INPP4B

Summary

INPP4B (inositol polyphosphate-4-phosphatase type II B, HGNC:6075) is a protein-coding gene on chromosome 4q31.21, encoding Inositol polyphosphate 4-phosphatase type II (O15327). Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate and inositol 3,4-trisphosphate.

INPP4B encodes the inositol polyphosphate 4-phosphatase type II, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate. There is limited data to suggest that the human type II enzyme is subject to alternative splicing, as has been established for the type I enzyme.

Source: NCBI Gene 8821 — RefSeq curated summary.

At a glance

• GWAS associations: 29
• Clinical variants (ClinVar): 123 total — 3 pathogenic
• MANE Select transcript: NM_001101669

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6075
Approved symbol	INPP4B
Name	inositol polyphosphate-4-phosphatase type II B
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109452
Ensembl biotype	protein_coding
OMIM	607494
Entrez	8821

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 19 protein_coding, 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay

ENST00000262992, ENST00000503927, ENST00000504632, ENST00000505483, ENST00000506000, ENST00000506217, ENST00000506243, ENST00000506297, ENST00000506517, ENST00000506788, ENST00000507462, ENST00000507861, ENST00000508084, ENST00000508116, ENST00000509777, ENST00000510812, ENST00000511838, ENST00000512489, ENST00000512630, ENST00000513000, ENST00000514525, ENST00000514964, ENST00000630044, ENST00000690114, ENST00000692370, ENST00000850954, ENST00000850955, ENST00000860883, ENST00000860884, ENST00000860885

RefSeq mRNA: 34 — MANE Select: NM_001101669 NM_001101669, NM_001331040, NM_001385334, NM_001385335, NM_001385336, NM_001385337, NM_001385338, NM_001385339, NM_001385340, NM_001385341, NM_001385342, NM_001385343, NM_001385344, NM_001385347, NM_001385348, NM_001385350, NM_001385351, NM_001385357, NM_001385362, NM_001385379, NM_001385380, NM_001385381, NM_001385382, NM_001385383, NM_001385450, NM_001385452, NM_001385454, NM_001385455, NM_001385457, NM_001385458, NM_001385459, NM_001385460, NM_001385461, NM_003866

CCDS: CCDS3757, CCDS82958

Canonical transcript exons

ENST00000262992 — 26 exons

Exon	Start	End
ENSE00001009075	142208896	142209026
ENSE00001009082	142208425	142208529
ENSE00002060765	142462663	142462726
ENSE00002071005	142725839	142725901
ENSE00002078205	142846209	142846301
ENSE00003462270	142431169	142431385
ENSE00003469473	142260492	142260564
ENSE00003470177	142173632	142173809
ENSE00003477168	142237864	142238011
ENSE00003487031	142429173	142429217
ENSE00003501118	142122128	142122245
ENSE00003505070	142160358	142160561
ENSE00003510099	142193087	142193195
ENSE00003537051	142145840	142145996
ENSE00003557267	142112542	142112682
ENSE00003567398	142108093	142108190
ENSE00003583793	142123292	142123415
ENSE00003602496	142086144	142086256
ENSE00003602716	142124588	142124760
ENSE00004282920	142402938	142403054
ENSE00004282921	142270663	142270774
ENSE00004282922	142314712	142314762
ENSE00004282923	142082031	142082185
ENSE00004282924	142023160	142028914
ENSE00004282928	142305458	142305537
ENSE00004282929	142405206	142405324

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 95.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.7585 / max 773.7250, expressed in 1461 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54174	17.7058	1264
54179	4.2354	236
54196	2.1200	580
54170	1.3256	282
54173	0.9469	405
54201	0.8370	356
54165	0.5611	156
54181	0.5418	125
54169	0.3198	117
54180	0.3148	111

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.65	gold quality
calcaneal tendon	UBERON:0003701	94.12	gold quality
male germ cell	CL:0000015	91.69	gold quality
left testis	UBERON:0004533	91.46	gold quality
right testis	UBERON:0004534	91.34	gold quality
superficial temporal artery	UBERON:0001614	89.50	gold quality
testis	UBERON:0000473	88.80	gold quality
colonic epithelium	UBERON:0000397	87.92	gold quality
sural nerve	UBERON:0015488	87.78	gold quality
parietal pleura	UBERON:0002400	87.31	gold quality
visceral pleura	UBERON:0002401	87.03	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.55	gold quality
biceps brachii	UBERON:0001507	86.04	gold quality
pleura	UBERON:0000977	85.91	gold quality
endometrium epithelium	UBERON:0004811	85.29	gold quality
epithelium of nasopharynx	UBERON:0001951	85.17	gold quality
heart right ventricle	UBERON:0002080	84.68	gold quality
germinal epithelium of ovary	UBERON:0001304	84.28	gold quality
adrenal tissue	UBERON:0018303	83.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	83.74	gold quality
tendon	UBERON:0000043	83.68	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.55	gold quality
cartilage tissue	UBERON:0002418	83.29	gold quality
thoracic mammary gland	UBERON:0005200	83.16	gold quality
secondary oocyte	CL:0000655	83.08	gold quality
mammary gland	UBERON:0001911	82.83	gold quality
mammary duct	UBERON:0001765	82.64	gold quality
stromal cell of endometrium	CL:0002255	82.49	gold quality
lower lobe of lung	UBERON:0008949	82.48	gold quality
epithelium of mammary gland	UBERON:0003244	82.29	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	71.35
E-CURD-122	yes	55.25
E-CURD-119	yes	50.32
E-HCAD-25	yes	41.35
E-ANND-3	yes	12.63
E-CURD-85	no	515.65
E-CURD-120	no	420.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

59 targeting INPP4B, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-6516-3P	99.65	68.57	1238

Literature-anchored findings (GeneRIF, showing 40)

• INPP4B has been identified as a tumor suppressor. Loss of heterozygosity (LOH) is found at the INPP4B locus in basal-like breast cancers, as well as in a significant fraction of ovarian cancers. (PMID:19647222)
• INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway (PMID:21127264)
• INPP4B: the new kid on the PI3K block. (PMID:21487159)
• Inositol phosphatase and bone mass: role of INPP4b. (PMID:22377302)
• INPP4B depletion significantly attenuated radiation-induced increases in Akt phosphorylation. (PMID:22895072)
• Codepletion of INPP4B and hexokinase 2 markedly sensitized radioresistant laryngeal cancer cells to irradiation or anticancer drug. (PMID:24051093)
• INPP4B has protein phosphatase activity. different residues within the catalytic site of INPP4B are responsible for activity with lipid and protein substrates and for substrate specificity than for PTEN. (PMID:24070612)
• INPP4B regulates PI3K/Akt signaling and exerts a tumor suppressor effect, impacting the proliferative, invasive, and tumorigenic capacity of melanoma cells. (PMID:24288008)
• INPP4B, which dephosphorylates PI(3,4)P2 to PI(3)P, is essential for macropinocytosis. (PMID:24591580)
• the combination of INPP4B gene transfection and PARP inhibitor had a synergistic antitumor effect on PC3 cells (PMID:24837011)
• Epigenetic inactivation of INPP4B is one of the key mechanisms in activating PI3K/AKT signaling cascade and playing a role in the tumorigenesis of nasopharyngeal carcinoma. (PMID:25126743)
• An association of an INPP4B polymorphism (rs13102150) with multiple sclerosis was observed (PMID:25129256)
• INPP4B is a novel suppressor of oncogenic PKC signaling, further emphasizing the role of INPP4B in maintaining normal physiology of the prostate epithelium and suppressing metastatic potential of prostate tumors. (PMID:25248616)
• ERalpha plays a protective role in bladder cancer initiation and growth at least partly via modulating the INPP4B/Akt pathway. (PMID:25277204)
• INPP4B is highly expressed in intermediate cells within proliferative inflammatory atrophic ducts, and expression is reduced in prostate carcinoma (PMID:25284366)
• Breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors. (PMID:25458846)
• ). We find that RAD50 and INPP4B expression levels have a synergistic influence on breast cancer survival, possibly through their effects on treatment response. (PMID:25528023)
• There were no significant associations of PIK3CA copy number, pAKt, or INPP4B with trastuzumab efficacy. (PMID:25542038)
• INPP4B overexpression is associated with therapy resistance in acute myeloid leukemia (PMID:25736236)
• A previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function. (PMID:25736313)
• Given that INPP4B loss has been found in 40% of ovarian cancer patients, this study provides the rationale for establishing INPP4B as a biomarker of PARP inhibitor response. (PMID:25868852)
• Study provides evidence that INPP4B loss can promote follicular-like thyroid cancer progression and metastasis in the context of PTEN haploinsufficiency through the isoform-specific regulation of AKT signaling at the endosomes. (PMID:25883022)
• Studies in human tissues suggest that reductions in INPP4B and PTEN co-occur in human thyroid and endometrial cancers. INPP4B may therefore be an important regulator of cancer progression, especially in the context of PTEN insufficiency. (PMID:25883023)
• Seventy-nine percent of the ovarian cancers demonstrated loss of INPP4B, most frequently in serous and endometrioid cancer subtypes. (PMID:26189250)
• Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease. (PMID:26411369)
• Data show that activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) plays an important role in inositol polyphosphate 4-phosphatase type II (INPP4B)-mediated melanoma cell proliferation. (PMID:26573229)
• The incidence of INPP4B loss of heterozygosity was significantly higher in the triple-negative breast tumor subtype and positively correlated with PTEN loss of heterozygosity. (PMID:26577950)
• Studies indicate that phosphatidylinositol 4-phosphate phosphatase (INPP4B) that acting as tumor suppressors by antagonizing AKT signaling at endosomes. (PMID:26700619)
• data show that gastric cancer and colorectal cancer with microsatellite instability-high could harbor INPP4B truncation mutation that might alter PI3K pathway (PMID:27068714)
• Mechanism analyses found polyphosphate 4-phosphatase type II (INPP4B) was the target of miR-937, miR-937 directly bound to the 3’UTR of INPP4B, knockdown of INPP4B in A549 with miR-937 inhibitor promoted anchorage -dependent and -independent growth, suggesting miR-937 contributed to cell proliferation of lung cancer (PMID:27179609)
• presented data indicate that INPP4B is crucial for docetaxel-resistant PCa cell survival, potentially by regulating EMT through the PI3K/Akt signaling pathway (PMID:27318090)
• INPP4B expression is associated with enhanced ATM-dependent DNA double strand break repair, which could be mediated by p65 nuclear translocation. (PMID:27342972)
• Immunohistochemical assessment of nestin and INPP4b provides an accurate, accessible and inexpensive tool to identify basal-like breast cancer subtype in the clinically problematic setting of weak oestrogen receptor positivity (PMID:27402148)
• This study sthe identification of a novel small transcript variant of INPP4B (INPP4B-S) that has a role in promoting proliferation of colon and breast cancer cells. INPP4B-S differed from full length INPP4B (INPP4B-FL) by the insertion of a small exon between exons 15 and 16 and the deletion of exons 20-24. (PMID:28189677)
• INPP4B role in regulating phosphatidylinositol-3-kinase signaling in the triple-negative breast cancer cells. (PMID:28196852)
• Low PINPP4B expression is associated with luminal breast cancer. (PMID:28224609)
• INPP4B acted as a tumour suppressor in human prostate cancer (PMID:28261855)
• Study shows that IRF2 knockdown inhibits growth, colony formation of OCI/AML-2, OCI/AML-3, and THP-1 cells. In addition, IRF2 knockdown induces apoptosis of acute myeloid leukemia (AML) cells by regulating apoptotic effectors. Further mechanism analysis shows that INPP4B contributes to the effects of IRF2 on apoptosis and growth of AML cells. Thus, IRF2 serves as an important regulator in AML by targeting INPP4B. (PMID:28579269)
• High INPP4B expression is associated with melanoma. (PMID:28656250)
• Luciferase reporter assay revealed that miR-1290 directly bound to the 3’-UTR of INPP4B; the mutated seed sites in miR-1290 abrogated this effect. Double knockdown of INPP4B and miR-1290 promoted CRC cell proliferation, suggesting miR-1290 promoted CRC cell proliferation by targeting INPP4B. (PMID:28915933)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	inpp4b	ENSDARG00000075201
mus_musculus	Inpp4b	ENSMUSG00000037940
rattus_norvegicus	Inpp4b	ENSRNOG00000018382
drosophila_melanogaster	CG42271	FBGN0259166
caenorhabditis_elegans		WBGENE00010975

Paralogs (1): INPP4A (ENSG00000040933)

Protein

Protein identifiers

Inositol polyphosphate 4-phosphatase type II — O15327 (reviewed: O15327)

Alternative names: Type II inositol 3,4-bisphosphate 4-phosphatase

All UniProt accessions (15): O15327, A0A0D9SF83, A0A8I5KPN5, A0A8I5KVN1, D6R9J5, D6RDJ7, D6RE59, D6RJC3, E7EQN9, E9PCZ3, E9PG59, E9PHC0, H0Y9Q3, H0YA10, Q9BS68

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate and inositol 3,4-trisphosphate. Plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3,4-bisphosphate in membrane ruffles. The lipid phosphatase activity is critical for tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival.

Tissue specificity. Widely expressed with highest levels occurring in the skeletal muscle and heart.

Activity regulation. Strongly inhibited by inositol hexakisphosphate.

Pathway. Signal transduction; phosphatidylinositol signaling pathway.

Similarity. Belongs to the inositol 3,4-bisphosphate 4-phosphatase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15327-1	1	yes
O15327-2	2, stubby

RefSeq proteins (34): NP_001095139, NP_001317969, NP_001372263, NP_001372264, NP_001372265, NP_001372266, NP_001372267, NP_001372268, NP_001372269, NP_001372270, NP_001372271, NP_001372272, NP_001372273, NP_001372276, NP_001372277, NP_001372279, NP_001372280, NP_001372286, NP_001372291, NP_001372308, NP_001372309, NP_001372310, NP_001372311, NP_001372312, NP_001372379, NP_001372381, NP_001372383, NP_001372384, NP_001372386, NP_001372387, NP_001372388, NP_001372389, NP_001372390, NP_003857 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR039034	INPP4	Family

Enzyme classification (BRENDA):

• EC 3.1.3.66 — phosphatidylinositol-3,4-bisphosphate 4-phosphatase (BRENDA: 4 organisms, 9 substrates, 7 inhibitors, 4 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-MYO-INOSITOL 1,3,4-TRISPHOSPHATE	0.034–0.046	2
D-MYO-INOSITOL 3,4-BISPHOSPHATE	0.028–0.039	2

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + phosphate (RHEA:17193)
• 1D-myo-inositol 3,4-bisphosphate + H2O = 1D-myo-inositol 3-phosphate + phosphate (RHEA:43388)
• 1D-myo-inositol 1,3,4-trisphosphate + H2O = 1D-myo-inositol 1,3-bisphosphate + phosphate (RHEA:43392)

UniProt features (15 total): mutagenesis site 4, region of interest 3, sequence conflict 2, splice variant 2, chain 1, domain 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15327-F1	82.85	0.61

Functional residue map

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

Mutagenesis-validated functional residues (4):

Position	Phenotype
843	increased phosphotyrosine phosphatase activity. does not alter lipid phosphatase activity for the substrate phosphatidyl
846	does not alter phosphotyrosine phosphatase activity. abolished lipid phosphatase activity.
847	significantly reduces phosphotyrosine phosphatase activity. not able to dephosphorylate phosphatidylinositol(3,4)p2 but
842	abolished phosphotyrosine phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1855183	Synthesis of IP2, IP, and Ins in the cytosol
R-HSA-1430728	Metabolism
R-HSA-1483249	Inositol phosphate metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 283 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_3_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, LEE_NAIVE_T_LYMPHOCYTE, ONKEN_UVEAL_MELANOMA_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, WANG_LMO4_TARGETS_DN

GO Biological Process (5): phosphatidylinositol biosynthetic process (GO:0006661), signal transduction (GO:0007165), inositol phosphate metabolic process (GO:0043647), lipid metabolic process (GO:0006629), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092)

