARP1, A7Z050, F4J8C6, O43314, O74429, P0C644, P91309, Q06685, Q5RDF1, Q5REW0, Q5XHF8, Q6PFW1, Q6ZQB6, Q84WW3, Q9VR59, Q9CMJ8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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
Activation of BAD and translocation to mitochondria	7	91.9×	7e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	81.1×	1e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	81.1×	1e-10
Activation of BH3-only proteins	7	59.9×	1e-09
RHO GTPases activate PKNs	7	38.3×	3e-08
Intrinsic Pathway for Apoptosis	7	35.3×	4e-08
FOXO-mediated transcription	5	29.0×	1e-05
SARS-CoV-1-host interactions	8	24.2×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	26.9×	3e-04
intracellular protein localization	8	12.3×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	3
Benign	36

Top pathogenic / likely-pathogenic (0)

SpliceAI

5246 predictions. Top by Δscore:

Variant	Effect	Δscore
5:103129692:G:GT	donor_gain	1.0000
5:103129704:G:GG	donor_gain	1.0000
5:103133523:A:T	donor_gain	1.0000
5:103133562:T:TA	donor_gain	1.0000
5:103133563:A:AA	donor_gain	1.0000
5:103133565:T:TA	donor_gain	1.0000
5:103133566:A:AA	donor_gain	1.0000
5:103133579:G:GT	donor_gain	1.0000
5:103133611:GCCTT:G	donor_gain	1.0000
5:103133658:G:T	donor_gain	1.0000
5:103146523:ATAG:A	acceptor_loss	1.0000
5:103146524:TA:T	acceptor_loss	1.0000
5:103146525:A:AG	acceptor_gain	1.0000
5:103146525:A:G	acceptor_loss	1.0000
5:103146526:G:GA	acceptor_gain	1.0000
5:103146526:GA:G	acceptor_gain	1.0000
5:103146526:GAAT:G	acceptor_gain	1.0000
5:103146678:AAAG:A	donor_loss	1.0000
5:103146680:AGG:A	donor_loss	1.0000
5:103146681:GGTAA:G	donor_loss	1.0000
5:103146682:G:GA	donor_loss	1.0000
5:103146683:T:G	donor_loss	1.0000
5:103148028:TTAAG:T	donor_loss	1.0000
5:103148029:TAAGG:T	donor_loss	1.0000
5:103148030:AAGG:A	donor_loss	1.0000
5:103148031:AG:A	donor_loss	1.0000
5:103148032:GGTAG:G	donor_loss	1.0000
5:103148033:G:C	donor_loss	1.0000
5:103148034:T:G	donor_loss	1.0000
5:103148219:T:TA	donor_gain	1.0000

AlphaMissense

8187 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:103133609:T:A	W91R	1.000
5:103133609:T:C	W91R	1.000
5:103136822:G:T	R134M	1.000
5:103138404:T:C	L141P	1.000
5:103146578:T:C	F180S	1.000
5:103146587:C:A	P183Q	1.000
5:103146589:T:C	F184L	1.000
5:103146591:T:A	F184L	1.000
5:103146591:T:G	F184L	1.000
5:103146626:T:A	V196D	1.000
5:103146632:T:A	I198N	1.000
5:103146634:T:G	Y199D	1.000
5:103146637:T:G	Y200D	1.000
5:103146671:T:A	L211H	1.000
5:103146671:T:C	L211P	1.000
5:103146673:T:A	F212I	1.000
5:103146673:T:C	F212L	1.000
5:103146673:T:G	F212V	1.000
5:103146674:T:C	F212S	1.000
5:103146674:T:G	F212C	1.000
5:103146675:T:A	F212L	1.000
5:103146675:T:G	F212L	1.000
5:103146676:A:G	R213G	1.000
5:103146677:G:C	R213T	1.000
5:103146677:G:T	R213I	1.000
5:103146678:A:C	R213S	1.000
5:103146678:A:T	R213S	1.000
5:103146679:A:G	K214E	1.000
5:103146681:G:C	K214N	1.000
5:103146681:G:T	K214N	1.000

dbSNP variants (sampled 300 via entrez): RS1000090798 (5:103126535 T>C,G), RS1000093244 (5:103170833 G>A), RS1000116486 (5:103143822 T>C), RS1000170656 (5:103144112 A>G), RS1000264444 (5:103192830 C>T), RS1000375342 (5:103185545 A>G), RS1000489898 (5:103185253 T>C), RS1000520674 (5:103157780 G>A), RS1000526682 (5:103126822 G>A), RS1000566784 (5:103212165 A>T), RS1000573228 (5:103158054 G>A), RS1000698908 (5:103206066 T>A,C), RS1000707733 (5:103199302 T>A), RS1000722229 (5:103192392 G>A), RS1000758578 (5:103198912 T>C,G)

Disease associations

OMIM: gene MIM:611648 | disease phenotypes: MIM:618422

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive 100	Moderate	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Limited	AR

Mondo (3): hearing loss, autosomal recessive 100 (MONDO:0032740), prostate cancer (MONDO:0008315), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001098	Abnormal fundus morphology
HP:0001751	Abnormal vestibular function
HP:0003577	Congenital onset

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003129_2	Primary biliary cholangitis	1.000000e-08
GCST005316_409	Intelligence (MTAG)	1.000000e-08
GCST007516_8	Type 2 diabetes (adjusted for BMI)	7.000000e-15
GCST007517_11	Type 2 diabetes	6.000000e-12
GCST007518_14	Type 2 diabetes (adjusted for BMI)	4.000000e-13
GCST007559_21	Sleep duration (short sleep)	2.000000e-08
GCST008110_2	Insulinogenic index	2.000000e-08
GCST010002_34	Refractive error	2.000000e-10
GCST90020025_1061	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST90020027_892	Waist-hip index	3.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0009961	Insulinogenic index measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C564609	Deafness, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523135 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.43	IC50	375	nM	CHEMBL4563780

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
hexakis(N,N-diethylethanamine);[1,1-difluoro-2-oxo-2-[[(2S,3R,5S,6R)-2,3,4,5,6-pentaphosphonooxycyclohexyl]amino]ethyl]phosphonic acid	1537767: Inhibition of recombinant N-terminal His6-tagged human PPIP5K2 kinase domain incubated for 30 min in presence of 1,5-[PP]2-InsP4 and ADP by luminescence based assay	ic50	0.3750	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	affects phosphorylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, affects expression, increases abundance	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Oils, Volatile	affects expression, increases abundance, affects cotreatment	1
Dronabinol	increases glycosylation	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin M1	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4334768	Binding	Inhibition of recombinant N-terminal His6-tagged human PPIP5K2 kinase domain incubated for 30 min in presence of 1,5-[PP]2-InsP4 and ADP by luminescence based assay	Synthesis of an α-phosphono-α,α-difluoroacetamide analogue of the diphosphoinositol pentakisphosphate 5-InsP7. — Medchemcomm

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_D7Y4	Ubigene A-549 PPIP5K2 KO	Cancer cell line	Male
CVCL_D8TK	Ubigene HCT 116 PPIP5K2 KO	Cancer cell line	Male
CVCL_D9P4	Ubigene HEK293 PPIP5K2 KO	Transformed cell line	Female
CVCL_E0LF	Ubigene HeLa PPIP5K2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer