INPP5F

Summary

INPP5F (inositol polyphosphate-5-phosphatase F, HGNC:17054) is a protein-coding gene on chromosome 10q26.11, encoding Phosphatidylinositide 4-phosphatase SAC2 (Q9Y2H2). Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate), PtdIns(4)P).

The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase and contains a Sac domain. The activity of this protein is specific for phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 22876 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 151 total — 1 pathogenic
• MANE Select transcript: NM_014937

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17054
Approved symbol	INPP5F
Name	inositol polyphosphate-5-phosphatase F
Location	10q26.11
Locus type	gene with protein product
Status	Approved
Aliases	SAC2, KIAA0966, hSac2
Ensembl gene	ENSG00000198825
Ensembl biotype	protein_coding
OMIM	609389
Entrez	22876

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 7 nonsense_mediated_decay, 1 retained_intron

ENST00000369081, ENST00000490818, ENST00000631485, ENST00000631555, ENST00000631572, ENST00000637174, ENST00000647699, ENST00000647933, ENST00000648166, ENST00000648262, ENST00000648515, ENST00000648621, ENST00000648661, ENST00000649251, ENST00000649297, ENST00000649454, ENST00000649742, ENST00000649957, ENST00000650305, ENST00000650409, ENST00000650623, ENST00000895116, ENST00000895117, ENST00000895118, ENST00000895119, ENST00000964566, ENST00000964567

RefSeq mRNA: 3 — MANE Select: NM_014937 NM_001243194, NM_001243195, NM_014937

CCDS: CCDS58098, CCDS7616, CCDS81513

Canonical transcript exons

ENST00000650623 — 20 exons

Exon	Start	End
ENSE00000933390	119823815	119823902
ENSE00000933394	119811757	119811955
ENSE00000933395	119810100	119810217
ENSE00000933396	119807932	119808060
ENSE00000933397	119806360	119806480
ENSE00000933398	119805384	119805461
ENSE00000933399	119804173	119804297
ENSE00000933400	119798543	119798610
ENSE00000987985	119791517	119791645
ENSE00000987987	119791869	119792036
ENSE00000987989	119792157	119792213
ENSE00000987990	119796715	119796913
ENSE00000987991	119797461	119797640
ENSE00001707439	119781635	119781771
ENSE00001763835	119751076	119751156
ENSE00003532970	119820846	119820917
ENSE00003543467	119823071	119823199
ENSE00003586308	119822431	119822504
ENSE00003834702	119826631	119829147
ENSE00003840874	119726050	119726359

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.7377 / max 746.3879, expressed in 1781 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107344	22.3149	821
107339	3.6003	1464
107340	3.1299	1374
107341	2.2226	1265
107342	1.0067	324
107345	0.4560	195
107346	0.4387	190
107347	0.2973	106
107343	0.2714	168

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.71	gold quality
superior vestibular nucleus	UBERON:0007227	99.52	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.48	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.01	gold quality
substantia nigra pars compacta	UBERON:0001965	98.93	gold quality
orbitofrontal cortex	UBERON:0004167	98.93	gold quality
middle temporal gyrus	UBERON:0002771	98.89	gold quality
ventral tegmental area	UBERON:0002691	98.71	gold quality
secondary oocyte	CL:0000655	98.70	gold quality
oocyte	CL:0000023	98.65	gold quality
medulla oblongata	UBERON:0001896	98.63	gold quality
CA1 field of hippocampus	UBERON:0003881	98.60	gold quality
parietal lobe	UBERON:0001872	98.52	gold quality
postcentral gyrus	UBERON:0002581	98.46	gold quality
lateral globus pallidus	UBERON:0002476	98.42	gold quality
occipital lobe	UBERON:0002021	98.35	gold quality
primary visual cortex	UBERON:0002436	98.30	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.28	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.20	gold quality
cortical plate	UBERON:0005343	98.04	gold quality
hypothalamus	UBERON:0001898	97.99	gold quality
entorhinal cortex	UBERON:0002728	97.76	gold quality
superior frontal gyrus	UBERON:0002661	97.64	gold quality
trigeminal ganglion	UBERON:0001675	97.62	gold quality
ganglionic eminence	UBERON:0004023	97.40	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.33	gold quality
embryo	UBERON:0000922	97.32	gold quality
dorsal root ganglion	UBERON:0000044	97.19	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.13	gold quality
cerebellar hemisphere	UBERON:0002245	97.11	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	942.04
E-MTAB-5061	yes	15.09
E-GEOD-81608	yes	7.95
E-ENAD-27	yes	4.24
E-ANND-3	no	5.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

85 targeting INPP5F, 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-4533	100.00	69.48	2758
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-101-3P	99.94	75.03	2230
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-6508-5P	99.92	70.67	2465
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-548O-3P	99.74	69.30	2228

Literature-anchored findings (GeneRIF, showing 6)

• Inpp5f is a polyphosphoinositide phosphatase that regulates cardiac hypertrophic responsiveness. (PMID:19875726)
• These findings suggest that INPP5F is a potential tumor suppressor in gliomas via inhibition of STAT3 pathway, and that deregulation of INPP5F may lead to contribution to gliomagenesis. (PMID:25476455)
• Sac2 colocalizes with early endosomal markers and is recruited to transferrin-containing vesicles during endocytic recycling. (PMID:25869669)
• we identified inositol polyphosphate-5-phosphatase F (INPP5F) as a prognostic factor for progression-free survival in Chronic lymphocytic leukemia (PMID:26430724)
• Imprinting aberrations of SNRPN, ZAC1 and INPP5F genes involved in the pathogenesis of congenital heart disease with extracardiac malformations. (PMID:32693431)
• Parkinson’s Disease rs117896735 Variant Regulates INPP5F Expression in Brain Tissues and Increases Risk of Alzheimer’s Disease. (PMID:35848021)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	inpp5f	ENSDARG00000061437
mus_musculus	Inpp5f	ENSMUSG00000042105
rattus_norvegicus	Inpp5f	ENSRNOG00000020388
drosophila_melanogaster	CG9784	FBGN0030761
drosophila_melanogaster	CG6805	FBGN0034179
drosophila_melanogaster	Synj	FBGN0034691
drosophila_melanogaster	sp3	FBGN0038890
caenorhabditis_elegans		WBGENE00006763
caenorhabditis_elegans	sac-2	WBGENE00012353

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), SYNJ1 (ENSG00000159082), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5B (ENSG00000204084), SACM1L (ENSG00000211456)

Protein

Protein identifiers

Phosphatidylinositide 4-phosphatase SAC2 — Q9Y2H2 (reviewed: Q9Y2H2)

Alternative names: Inositol polyphosphate 5-phosphatase F, Sac domain-containing inositol phosphatase 2, Sac domain-containing phosphoinositide 4-phosphatase 2

All UniProt accessions (17): Q9Y2H2, A0A0J9YVW6, A0A0J9YWP2, A0A0J9YY79, A0A0J9YYL5, A0A1B0GUS5, A0A3B3IRJ9, A0A3B3IRT4, A0A3B3IS29, A0A3B3IS98, A0A3B3ISG0, A0A3B3ISI3, A0A3B3ISJ5, A0A3B3ISK0, A0A3B3ITL0, A0A3B3ITR9, A0A3B3IU10

UniProt curated annotations — full annotation on UniProt →

Function. Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate), PtdIns(4)P). May be functionally linked to OCRL, which converts phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to PtdIns, for a sequential dephosphorylation of (PtdIns(4,5)P2) at the 5 and 4 position of inositol, thus playing an important role in the endocytic recycling. Regulator of TF:TFRC and integrins recycling pathway, is also involved in cell migration mechanisms. Modulates AKT/GSK3B pathway by decreasing AKT and GSK3B phosphorylation. Negatively regulates STAT3 signaling pathway through inhibition of STAT3 phosphorylation and translocation to the nucleus. Functionally important modulator of cardiac myocyte size and of the cardiac response to stress. May play a role as negative regulator of axon regeneration after central nervous system injuries. May be involved in insulin granule docking at the plasma membrane of pancreatic cells, an essential step for insulin secretion.

Subunit / interactions. Homodimer. Interacts with OCRL and RAB5A. Interacts with INPP5B and INPP4A. Interacts with STAT3; the interaction is independent of STAT3 ‘Tyr-705’ phosphorylation status.

Subcellular location. Membrane. Clathrin-coated pit. Early endosome. Recycling endosome.

Tissue specificity. Ubiquitous. Highly expressed in brain. Expressed in pancreatic islets.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y2H2-1	1	yes
Q9Y2H2-2	2
Q9Y2H2-3	3
Q9Y2H2-4	4

RefSeq proteins (3): NP_001230123, NP_001230124, NP_055752* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002013	SAC_dom	Domain
IPR022158	Inositol_phosphatase	Domain
IPR034753	hSac2	Domain

Pfam: PF02383, PF12456

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (RHEA:55652)

UniProt features (38 total): strand 8, modified residue 7, splice variant 6, sequence conflict 4, helix 3, region of interest 3, domain 2, sequence variant 2, chain 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4XUU	X-RAY DIFFRACTION	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2H2-F1	67.64	0.30

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 (7): 881, 907, 910, 1103, 827, 830, 878

Mutagenesis-validated functional residues (1):

Position	Phenotype
458	loss of inositol 4-phosphatase activity. alters tfrc distribution and delays tf recycling.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1430728	Metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 286 (showing top): GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_BEHAVIOR, TGCGCANK_UNKNOWN, GOBP_ADULT_BEHAVIOR, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, MODULE_418, GOZGIT_ESR1_TARGETS_DN, AREB6_01, GOBP_REGENERATION, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_16HR_UP, TGACCTY_ERR1_Q2

GO Biological Process (13): positive regulation of receptor recycling (GO:0001921), phosphatidylinositol biosynthetic process (GO:0006661), adult locomotory behavior (GO:0008344), cardiac muscle hypertrophy in response to stress (GO:0014898), phosphatidylinositol catabolic process (GO:0031161), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), phosphatidylinositol dephosphorylation (GO:0046856), negative regulation of axon regeneration (GO:0048681), clathrin-dependent endocytosis (GO:0072583), regulation of cell motility (GO:2000145), regulation of endocytic recycling (GO:2001135), phosphatidylinositol-mediated signaling (GO:0048015), vacuolar proton-transporting V-type ATPase complex assembly (GO:0070072)

GO Molecular Function (9): phosphatidylinositol phosphate 5-phosphatase activity (GO:0034595), phosphatidylinositol phosphate 4-phosphatase activity (GO:0034596), protein homodimerization activity (GO:0042803), phosphatidylinositol-4-phosphate phosphatase activity (GO:0043812), inositol monophosphate 4-phosphatase activity (GO:0052833), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), inositol monophosphate phosphatase activity (GO:0052834)

GO Cellular Component (13): early endosome (GO:0005769), clathrin-coated pit (GO:0005905), axon (GO:0030424), dendrite (GO:0030425), early endosome membrane (GO:0031901), neuronal cell body (GO:0043025), clathrin-coated endocytic vesicle (GO:0045334), recycling endosome (GO:0055037), cytoplasm (GO:0005737), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
PI Metabolism	1
Phospholipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol metabolic process	3
endomembrane system	3
phosphatidylinositol phosphate phosphatase activity	2
endosome	2
neuron projection	2
cellular anatomical structure	2
cytoplasm	2
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
biosynthetic process	1
locomotory behavior	1
adult behavior	1
muscle hypertrophy in response to stress	1
cardiac muscle hypertrophy	1
cardiac muscle adaptation	1
catabolic process	1
intracellular signaling cassette	1
phospholipid dephosphorylation	1
axon regeneration	1
negative regulation of response to external stimulus	1
regulation of axon regeneration	1
negative regulation of neuron projection regeneration	1
negative regulation of response to wounding	1
receptor-mediated endocytosis	1
regulation of locomotion	1
cell motility	1
regulation of cellular process	1
regulation of intracellular transport	1
endocytic recycling	1
regulation of vesicle-mediated transport	1
intracellular signal transduction	1
proton-transporting V-type ATPase complex assembly	1
identical protein binding	1
protein dimerization activity	1
phosphatidylinositol phosphate 4-phosphatase activity	1
phosphatidylinositol monophosphate phosphatase activity	1
inositol monophosphate phosphatase activity	1
binding	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INPP5F	FGD2	Q7Z6J4	462
INPP5F	TRPV2	Q9Y5S1	461
INPP5F	NAP1L5	Q96NT1	406
INPP5F	PRKAG2	Q9UGJ0	390
INPP5F	SPATA31A1	Q5TZJ5	370
INPP5F	SIPA1L2	Q9P2F8	367
INPP5F	HTRA3	P83110	337
INPP5F	HDAC2	Q92769	327
INPP5F	SPAG8	Q99932	326
INPP5F	TMEM229B	Q8NBD8	323
INPP5F	CFAP126	Q5VTH2	320
INPP5F	CLPTM1	O96005	305
INPP5F	NDUFB1	O75438	304
INPP5F	MAB21L2	Q9Y586	301
INPP5F	XPO7	Q9UIA9	297