GO Molecular Function (7): phosphatidylinositol-3,4-bisphosphate 4-phosphatase activity (GO:0016316), inositol-1,3,4-trisphosphate 4-phosphatase activity (GO:0017161), inositol-3,4-bisphosphate 4-phosphatase activity (GO:0052828), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on ester bonds (GO:0016788), phosphatase activity (GO:0016791)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
PI Metabolism	2
Metabolism	2
Inositol phosphate metabolism	1
Phospholipid metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
biosynthetic process	1
phosphatidylinositol metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
organophosphate metabolic process	1
polyol metabolic process	1
primary metabolic process	1
phosphatidylinositol phosphate biosynthetic process	1
phosphatidylinositol phosphate 4-phosphatase activity	1
phosphatidylinositol-3-phosphate biosynthetic process	1
phosphatidylinositol-3,4-bisphosphate phosphatase activity	1
inositol trisphosphate phosphatase activity	1
inositol bisphosphate phosphatase activity	1
binding	1
catalytic activity	1
hydrolase activity	1
phosphoric ester hydrolase activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INPP4B	PTEN	P60484	685
INPP4B	PIK3CA	P42336	650
INPP4B	PLEK	P08567	637
INPP4B	INPPL1	O15357	614
INPP4B	SGK3	Q96BR1	605
INPP4B	PIK3R2	O00459	597
INPP4B	AKT1	P31749	596
INPP4B	ARHGEF1	Q92888	592
INPP4B	INPP5J	Q15735	584
INPP4B	MCF2	P10911	582
INPP4B	WDR18	Q9BV38	538
INPP4B	PIK3CB	P42338	526
INPP4B	FOXA1	P55317	509
INPP4B	ERBB2	P04626	507
INPP4B	PIK3R1	P27986	507

IntAct

15 interactions, top by confidence:

A	B	Type	Score
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
PYCARD	MYO1C	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
ZNF252P-AS1	INPP4B	psi-mi:“MI:0914”(association)	0.350
AKT1	INPP4B	psi-mi:“MI:2364”(proximity)	0.270
BRAF	INPP4B	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	INPP4B	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	INPP4B	psi-mi:“MI:2364”(proximity)	0.270
INPP4B	EGFR	psi-mi:“MI:2364”(proximity)	0.270
INPP4B	PTPN11	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (28): INPP4B (Affinity Capture-MS), INPP4B (Affinity Capture-MS), INPP4B (Affinity Capture-MS), INPP4B (Affinity Capture-MS), EEF1E1 (Co-fractionation), HNRNPR (Co-fractionation), AP1G1 (Co-fractionation), UBA1 (Co-fractionation), CAP2 (Co-fractionation), MSH2 (Co-fractionation), GBE1 (Co-fractionation), AP1B1 (Co-fractionation), AIMP2 (Co-fractionation), DNAJC3 (Co-fractionation), ITPK1 (Co-fractionation)

ESM2 similar proteins: A0JMF6, A2BGG1, A4FU01, B1WC10, E7FAW3, E9PUQ8, E9PXF8, F4JWB3, O00750, O15327, O70167, O70173, O95248, O95876, P0CE43, P97874, Q2I0E5, Q2I6J0, Q32NR9, Q3V1L6, Q4R4D7, Q5PQT2, Q5R991, Q5RA60, Q5U581, Q5ZLG9, Q60760, Q60949, Q68DX3, Q6NTN5, Q6NU08, Q6P1Y8, Q6PJI9, Q6ZPE2, Q6ZS30, Q7TPM9, Q7ZXF1, Q80U56, Q86WG5, Q8C0M0

Diamond homologs: O15327, Q4R4D7, Q5RA60, Q62784, Q6P1Y8, Q96PE3, Q9EPW0, Q9QWG5, Q69ZK0, Q8TCU6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
INPP4B	“down-regulates quantity”	“phosphatidylinositol bisphosphate”	“chemical modification”
INPP4B	“down-regulates activity”	PTEN	dephosphorylation
INPP4B	“down-regulates activity”	AKT1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of ERK1 and ERK2 cascade	5	42.6×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	87
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4070973	NM_001101669.3(INPP4B):c.2267T>C (p.Leu756Pro)	Pathogenic
4070974	NM_001101669.3(INPP4B):c.1909T>C (p.Cys637Arg)	Pathogenic
442514	GRCh37/hg19 4q25-35.2(chr4:109199664-189752726)x3	Pathogenic

