INPP5B

Summary

INPP5B (inositol polyphosphate-5-phosphatase B, HGNC:6077) is a protein-coding gene on chromosome 1p34.3, encoding Type II inositol 1,4,5-trisphosphate 5-phosphatase (P32019). Regulates phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) cellular levels by cleaving the phosphate at the 5-position producing PtdIns(4)P.

This gene encodes a member of a family of inositol polyphosphate-5-phosphatases. These enzymes function in the regulation of calcium signaling by inactivating inositol phosphates. The encoded protein is localized to the cytosol and mitochondria, and associates with membranes through an isoprenyl modification near the C-terminus. Alternatively spliced transcript variants of this gene have been described.

Source: NCBI Gene 3633 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 224 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005540

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6077
Approved symbol	INPP5B
Name	inositol polyphosphate-5-phosphatase B
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204084
Ensembl biotype	protein_coding
OMIM	147264
Entrez	3633

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 10 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000373021, ENST00000373024, ENST00000373026, ENST00000373027, ENST00000467066, ENST00000470364, ENST00000474758, ENST00000487328, ENST00000491406, ENST00000875044, ENST00000875045, ENST00000875046, ENST00000875047, ENST00000923582, ENST00000948250

RefSeq mRNA: 10 — MANE Select: NM_005540 NM_001297434, NM_001350227, NM_001350228, NM_001365820, NM_001365821, NM_001365822, NM_001365823, NM_001365824, NM_001365825, NM_005540

CCDS: CCDS41306, CCDS72760

Canonical transcript exons

ENST00000373024 — 24 exons

Exon	Start	End
ENSE00001459356	37885638	37885825
ENSE00001643693	37891358	37891454
ENSE00001648711	37940688	37940798
ENSE00001650306	37872930	37873165
ENSE00001676368	37860697	37862430
ENSE00001686092	37864312	37864423
ENSE00001710165	37865761	37865888
ENSE00001741601	37873993	37874155
ENSE00001742245	37889557	37889724
ENSE00001780358	37878188	37878323
ENSE00001780489	37931913	37932053
ENSE00003471861	37946252	37946334
ENSE00003562601	37943796	37943893
ENSE00003587531	37866459	37866543
ENSE00003591819	37945756	37945850
ENSE00003618697	37888243	37888344
ENSE00003635361	37886888	37887004
ENSE00003635891	37887351	37887465
ENSE00003683926	37943640	37943669
ENSE00003686925	37868501	37868614
ENSE00003714556	37880085	37880194
ENSE00003733113	37875606	37875716
ENSE00003741373	37882807	37882918
ENSE00003841857	37946990	37947053

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 91.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5451 / max 108.3331, expressed in 1778 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11818	6.9847	1578
11816	3.5484	1043
11817	0.0120	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	91.18	silver quality
left ovary	UBERON:0002119	90.27	gold quality
mucosa of stomach	UBERON:0001199	90.11	gold quality
popliteal artery	UBERON:0002250	89.80	gold quality
tibial artery	UBERON:0007610	89.78	gold quality
aorta	UBERON:0000947	88.94	gold quality
right coronary artery	UBERON:0001625	88.76	gold quality
right ovary	UBERON:0002118	88.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.46	gold quality
lower esophagus	UBERON:0013473	88.43	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.35	gold quality
granulocyte	CL:0000094	88.27	gold quality
ascending aorta	UBERON:0001496	88.27	gold quality
left coronary artery	UBERON:0001626	88.26	gold quality
cerebellar hemisphere	UBERON:0002245	88.18	gold quality
thoracic aorta	UBERON:0001515	88.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.05	gold quality
cerebellar cortex	UBERON:0002129	88.03	gold quality
descending thoracic aorta	UBERON:0002345	88.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.71	gold quality
right lobe of liver	UBERON:0001114	87.14	gold quality
coronary artery	UBERON:0001621	86.91	gold quality
adrenal tissue	UBERON:0018303	86.83	gold quality
tibial nerve	UBERON:0001323	86.45	gold quality
body of uterus	UBERON:0009853	86.37	gold quality
upper lobe of left lung	UBERON:0008952	86.22	gold quality
body of stomach	UBERON:0001161	86.15	gold quality
buccal mucosa cell	CL:0002336	86.04	gold quality
ovary	UBERON:0000992	86.00	gold quality
endocervix	UBERON:0000458	85.96	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	137.35
E-ANND-3	yes	6.14
E-MTAB-6678	yes	4.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

86 targeting INPP5B, 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-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-92A-2-5P	99.75	67.01	2164

Literature-anchored findings (GeneRIF, showing 7)

• INPP5B is also localised to the early secretory pathway including the Golgi apparatus and ER-to-Golgi intermediate compartment (ERGIC). (PMID:17956944)
• The NH2-terminal region of OCRL, but not of INPP5B, binds clathrin heavy chain. (PMID:19536138)
• The homologous phosphatase Inpp5b was unable to complement the Ocrl1-dependent cell migration defect. (PMID:19700499)
• study found mouse Inpp5b and human INPP5B differ in their transcription, splicing and amino acid sequence; observations form foundation for analyzing the functional basis for the difference in how Inpp5b and INPP5B compensate for loss of Ocrl function (PMID:20872266)
• The crystal structures of human INPP5B in complex with phosphoinositide substrate analogs revealed a membrane interaction patch likely to assist in sequestering substrates from the lipid bilayer. (PMID:24704254)
• OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells (PMID:25305077)
• The inositol 5-phosphatase INPP5B regulates B cell receptor clustering and signaling. (PMID:35878408)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	inpp5b	ENSDARG00000103683
mus_musculus	Inpp5b	ENSMUSG00000028894
rattus_norvegicus	Inpp5b	ENSRNOG00000048506
drosophila_melanogaster	Ocrl	FBGN0023508
caenorhabditis_elegans	ocrl-1	WBGENE00007620

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), SYNJ1 (ENSG00000159082), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), SACM1L (ENSG00000211456)

Protein

Protein identifiers

Type II inositol 1,4,5-trisphosphate 5-phosphatase — P32019 (reviewed: P32019)

Alternative names: 75 kDa inositol polyphosphate-5-phosphatase, Phosphoinositide 5-phosphatase

All UniProt accessions (2): B1ARF3, P32019

UniProt curated annotations — full annotation on UniProt →

Function. Regulates phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) cellular levels by cleaving the phosphate at the 5-position producing PtdIns(4)P. Also hydrolyzes the 5-position phosphate from inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), thereby modulating cellular signaling events.

Subunit / interactions. Interacts with APPL1, PHETA1 and PHETA2. Interacts with several Rab GTPases, at least RAB1A, RAB2A, RAB5A, RAB6A, RAB8A, RAB9A and RAB33B; these interactions may play a dual role in targeting INPP5B to the specific membranes and stimulating its phosphatase activity (PubMed:17956944, PubMed:26824392, Ref.12). Interacts preferentially with non-phosphorylated RAB8A; phosphorylation of RAB8A on ‘Thr-72’ disrupts this interaction. Interacts with INPP5F.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum-Golgi intermediate compartment. Early endosome membrane. Membrane. Cytoplasmic vesicle. Phagosome membrane. Golgi apparatus.

Tissue specificity. Platelets.

Post-translational modifications. Isoprenylation at Cys-990 may be required for localization at the membrane. May be proteolytically cleaved after Lys-320 as inferred from N-terminal protein sequence of the 75 kda form.

Domain organisation. The ASH (ASPM-SPD2-Hydin) and RhoGAP (Rho GTPase activating) domains form a single folding module. The ASH domain has an immunoglobulin-like fold, the Rho-GAP domain lacks the catalytic arginine and is catalytically inactive. The ASH-RhoGAP module regulates the majority of the protein-protein interactions currently described. The ASH domain mediates association with membrane-targeting Rab GTPases. The Rho-GAP domain interacts with the endocytic adapter APPL1, which is then displaced by PHETA1 and PHETA2 as endosomes mature, all three interactions rely on F&H motifs, an approximately 12-13 amino-acid sequence centered around Phe and His residues essential for binding.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P32019-1	1	yes
P32019-2	2
P32019-3	3
P32019-4	4

RefSeq proteins (10): NP_001284363, NP_001337156, NP_001337157, NP_001352749, NP_001352750, NP_001352751, NP_001352752, NP_001352753, NP_001352754, NP_005531* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR000300	IPPc	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR031896	INPP5B_PH_dom	Domain
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR037793	OCRL1/INPP5B_INPP5c	Domain
IPR046985	IP5	Family
IPR047078	RhoGAP_OCRL1	Domain
IPR048869	OCRL-1_2_ASH	Domain

Pfam: PF00620, PF16776, PF21310, 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), 2 shown:

