INPP5E

Summary

INPP5E (inositol polyphosphate-5-phosphatase E, HGNC:21474) is a protein-coding gene on chromosome 9q34.3, encoding Phosphatidylinositol polyphosphate 5-phosphatase type IV (Q9NRR6). Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).

The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 56623 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Joubert syndrome 1 (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 950 total — 33 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_019892

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21474
Approved symbol	INPP5E
Name	inositol polyphosphate-5-phosphatase E
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	PPI5PIV, CORS1, pharbin
Ensembl gene	ENSG00000148384
Ensembl biotype	protein_coding
OMIM	613037
Entrez	56623

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000371712, ENST00000635815, ENST00000674513, ENST00000674693, ENST00000675256, ENST00000676019, ENST00000910889, ENST00000910890, ENST00000910891, ENST00000930356, ENST00000930357, ENST00000930358, ENST00000930359, ENST00000930360, ENST00000960334, ENST00000960335, ENST00000960336, ENST00000960337

RefSeq mRNA: 2 — MANE Select: NM_019892 NM_001318502, NM_019892

CCDS: CCDS7000

Canonical transcript exons

ENST00000371712 — 10 exons

Exon	Start	End
ENSE00000984903	136434740	136434863
ENSE00000984904	136434037	136434134
ENSE00000984906	136432956	136433075
ENSE00001095481	136430277	136430413
ENSE00001125173	136431002	136431117
ENSE00001125180	136431824	136431985
ENSE00001279094	136433155	136433279
ENSE00001345888	136432479	136432586
ENSE00001854834	136438608	136439845
ENSE00001951530	136428619	136429807

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 96.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6685 / max 91.6704, expressed in 1737 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103159	7.6685	1737

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.60	gold quality
secondary oocyte	CL:0000655	96.26	gold quality
oocyte	CL:0000023	95.86	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.76	gold quality
apex of heart	UBERON:0002098	92.89	gold quality
cerebellar hemisphere	UBERON:0002245	92.60	gold quality
cerebellar cortex	UBERON:0002129	92.40	gold quality
metanephros cortex	UBERON:0010533	92.24	gold quality
endocervix	UBERON:0000458	91.98	gold quality
right lobe of thyroid gland	UBERON:0001119	91.88	gold quality
body of uterus	UBERON:0009853	91.72	gold quality
left ovary	UBERON:0002119	91.63	gold quality
right ovary	UBERON:0002118	91.57	gold quality
left lobe of thyroid gland	UBERON:0001120	91.48	gold quality
cerebellum	UBERON:0002037	91.44	gold quality
left testis	UBERON:0004533	91.36	gold quality
tibial nerve	UBERON:0001323	91.33	gold quality
spleen	UBERON:0002106	91.28	gold quality
right testis	UBERON:0004534	91.10	gold quality
right frontal lobe	UBERON:0002810	91.04	gold quality
left uterine tube	UBERON:0001303	91.01	gold quality
pituitary gland	UBERON:0000007	90.51	gold quality
lower esophagus mucosa	UBERON:0035834	90.37	gold quality
adenohypophysis	UBERON:0002196	90.24	gold quality
thyroid gland	UBERON:0002046	90.17	gold quality
ectocervix	UBERON:0012249	89.89	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.63	gold quality
granulocyte	CL:0000094	89.57	gold quality
mucosa of stomach	UBERON:0001199	89.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.42	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting INPP5E, 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-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-4432	97.80	67.87	705
HSA-MIR-6737-5P	97.75	66.54	1044

Literature-anchored findings (GeneRIF, showing 22)

• Functional analysis of the mouse counterpart. (PMID:10806194)
• INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in humans. (PMID:19668215)
• Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. (PMID:19668216)
• findings indicate that ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network that is involved in JBTS and NPHP but independent of the ones previously defined by NPHP and MKS proteins (PMID:23150559)
• Identification of 12 different INPP5E mutations in patients with Joubert syndrome with an overall 2.7% mutation frequency. (PMID:23386033)
• Proteomic analysis identified INPP5E, whose mutations also lead to Joubert syndrome as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. (PMID:24166846)
• These findings establish the first direct link between AURKA and phosphoinositide signaling and suggest that the function of INPP5E in cilia is at least partly mediated by its interactions with AURKA (PMID:25395580)
• MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content. (PMID:26490104)
• PIPKIgamma and INPP5E localize to the centrosome and coordinate the initiation of ciliogenesis. (PMID:26916822)
• we identify Inpp5e as an essential inhibitor of the PI3K/Akt/mTORC1 signaling axis in renal epithelial cells, and demonstrate a critical role for Inpp5e-dependent mTORC1 regulation in Polycystic kidney disease (PKD) suppression (PMID:27056978)
• In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the autophagosome-lysosome fusion step. (PMID:27340123)
• ARL13B regulates IFT-A-mediated retrograde protein trafficking within cilia through its interaction with INPP5E. (PMID:27927754)
• INPP5E is an essential point of convergence between Hedgehog and phosphoinositide signaling at cilia that maintains transition zone function and Hedgehog-dependent embryonic development. (PMID:27998989)
• INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. (PMID:28031327)
• INPP5E associates with the N-terminus of RPGR and trafficking of INPP5E to cilia is dependent upon the ciliary localization of RPGR. (PMID:28172980)
• miR598 contributed to cell proliferation and cell cycle progression in colorectal carcinoma by targeting INPP5E. (PMID:29257251)
• Formation of primary cilia is downregulated in TULP3-knockout (KO) RPE1 cells. ARL13B and INPP5E fail to localize to primary cilia in TULP3-KO cells. (PMID:30583862)
• Interaction of INPP5E with ARL13B is essential for its ciliary membrane retention but dispensable for its ciliary entry. (PMID:33372066)
• The Major Ciliary Isoforms of RPGR Build Different Interaction Complexes with INPP5E and RPGRIP1L. (PMID:33808286)
• The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling. (PMID:35584663)
• TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia. (PMID:36334440)
• INPP5E Regulates the Distribution of Phospholipids on Cilia in RPE1 Cells. (PMID:38514901)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	inpp5e	ENSDARG00000103926
mus_musculus	Inpp5e	ENSMUSG00000026925
rattus_norvegicus	Inpp5e	ENSRNOG00000019039
drosophila_melanogaster	INPP5E	FBGN0036273
caenorhabditis_elegans		WBGENE00012016

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), SYNJ1 (ENSG00000159082), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), INPP5B (ENSG00000204084), SACM1L (ENSG00000211456)

Protein

Protein identifiers

Phosphatidylinositol polyphosphate 5-phosphatase type IV — Q9NRR6 (reviewed: Q9NRR6)

Alternative names: 72 kDa inositol polyphosphate 5-phosphatase, Inositol polyphosphate-5-phosphatase E, Phosphatidylinositol 4,5-bisphosphate 5-phosphatase, Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase

All UniProt accessions (2): Q9NRR6, A0A6Q8PH37

UniProt curated annotations — full annotation on UniProt →

Function. Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Specific for lipid substrates, inactive towards water soluble inositol phosphates. Plays an essential role in the primary cilium by controlling ciliary growth and phosphoinositide 3-kinase (PI3K) signaling and stability.

Subunit / interactions. Interacts (when prenylated) with PDE6D; this is important for normal location in cilia.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium axoneme. Golgi apparatus. Golgi stack membrane. Cell membrane. Cell projection. Ruffle. Nucleus.

Tissue specificity. Detected in brain, heart, pancreas, testis and spleen.

Disease relevance. Joubert syndrome 1 (JBTS1) [MIM:213300] A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. The disease is caused by variants affecting the gene represented in this entry. Impaired intellectual development, truncal obesity, retinal dystrophy, and micropenis (MORMS) [MIM:610156] An autosomal recessive disorder characterized by moderate intellectual disability, truncal obesity, congenital non-progressive retinal dystrophy, and micropenis in males. The phenotype is similar to Bardet-Biedl syndrome and Cohen syndrome Distinguishing features are the age of onset, the non-progressive nature of the visual impairment, lack of dysmorphic facies, skin or gingival infection, microcephaly, mottled retina, polydactyly, and testicular anomalies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Active in the presence of octyl-glucoside or Triton X-100, but completely inhibited by CTAB.