SpliceAI

7751 predictions. Top by Δscore:

Variant	Effect	Δscore
4:142028756:T:TA	donor_gain	1.0000
4:142028784:A:AC	donor_gain	1.0000
4:142028785:G:C	donor_gain	1.0000
4:142030130:A:AC	donor_gain	1.0000
4:142108084:CATA:C	donor_gain	1.0000
4:142108087:A:AC	donor_gain	1.0000
4:142108088:C:CC	donor_gain	1.0000
4:142108091:A:AC	donor_gain	1.0000
4:142108092:C:CC	donor_gain	1.0000
4:142108092:CA:C	donor_gain	1.0000
4:142108092:CAA:C	donor_gain	1.0000
4:142108092:CAAT:C	donor_gain	1.0000
4:142108186:CAAAC:C	acceptor_gain	1.0000
4:142108188:AAC:A	acceptor_gain	1.0000
4:142108188:AACC:A	acceptor_loss	1.0000
4:142108189:AC:A	acceptor_gain	1.0000
4:142108190:CC:C	acceptor_gain	1.0000
4:142108191:C:CC	acceptor_gain	1.0000
4:142108191:CT:C	acceptor_loss	1.0000
4:142108192:T:A	acceptor_loss	1.0000
4:142108198:C:CT	acceptor_gain	1.0000
4:142108199:A:T	acceptor_gain	1.0000
4:142112536:GCTTA:G	donor_loss	1.0000
4:142112537:CTTA:C	donor_loss	1.0000
4:142112538:TTA:T	donor_loss	1.0000
4:142112539:TA:T	donor_loss	1.0000
4:142112540:A:AT	donor_loss	1.0000
4:142112541:C:CA	donor_loss	1.0000
4:142112681:CT:C	acceptor_gain	1.0000
4:142112683:C:CC	acceptor_gain	1.0000

AlphaMissense

6114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:142028893:A:C	N888K	1.000
4:142028893:A:T	N888K	1.000
4:142028904:G:T	R885S	1.000
4:142028910:C:G	G883R	1.000
4:142028910:C:T	G883R	1.000
4:142082129:C:A	R848S	1.000
4:142082129:C:G	R848S	1.000
4:142082130:C:A	R848M	1.000
4:142082133:T:A	D847V	1.000
4:142082133:T:G	D847A	1.000
4:142082134:C:G	D847H	1.000
4:142082145:T:A	K843I	1.000
4:142028843:A:G	L905P	0.999
4:142028857:G:C	F900L	0.999
4:142028857:G:T	F900L	0.999
4:142028858:A:G	F900S	0.999
4:142028859:A:G	F900L	0.999
4:142028861:G:T	A899D	0.999
4:142028865:A:C	Y898D	0.999
4:142028895:T:C	N888D	0.999
4:142028903:C:G	R885P	0.999
4:142028909:C:T	G883E	0.999
4:142082033:T:A	R880S	0.999
4:142082033:T:G	R880S	0.999
4:142082034:C:A	R880I	0.999
4:142082034:C:G	R880T	0.999
4:142082091:A:G	L861S	0.999
4:142082099:G:C	C858W	0.999
4:142082109:A:G	L855P	0.999
4:142082112:G:C	T854R	0.999

dbSNP variants (sampled 300 via entrez): RS1000004419 (4:142476282 T>C), RS1000005831 (4:142474275 G>A), RS1000006195 (4:142794358 G>C), RS1000009258 (4:142776935 T>A), RS1000009288 (4:142428454 A>G,T), RS1000010275 (4:142053560 C>G,T), RS1000011799 (4:142173105 T>C), RS1000015788 (4:142726730 T>C,G), RS10000301 (4:142073199 C>T), RS1000031264 (4:142384326 C>A,T), RS1000035460 (4:142255325 T>C,G), RS1000040095 (4:142260167 G>A), RS1000040867 (4:142809031 A>T), RS1000041567 (4:142092298 T>G), RS1000044694 (4:142388485 G>A,C)

Disease associations

OMIM: gene MIM:607494 | disease phenotypes: MIM:143890

GenCC curated gene-disease

Mondo (1): hypercholesterolemia, familial, 1 (MONDO:0007750)