• 1D-myo-inositol 1,4,5-trisphosphate + H2O = 1D-myo-inositol 1,4-bisphosphate + phosphate (RHEA:19797)
• 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)

UniProt features (52 total): strand 16, helix 10, binding site 6, splice variant 4, region of interest 3, domain 2, sequence variant 2, sequence conflict 2, chain 1, propeptide 1, site 1, modified residue 1, lipid moiety-binding region 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4CML	X-RAY DIFFRACTION	2.3
3MTC	X-RAY DIFFRACTION	2.4
3N9V	X-RAY DIFFRACTION	2.65
5A7I	X-RAY DIFFRACTION	2.89
5A7J	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32019-F1	79.88	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 852 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Ligand- & substrate-binding residues (6): 383; 459–460; 582–583; 596–598; 355; 383

Post-translational modifications (2): 990, 990

Mutagenesis-validated functional residues (1):

Position	Phenotype
990	loss of prenylation and membrane localization; when tested in a heterologous system. does not affect catalytic activity

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1855183	Synthesis of IP2, IP, and Ins in the cytosol
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol

MSigDB gene sets: 251 (showing top): GOBP_LIPID_MODIFICATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MALE_GAMETE_GENERATION, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, KESHELAVA_MULTIPLE_DRUG_RESISTANCE

GO Biological Process (8): in utero embryonic development (GO:0001701), signal transduction (GO:0007165), spermatogenesis (GO:0007283), flagellated sperm motility (GO:0030317), inositol phosphate metabolic process (GO:0043647), phosphatidylinositol dephosphorylation (GO:0046856), regulation of protein processing (GO:0070613), lipid metabolic process (GO:0006629)

GO Molecular Function (8): phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity (GO:0004439), metal ion binding (GO:0046872), inositol-1,4,5-trisphosphate 5-phosphatase activity (GO:0052658), inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity (GO:0052659), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), inositol phosphate phosphatase activity (GO:0052745)

GO Cellular Component (12): cytoplasm (GO:0005737), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), phagocytic vesicle membrane (GO:0030670), early endosome membrane (GO:0031901), neuron projection (GO:0043005), ciliary tip (GO:0097542), endosome (GO:0005768), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Inositol phosphate metabolism	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	4
inositol-polyphosphate 5-phosphatase activity	2
intracellular membrane-bounded organelle	2
endomembrane system	2
chordate embryonic development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
developmental process involved in reproduction	1
male gamete generation	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
organophosphate metabolic process	1
polyol metabolic process	1
phosphatidylinositol metabolic process	1
phospholipid dephosphorylation	1
protein processing	1
regulation of proteolysis	1
regulation of protein maturation	1
primary metabolic process	1
phosphatidylinositol phosphate 5-phosphatase activity	1
phosphatidylinositol-4,5-bisphosphate phosphatase activity	1
cation binding	1
inositol tetrakisphosphate phosphatase activity	1
binding	1
catalytic activity	1
phosphoric ester hydrolase activity	1
phosphatase activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
endocytic vesicle membrane	1
phagocytic vesicle	1
early endosome	1
endosome membrane	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INPP5B	INPP5A	Q14642	867
INPP5B	PHETA1	Q8N4B1	715
INPP5B	APPL1	Q9UKG1	628
INPP5B	SCIN	Q9Y6U3	556
INPP5B	INPP4A	Q96PE3	550
INPP5B	AKT1	P31749	536
INPP5B	ASPM	Q8IZT6	519
INPP5B	GSN	P06396	500
INPP5B	AP2A1	O95782	493
INPP5B	HYDIN	Q4G0P3	476
INPP5B	SERPINB5	P36952	464
INPP5B	RAB35	Q15286	459
INPP5B	INPP4B	O15327	453
INPP5B	RAB5A	P20339	450
INPP5B	SNX9	Q9Y5X1	442

IntAct

27 interactions, top by confidence:

A	B	Type	Score
JUN	ATF2	psi-mi:“MI:0914”(association)	0.950
OCRL	AP2A1	psi-mi:“MI:0914”(association)	0.640
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
NUF2	SPC24	psi-mi:“MI:0914”(association)	0.530
PHETA2	SEMG1	psi-mi:“MI:0914”(association)	0.530
Tuba3a	CCHCR1	psi-mi:“MI:0914”(association)	0.350
Shoc2	GABPB1	psi-mi:“MI:0914”(association)	0.350
Dync1li1	SSR3	psi-mi:“MI:0914”(association)	0.350
CEP43	CCHCR1	psi-mi:“MI:0914”(association)	0.350
PARD6B	PARD3	psi-mi:“MI:0914”(association)	0.350
Cdc26		psi-mi:“MI:0914”(association)	0.350
KIF20A	NEURL4	psi-mi:“MI:0914”(association)	0.350
Rmdn3	DERL1	psi-mi:“MI:0914”(association)	0.350
Clspn	MCM3	psi-mi:“MI:0914”(association)	0.350
Setdb1	INPP5B	psi-mi:“MI:0914”(association)	0.350
DNAJC11		psi-mi:“MI:0914”(association)	0.350
RNASEH2A	PHF20L1	psi-mi:“MI:0914”(association)	0.350
Cbx4	DNAJB6	psi-mi:“MI:0914”(association)	0.350
JAK3	WDR46	psi-mi:“MI:0914”(association)	0.350
RAB8A	CHM	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
PHETA1	INPP5B	psi-mi:“MI:0914”(association)	0.350
PHETA1	CTNND1	psi-mi:“MI:0914”(association)	0.350
PHETA2	INPP5B	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS), INPP5B (Affinity Capture-MS)

ESM2 similar proteins: A0AVI2, A0FGR9, A3KGK3, A6NCM1, A6QQP7, B0DOB4, B3DLH6, B7FF09, B7ZC32, D3ZGS3, F1S5L4, O00329, O35904, O70145, O75923, P0DM40, P32019, P58069, P97564, Q0VA04, Q15283, Q17I16, Q1LXZ7, Q2WGJ9, Q32PH0, Q5DTI8, Q5GJ77, Q5RE88, Q5T0N1, Q5XIZ9, Q61586, Q62240, Q63713, Q69ZN7, Q6DCF6, Q6P5U7, Q6PA97, Q86VS3, Q86YR7, Q8BWR4

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

2 interactions.

A	Effect	B	Mechanism
RAB5A	“up-regulates activity”	INPP5B	binding
INPP5B	“down-regulates quantity”	“1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	125
Likely benign	11
Benign	50

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
548655	NM_005540.3(INPP5B):c.152C>T (p.Ala51Val)	Likely pathogenic

SpliceAI

4337 predictions. Top by Δscore:

Variant	Effect	Δscore
1:37862427:CTAG:C	acceptor_gain	1.0000
1:37862430:GCTG:G	acceptor_loss	1.0000
1:37862431:C:CC	acceptor_gain	1.0000
1:37864306:GCTTA:G	donor_loss	1.0000
1:37864307:CTTA:C	donor_loss	1.0000
1:37864308:TTA:T	donor_loss	1.0000
1:37864309:TA:T	donor_loss	1.0000
1:37864310:A:AC	donor_gain	1.0000
1:37864310:ACCT:A	donor_loss	1.0000
1:37864311:C:CC	donor_gain	1.0000
1:37864419:ATGAC:A	acceptor_gain	1.0000
1:37864420:TGAC:T	acceptor_gain	1.0000
1:37864421:GAC:G	acceptor_gain	1.0000
1:37864421:GACC:G	acceptor_loss	1.0000
1:37864422:ACCT:A	acceptor_loss	1.0000
1:37864423:CCTGA:C	acceptor_loss	1.0000
1:37864424:C:CA	acceptor_loss	1.0000
1:37864424:C:CC	acceptor_gain	1.0000
1:37864425:T:A	acceptor_loss	1.0000
1:37865899:CAT:C	acceptor_gain	1.0000
1:37868496:CCTA:C	donor_loss	1.0000
1:37868499:A:C	donor_loss	1.0000
1:37868500:C:CG	donor_loss	1.0000
1:37868500:CCTG:C	donor_gain	1.0000
1:37868610:AGAGT:A	acceptor_gain	1.0000
1:37868611:GAGT:G	acceptor_gain	1.0000
1:37868613:GT:G	acceptor_gain	1.0000
1:37868615:C:CC	acceptor_gain	1.0000
1:37868615:CTG:C	acceptor_loss	1.0000
1:37868616:T:G	acceptor_loss	1.0000