Similarity. Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type IV family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRR6-1	1	yes
Q9NRR6-2	2

RefSeq proteins (2): NP_001305431, NP_063945* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000300	IPPc	Domain
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR042478	INPP5E	Family

Pfam: PF22669

Enzyme classification (BRENDA):

• EC 3.1.3.36 — phosphoinositide 5-phosphatase (BRENDA: 28 organisms, 75 substrates, 33 inhibitors, 14 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDYL-MYO-INOSITOL 4,5-BISPHOSPHATE	0.143–0.27	4
1-PHOSPHATIDYL-1D-MYO-INOSITOL 4,5-BISPHOSPHATE	0.0316–0.0738	2
1-PHOSPHATIDYL-1D-MYO-INOSITOL 3,4,5-TRIPHOSPHAT	0.088	1
1D-MYO-INOSITOL 1,4,5-TRISPHOSPHATE	0.421	1
7-METHYL-6-THIOGUANOSINE	0.056	1
INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	0.028	1
INOSITOL 1,4,5-TRISPHOSPHATE	0.123	1

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + phosphate (RHEA:22764)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + phosphate (RHEA:25528)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + phosphate (RHEA:32955)

UniProt features (72 total): sequence variant 17, strand 16, repeat 13, helix 11, modified residue 4, compositionally biased region 3, region of interest 2, chain 1, propeptide 1, lipid moiety-binding region 1, splice variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2XSW	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRR6-F1	72.65	0.52

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): 99, 241, 256, 641, 641

Mutagenesis-validated functional residues (1):

Position	Phenotype
641	abolishes farnesylation-dependent interaction with pde6d.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-5624958	ARL13B-mediated ciliary trafficking of INPP5E
R-HSA-1430728	Metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-556833	Metabolism of lipids
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane

MSigDB gene sets: 397 (showing top): GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, MORF_MSH3, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, MORF_BRCA1, MORF_ATRX, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOCC_RUFFLE, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_PHOSPHATIDYLINOSITOL_3_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (12): phosphatidylinositol biosynthetic process (GO:0006661), negative regulation of translation (GO:0017148), phosphatidylinositol dephosphorylation (GO:0046856), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), cilium assembly (GO:0060271), response to inositol (GO:1902140), negative regulation of protein localization to cilium (GO:1903565), lipid metabolic process (GO:0006629), phosphate-containing compound metabolic process (GO:0006796), organophosphate metabolic process (GO:0019637), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), phosphatidylinositol metabolic process (GO:0046488)

GO Molecular Function (9): phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity (GO:0004439), inositol-polyphosphate 5-phosphatase activity (GO:0004445), phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity (GO:0016314), phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity (GO:0034485), phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity (GO:0043813), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), phosphatidylinositol-4,5-bisphosphate phosphatase activity (GO:0106019)

GO Cellular Component (14): Golgi membrane (GO:0000139), ruffle (GO:0001726), nucleus (GO:0005634), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), Golgi cisterna membrane (GO:0032580), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020), cell projection (GO:0042995), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
PI Metabolism	1
Cargo trafficking to the periciliary membrane	1
Phospholipid metabolism	1
Metabolism of lipids	1
Metabolism	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
phosphatidylinositol phosphate 5-phosphatase activity	3
phosphatidylinositol metabolic process	2
protein localization to cilium	2
phosphorus metabolic process	2
phosphatidylinositol trisphosphate phosphatase activity	2
plasma membrane bounded cell projection	2
intracellular membrane-bounded organelle	2
cytoplasm	2
biosynthetic process	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
phospholipid dephosphorylation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
negative regulation of intracellular signal transduction	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
response to oxygen-containing compound	1
regulation of protein localization to cilium	1
negative regulation of protein localization	1
primary metabolic process	1
metabolic process	1
phosphatidylinositol phosphate biosynthetic process	1
phosphatidylinositol-4,5-bisphosphate phosphatase activity	1
inositol trisphosphate phosphatase activity	1
phosphatidylinositol-3-phosphate biosynthetic process	1
phosphatidylinositol-3,5-bisphosphate phosphatase activity	1
binding	1
catalytic activity	1
phosphoric ester hydrolase activity	1
phosphatidylinositol bisphosphate phosphatase activity	1
Golgi apparatus	1

Protein interactions and networks

STRING

1158 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INPP5E	INPP5A	Q14642	593
INPP5E	ARL13B	Q3SXY8	583
INPP5E	CEP164	Q9UPV0	565
INPP5E	ARHGAP1	Q07960	538
INPP5E	TULP3	O75386	536
INPP5E	PDE6D	O43924	517
INPP5E	BBS12	Q6ZW61	500
INPP5E	CEP290	O15078	485
INPP5E	BBS10	Q8TAM1	480
INPP5E	BBS7	Q8IWZ6	476
INPP5E	IFT122	Q9HBG6	473
INPP5E	PIP5K1B	P78518	472
INPP5E	GPR161	Q8N6U8	469
INPP5E	SCIN	Q9Y6U3	460
INPP5E	VPS13B	Q7Z7G8	457

IntAct

77 interactions, top by confidence:

A	B	Type	Score
PDE6D	ARL3	psi-mi:“MI:0914”(association)	0.920
INPP5E	YWHAH	psi-mi:“MI:0915”(physical association)	0.740
INPP5E	PDE6D	psi-mi:“MI:0914”(association)	0.730
RPGR	PDE6D	psi-mi:“MI:0914”(association)	0.660
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
YWHAE	DCAF7	psi-mi:“MI:0914”(association)	0.510
INPP5E	HNRNPH2	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
YWHAB	BRAF	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
YWHAG	BRAF	psi-mi:“MI:0914”(association)	0.350
YWHAH	BRAF	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
PDE6D	SUN1	psi-mi:“MI:0914”(association)	0.350
PDE6D	UBL3	psi-mi:“MI:0914”(association)	0.350
INPP5E	DCLK1	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	SIPA1L1	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	KIF1C	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	PDE6D	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	MAST3	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	SRGAP2	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	GIGYF1	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	NADK	psi-mi:“MI:0915”(physical association)	0.000
INPP5E	NF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (74): PDE6D (Affinity Capture-MS), KCTD3 (Affinity Capture-MS), CGN (Affinity Capture-MS), KIF13B (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), INPP5E (Affinity Capture-MS), RALGPS2 (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), INPP5E (Affinity Capture-MS), MAST3 (Affinity Capture-MS), INPP5E (Affinity Capture-MS), LRFN1 (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), INPP5E (Affinity Capture-MS), INPP5E (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NFE2, A0FI79, B1AVH7, B5DFA1, D2H0G5, D7PF45, O00750, O15357, O70143, P29353, P97573, P98083, Q00IB7, Q0IIE2, Q15678, Q16825, Q17R13, Q2I6J0, Q2I6J1, Q2V2M9, Q5JV73, Q5M824, Q5R7W7, Q5U2X5, Q61120, Q62130, Q62136, Q62728, Q62925, Q69Z98, Q6P4S2, Q6P549, Q80TI1, Q8AY68, Q8BMC3, Q8BYW1, Q8IWQ3, Q8K245, Q92529, Q92835

Diamond homologs: A0A8I3NFE2, A0FI79, A0JNB0, A1Y2K1, A6QLK6, B2RZ59, B5KFD7, D3ZGS3, D7PF45, F1RDG9, G5ECJ6, O14306, O14796, O15357, O35324, O60880, O88890, O88900, P00519, P00520, P00521, P00522, P03949, P06239, P06241, P09851, P0CE43, P10447, P17713, P20936, P29350, P29351, P32019, P34370, P39688, P42684, P42685, P42686, P50904, P53356