Orphanet (1): Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

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

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST002337_111	Amyotrophic lateral sclerosis (sporadic)	9.000000e-07
GCST003145_2	Severe malaria	6.000000e-06
GCST004496_1	BMI (smoking interaction)	3.000000e-06
GCST004498_16	BMI in smokers	5.000000e-06
GCST004616_3	Platelet distribution width	2.000000e-14
GCST005929_7	Severity of nausea and vomiting of pregnancy	1.000000e-08
GCST006190_16	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-11
GCST006190_57	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-11
GCST006192_36	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-11
GCST006192_86	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-13
GCST006193_48	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-10
GCST006193_86	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-09
GCST006195_37	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	6.000000e-12
GCST006195_78	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-10
GCST007325_181	General risk tolerance (MTAG)	1.000000e-08
GCST007328_44	Alcohol consumption (drinks per week)	2.000000e-08
GCST008522_64	Bitter alcoholic beverage consumption	1.000000e-06
GCST008810_24	Smoking initiation (ever regular vs never regular)	2.000000e-09
GCST008811_8	Alcohol consumption (drinks per week)	1.000000e-08
GCST008972_215	Urate levels	8.000000e-09
GCST009391_506	Metabolite levels	1.000000e-06
GCST010396_50	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06
GCST010725_4	Malaria	4.000000e-10
GCST010725_84	Malaria	7.000000e-11
GCST010725_89	Malaria	7.000000e-11
GCST010988_80	Adult body size	5.000000e-08
GCST010988_81	Adult body size	3.000000e-08
GCST90002401_151	Platelet distribution width	8.000000e-13
GCST90002401_152	Platelet distribution width	4.000000e-66

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0004340	body mass index
EFO:0007984	platelet component distribution width
EFO:0009265	nausea and vomiting of pregnancy severity measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0005670	smoking initiation
EFO:0004531	urate measurement
EFO:0010527	pyridoxate measurement
EFO:0007874	gut microbiome measurement

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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression	8
Estradiol	decreases expression, decreases reaction, affects cotreatment, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Tobacco Smoke Pollution	decreases expression, increases methylation	3
bisphenol A	increases expression, increases methylation	2
Resveratrol	decreases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Calcitriol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	decreases reaction, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	affects expression	1
sodium arsenate	increases abundance, increases expression	1
methylparaben	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
hydroquinone	increases expression	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT00005168	Not specified	COMPLETED	Hyperapo B and Coronary Heart Disease
NCT01753232	Not specified	COMPLETED	Safety and Efficacy of the DALI LDL-adsorber and MONET Lipoprotein Filter
NCT03018678	Not specified	COMPLETED	Screening Protocol for a Gene Therapy Trial in Subjects With Homozygous Familial Hypercholesterolemia
NCT03110432	Not specified	COMPLETED	Prospective German Very High Cardiovascular Risk Patients Dyslipidemia Treatment Indication Registry
NCT03795038	Not specified	COMPLETED	Comparison of the Plasma Lipoprotein Apheresis Systems DIAMED and MONET vs. the Whole Blood Apheresis System DALI
NCT03989167	Not specified	RECRUITING	Clinical Decision Support for Familial Hypercholesterolemia
NCT04073797	Not specified	RECRUITING	PET Imaging of Inflammation and Lipid Lowering Study
NCT04118348	Not specified	COMPLETED	Evaluating the Efficacy of Pediatric Lipid Screening Alerts
NCT04313270	Not specified	UNKNOWN	Subclinical Atherosclerosis in Patients With Familial Hypercholesterolemia Treated With Evolocumab®
NCT04526457	Not specified	COMPLETED	Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH
NCT04722068	Not specified	COMPLETED	Regeneron 1331 Kinetics Sub-Study HoFH
NCT04837638	Not specified	UNKNOWN	Diet Quality and Coronary Artery Calcification in Adults With Heterozygous Familial Hypercholesterolemia
NCT06555120	Not specified	RECRUITING	Screening for Familial Hypercholesterolemia in Children
NCT07543731	Not specified	NOT_YET_RECRUITING	A Real-World Study of Long-Term Adherence and Persistence to Inclisiran, Evolocumab, and Alirocumab