AlphaMissense

6077 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:37874032:A:G	W718R	0.999
1:37874032:A:T	W718R	0.999
1:37878210:A:T	V632D	0.999
1:37878220:G:C	H629D	0.999
1:37878224:A:C	S627R	0.999
1:37878224:A:T	S627R	0.999
1:37878226:T:G	S627R	0.999
1:37878291:C:G	R605P	0.999
1:37878301:A:G	W602R	0.999
1:37878301:A:T	W602R	0.999
1:37882891:G:C	N529K	0.999
1:37882891:G:T	N529K	0.999
1:37885724:C:A	R491S	0.999
1:37885724:C:G	R491S	0.999
1:37885725:C:A	R491M	0.999
1:37885725:C:G	R491T	0.999
1:37885759:G:C	H480D	0.999
1:37885807:C:G	A464P	0.999
1:37885817:C:A	K460N	0.999
1:37885817:C:G	K460N	0.999
1:37885818:T:A	K460M	0.999
1:37885819:T:C	K460E	0.999
1:37885819:T:G	K460Q	0.999
1:37885820:G:C	N459K	0.999
1:37885820:G:T	N459K	0.999
1:37887401:A:G	W402R	0.999
1:37887401:A:T	W402R	0.999
1:37887457:T:A	E383V	0.999
1:37873041:A:C	F772L	0.998
1:37873041:A:T	F772L	0.998

dbSNP variants (sampled 300 via entrez): RS1000021776 (1:37883885 C>T), RS1000027966 (1:37904104 A>G), RS1000097446 (1:37883683 G>A,T), RS1000123130 (1:37928164 A>T), RS1000167692 (1:37864937 A>G), RS1000183192 (1:37910498 A>G), RS1000196910 (1:37909577 A>T), RS1000211308 (1:37945139 G>A), RS1000316709 (1:37863309 G>C), RS1000317556 (1:37863092 G>A), RS1000409440 (1:37869764 A>C,G), RS1000519178 (1:37909191 T>C), RS1000520747 (1:37904503 A>G), RS1000539574 (1:37940584 C>T), RS1000592951 (1:37909523 TTTC>T)

Disease associations

OMIM: gene MIM:147264 | disease phenotypes: MIM:300555

GenCC curated gene-disease

Mondo (1): Dent disease type 2 (MONDO:0010359)

Orphanet (2): Dent disease (Orphanet:1652), Dent disease type 2 (Orphanet:93623)

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002318_80	Rheumatoid arthritis	3.000000e-12
GCST002318_81	Rheumatoid arthritis	6.000000e-09
GCST002337_173	Amyotrophic lateral sclerosis (sporadic)	2.000000e-08
GCST003476_2	Eyebrow thickness	7.000000e-06
GCST004621_7	Red cell distribution width	6.000000e-09
GCST004775_1	Pulse pressure	2.000000e-09
GCST004775_35	Pulse pressure	1.000000e-11
GCST006585_2166	Blood protein levels	2.000000e-55
GCST006959_154	Rheumatoid arthritis	6.000000e-12
GCST006959_22	Rheumatoid arthritis	5.000000e-09
GCST007932_12	Medication use (thyroid preparations)	3.000000e-11
GCST008839_140	Height	2.000000e-12
GCST010571_4	Autoimmune thyroid disease	2.000000e-10
GCST011365_82	Myocardial infarction	4.000000e-07
GCST012489_78	Heel bone mineral density x serum urate levels interaction	5.000000e-09
GCST90002393_123	Monocyte count	1.000000e-10
GCST90014023_11	Type 1 diabetes	4.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0005763	pulse pressure measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0005091	monocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564487	Dent Disease 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2636 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Inositol polyphosphate phosphatases

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.20	IC50	6300	nM	CHEMBL4538474

PubChem BioAssay actives

1 with measured affinity, of 11 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
(2,4,5-triphosphonooxyphenyl) dihydrogen phosphate	1547661: Inhibition of recombinant human C-terminal His-tagged INPP5B (259 to 563 residues) expressed in Escherichia coli BL21 (DE3) incubated for 5 mins using Ins(1,4,5)P3 as substrate by malachite green reagent based phosphate assay	ic50	6.3000	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	increases expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Microplastics	decreases expression, increases abundance	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases oxidation, affects cotreatment, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Polyethylene Terephthalates	decreases expression, increases abundance	1
Tunicamycin	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1
Volatile Organic Compounds	increases oxidation, affects cotreatment	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4345051	Binding	Inhibition of recombinant human C-terminal His-tagged INPP5B (259 to 563 residues) expressed in Escherichia coli BL21 (DE3) incubated for 5 mins using Ins(1,4,5)P3 as substrate by malachite green reagent based phosphate assay	Regioisomeric Family of Novel Fluorescent Substrates for SHIP2. — ACS Med Chem Lett

Clinical trials (associated diseases)

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