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	84.0×	1e-08
Activation of BAD and translocation to mitochondria	5	79.3×	2e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	70.0×	3e-07
Activation of BH3-only proteins	5	51.7×	1e-06
RHO GTPases activate PKNs	6	39.6×	3e-07
Intrinsic Pathway for Apoptosis	5	30.5×	1e-05
Transcriptional and post-translational regulation of MITF-M expression and activity	5	18.6×	1e-04
SARS-CoV-1-host interactions	5	18.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	27.8×	4e-04
intracellular protein localization	6	9.5×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	34
Uncertain significance	405
Likely benign	328
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069370	NM_019892.6(INPP5E):c.1629C>G (p.Tyr543Ter)	Pathogenic
1070977	NM_019892.6(INPP5E):c.1253_1256del (p.Phe418fs)	Pathogenic
1075353	NM_019892.6(INPP5E):c.1795C>T (p.Arg599Ter)	Pathogenic
1420962	NM_019892.6(INPP5E):c.1367A>C (p.Asn456Thr)	Pathogenic
1444511	NM_019892.6(INPP5E):c.1726T>G (p.Cys576Gly)	Pathogenic
1452581	NM_019892.6(INPP5E):c.166del (p.Ala56fs)	Pathogenic
1458128	NM_019892.6(INPP5E):c.15_16del (p.Asn7fs)	Pathogenic
1805447	NM_019892.6(INPP5E):c.226dup (p.Ala76fs)	Pathogenic
1930282	NM_019892.6(INPP5E):c.781dup (p.Ala261fs)	Pathogenic
2020468	NM_019892.6(INPP5E):c.1324_1327dup (p.Val443fs)	Pathogenic
2032908	NM_019892.6(INPP5E):c.1103del (p.His368fs)	Pathogenic
2048453	NM_019892.6(INPP5E):c.1761_1763dup (p.Tyr588Ter)	Pathogenic
2158999	NM_019892.6(INPP5E):c.931C>T (p.Gln311Ter)	Pathogenic
217655	NM_019892.6(INPP5E):c.1064C>T (p.Thr355Met)	Pathogenic
217658	NM_019892.6(INPP5E):c.1897_1898del (p.Gln633fs)	Pathogenic
217662	NM_019892.6(INPP5E):c.944C>T (p.Pro315Leu)	Pathogenic
217664	NM_019892.6(INPP5E):c.1249T>C (p.Ser417Pro)	Pathogenic
2198850	NM_019892.6(INPP5E):c.925C>T (p.Gln309Ter)	Pathogenic
2701602	NM_019892.6(INPP5E):c.1888C>T (p.Gln630Ter)	Pathogenic
279812	NM_019892.6(INPP5E):c.490dup (p.Val164fs)	Pathogenic
3249361	NM_019892.6(INPP5E):c.964del (p.Leu322fs)	Pathogenic
3720920	NM_019892.6(INPP5E):c.1426G>A (p.Gly476Arg)	Pathogenic
375472	NM_019892.6(INPP5E):c.1303C>T (p.Arg435Trp)	Pathogenic
396	NM_019892.6(INPP5E):c.1879C>T (p.Gln627Ter)	Pathogenic
4693474	NM_019892.6(INPP5E):c.1082dup (p.Leu362fs)	Pathogenic
4705386	NM_019892.6(INPP5E):c.1784_1787del (p.Val595fs)	Pathogenic
4727271	NM_019892.6(INPP5E):c.1516C>T (p.Gln506Ter)	Pathogenic
4734048	NM_019892.6(INPP5E):c.893del (p.Asn298fs)	Pathogenic
568818	NM_019892.6(INPP5E):c.1844T>G (p.Leu615Ter)	Pathogenic
581255	NM_019892.6(INPP5E):c.1922del (p.Cys641fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4150 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:136430329:G:C	H584D	1.000
9:136433023:C:A	K404N	1.000
9:136433023:C:G	K404N	1.000
9:136434760:A:G	W306R	1.000
9:136434760:A:T	W306R	1.000
9:136429783:A:C	F609L	0.999
9:136429783:A:T	F609L	0.999
9:136429785:A:G	F609L	0.999
9:136430327:G:C	H584Q	0.999
9:136430327:G:T	H584Q	0.999
9:136430334:G:A	S582F	0.999
9:136431062:C:A	K535N	0.999
9:136431062:C:G	K535N	0.999
9:136431064:T:C	K535E	0.999
9:136431936:G:C	N479K	0.999
9:136431936:G:T	N479K	0.999
9:136431943:T:A	D477V	0.999
9:136431946:C:A	G476V	0.999
9:136431946:C:T	G476E	0.999
9:136431953:A:G	W474R	0.999
9:136431953:A:T	W474R	0.999
9:136432965:G:C	H424D	0.999
9:136433022:C:A	G405W	0.999
9:136433022:C:G	G405R	0.999
9:136433022:C:T	G405R	0.999
9:136433024:T:A	K404M	0.999
9:136433025:T:C	K404E	0.999
9:136433272:A:G	W348R	0.999
9:136433272:A:T	W348R	0.999
9:136434052:T:A	E340V	0.999

dbSNP variants (sampled 300 via entrez): RS1000252330 (9:136437428 C>G,T), RS1000486998 (9:136441491 C>G,T), RS1000863768 (9:136433485 T>C,G), RS1000948846 (9:136438248 C>T), RS1001019043 (9:136434011 C>T), RS1001407812 (9:136429514 G>A,T), RS1001569089 (9:136433532 C>T), RS1001583834 (9:136433649 T>C), RS1002230416 (9:136429624 G>C), RS1002339331 (9:136437729 G>A), RS1002842969 (9:136439945 G>A,C), RS1002886771 (9:136436558 G>A), RS1003093040 (9:136438698 C>T), RS1003244838 (9:136434318 T>A,C), RS1003472315 (9:136432799 G>A,T)

Disease associations

OMIM: gene MIM:613037 | disease phenotypes: MIM:213300, MIM:610156, MIM:119800, MIM:607411, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome 1	Definitive	Autosomal recessive
MORM syndrome	Definitive	Autosomal recessive
COACH syndrome 1	Supportive	Autosomal recessive
Joubert syndrome with ocular defect	Supportive	Autosomal recessive
Joubert syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
MORM syndrome	Moderate	AR
Joubert syndrome 1	Definitive	AR

Mondo (17): Joubert syndrome 1 (MONDO:0008944), MORM syndrome (MONDO:0012423), Joubert syndrome (MONDO:0018772), inherited retinal dystrophy (MONDO:0019118), Joubert syndrome and related disorders (MONDO:0015369), optic atrophy (MONDO:0003608), clubfoot (MONDO:0007342), patent ductus arteriosus (MONDO:0011827), interstitial lung disease (MONDO:0015925), femoral agenesis/hypoplasia (MONDO:0016032), cleft palate (MONDO:0016064), skeletal dysplasia (MONDO:0018230), respiratory failure (MONDO:0021113), focal segmental glomerulosclerosis (MONDO:0100313), Leber congenital amaurosis (MONDO:0018998)

Orphanet (12): Isolated Joubert syndrome (Orphanet:475), MORM syndrome (Orphanet:75858), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Joubert syndrome and related disorders (Orphanet:140874), Interstitial lung disease (Orphanet:182095), Isolated femoral agenesis/hypoplasia (Orphanet:1987), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Cleft palate (Orphanet:2014), Primary bone dysplasia (Orphanet:364526), Leber congenital amaurosis (Orphanet:65), Familial patent arterial duct (Orphanet:466729), NON RARE IN EUROPE: Patent arterial duct (Orphanet:706)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D004374	Ductus Arteriosus, Patent	C14.240.400.340; C14.280.400.340; C16.131.240.400.340
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D017563	Lung Diseases, Interstitial	C08.381.483
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012131	Respiratory Insufficiency	C08.618.846
D058499	Retinal Dystrophies	C11.768.585.658
C536984	MORM syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Inositol polyphosphate phosphatases

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
dicrotophos	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Fluorouracil	affects reaction, decreases expression	1
Phthalic Acids	decreases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Smoke	decreases expression	1
Sulindac	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SS68	HAP1 INPP5E (-) 1	Cancer cell line	Male
CVCL_SS69	HAP1 INPP5E (-) 2	Cancer cell line	Male
CVCL_SS70	HAP1 INPP5E (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	PHASE4	COMPLETED	Clubfoot Tenotomy Trial
NCT00217191	PHASE4	COMPLETED	Ibuprofen and Renal Function in Premature Infants
NCT00642330	PHASE4	COMPLETED	Comparative Study of Efficacy and Safety of Oral Ibuprofen and Intravenous Ibuprofen in Closure of Patent Ductus Arteriosus in Very Low Birth Weight Infants
NCT00767039	PHASE4	TERMINATED	Curosurf and Survanta Treatment(CAST)of RDS in Very Premature Infants
NCT00961753	PHASE4	TERMINATED	Safety/Efficacy Study of Optimizing Ibuprofen Dosing to Achieve Higher PDA Closure Rates
NCT01536158	PHASE4	COMPLETED	Oral Paracetamol Versus Oral Ibuprofen in Management of Patent Ductus Arteriosus in Preterm Infants: A Randomised Controlled Trial
NCT01544972	PHASE4	UNKNOWN	Serum Level Measurement of Oral Paracetamol and Oral Ibuprofen for Patent Ductus Arteriosus Treatment in Preterm Infants
NCT03265782	PHASE4	UNKNOWN	Paracetamol Versus Ibuprofen for PDA Closure
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00637065	PHASE4	UNKNOWN	Bosentan in Pulmonary Hypertension in Interstitial Lung Disease Treatment Study
NCT00882817	PHASE4	COMPLETED	Pulmonary Rehabilitation in Interstitial Lung Diseases
NCT02143687	PHASE4	COMPLETED	Patients With Pulmonary Hypertension or Interstitial Lung Disease at Altitude - Effect of Oxygen on Exercise Performance
NCT02150616	PHASE4	UNKNOWN	Patients With Pulmonary Hypertension or Interstitial Lung Disease at Altitude - Effect of Oxygen on Breathing and Sleep
NCT02622022	PHASE4	COMPLETED	Palliation of Dyspnea With Morphine in Patients With Interstitial Lung Disease
NCT02821689	PHASE4	UNKNOWN	Pirfenidone in Progressive Interstitial Lung Disease Associated With Clinically Amyopathic Dermatomyositis
NCT04036721	PHASE4	SUSPENDED	Coorticosteroid Regimen in Patients With Anti-PD-1/PD-L1 Induced Pneumonitis
NCT04311567	PHASE4	TERMINATED	Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease
NCT04619680	PHASE4	COMPLETED	The Study of the Use of Nintedanib in Slowing Lung Disease in Patients With Fibrotic or Non-Fibrotic Interstitial Lung Disease Related to COVID-19
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT04988282	PHASE4	COMPLETED	Systemic Corticosteroids in Treatment of Post-COVID-19 Interstitial Lung Disease
NCT05129410	PHASE4	UNKNOWN	Clinical Study of MMF in Treatment of IIM-ILD and Its Effect on Peripheral Blood Treg Cells
NCT05375435	PHASE4	UNKNOWN	Efficacy and Safety of Triple Therapy in Patients With Anti-MDA5 Antibody-positive Dermatomyositis
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT07077486	PHASE4	RECRUITING	Effects of Telitacicept vs Cyclophosphamide on Lupus Related Interstitial Lung Disease
NCT07319598	PHASE4	RECRUITING	A Study to Test Tetrandrine Tablets for Connective Tissue Disease-Related Lung Disease
NCT07570888	PHASE4	NOT_YET_RECRUITING	This is a Trial Designed to Evaluate the Combination of Nerandomilast With Mycophenolate Across a Wide Variety of Pulmonary Fibrosis Subtypes, With the Aim of Providing Clinicians With Assurance That This is an Appropriate Therapeutic Combination.
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00440804	PHASE3	COMPLETED	Safety and Efficacy Study of Ibuprofen l-Lysine Solution in Premature Infants for Treatment of PDA
NCT00485160	PHASE3	COMPLETED	Ibuprofen vs. Continuous Indomethacin in the Treatment of PDA
NCT01593163	PHASE3	COMPLETED	Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus
NCT01630278	PHASE3	COMPLETED	Early Ibuprofen Treatment of Patent Ductus Arteriosus (PDA) in Premature Infants (TRIOCAPI)
NCT01755728	PHASE3	COMPLETED	Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants
NCT03022253	PHASE3	COMPLETED	Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates
NCT03456336	PHASE3	ACTIVE_NOT_RECRUITING	Management of the PDA Trial
NCT03537144	PHASE3	TERMINATED	Acetaminophen vs Indomethacin in Treating hsPDA
NCT01570764	PHASE3	COMPLETED	Cyclophosphamide Systemic Sclerosis Associated Interstitial Lung Disease
NCT02896205	PHASE3	COMPLETED	Study to Compare the Efficacy of Mycophenolate Mofetil in Systemic Sclerosis Related Early Interstitial Lung Disease
NCT03018756	PHASE3	COMPLETED	Nebulized Fentanyl in Patients With Mild to Moderate Interstitial Lung Disease and Chronic Dyspnea