IntAct

26 interactions, top by confidence:

A	B	Type	Score
LAMTOR5	LAMTOR4	psi-mi:“MI:0914”(association)	0.960
YWHAB	WDR62	psi-mi:“MI:0914”(association)	0.770
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TRPV2	INPP5F	psi-mi:“MI:0915”(physical association)	0.370
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAQ	SHTN1	psi-mi:“MI:0914”(association)	0.350
ARRDC3	ESYT2	psi-mi:“MI:0914”(association)	0.350
STYK1	FAM171A2	psi-mi:“MI:2364”(proximity)	0.270
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAZ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	PLEKHG3	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (61): INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS), INPP5F (Proximity Label-MS)

ESM2 similar proteins: A0A571BF63, A0A8M9QN10, A0JMA8, A1A535, A1A5P5, A1L1K1, A2AVJ5, A7YDW0, B3MJV4, B4MV81, O00443, O08576, O17237, Q0V9V7, Q12923, Q14D04, Q17QK1, Q1LYM3, Q2NKQ1, Q3UGY8, Q59EK9, Q5EB20, Q5JWR5, Q5PQS3, Q5R565, Q5RAY1, Q5TH69, Q5U245, Q5U3W3, Q5XHG1, Q61194, Q61QK6, Q64512, Q6ING4, Q6MZQ0, Q6ZUJ8, Q7Z3E5, Q803Q4, Q80U12, Q8BPQ7

Diamond homologs: A1L244, A4VCH0, A6QL88, A8E7C5, O14127, O15056, O18964, O43001, O43426, O55207, O60162, P32368, P42837, P50942, Q12271, Q55AW9, Q5R921, Q62910, Q6GM29, Q7X911, Q7Z9H9, Q8CDA1, Q8CHC4, Q96328, Q9C5G5, Q9D2G5, Q9EP69, Q9ES21, Q9NTJ5, Q9W0I6, Q9Y2H2, A8MR21, D3ZGS3, D7PF45, G5ECL2, P32019, P59644, Q01968, Q0WQ41, Q0WT19

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	355.3×	6e-16
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	313.5×	9e-16
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	313.5×	9e-16
Activation of BH3-only proteins	7	231.7×	8e-15
RHO GTPases activate PKNs	7	148.0×	2e-13
Intrinsic Pathway for Apoptosis	7	136.7×	4e-13
FOXO-mediated transcription	5	112.0×	3e-09
SARS-CoV-1-host interactions	7	82.0×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	107.8×	5e-08
intracellular protein localization	7	43.1×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	132
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4082117	NM_014937.4(INPP5F):c.1132del (p.Leu377_Val378insTer)	Pathogenic

SpliceAI

4237 predictions. Top by Δscore:

Variant	Effect	Δscore
10:119757861:T:A	acceptor_gain	1.0000
10:119757865:T:TA	acceptor_gain	1.0000
10:119757874:AT:A	acceptor_gain	1.0000
10:119757875:T:TA	acceptor_gain	1.0000
10:119791515:A:AG	acceptor_gain	1.0000
10:119791516:G:GG	acceptor_gain	1.0000
10:119791642:GAAA:G	donor_gain	1.0000
10:119791646:G:GG	donor_gain	1.0000
10:119792212:GT:G	donor_gain	1.0000
10:119792214:G:GG	donor_gain	1.0000
10:119796713:A:AG	acceptor_gain	1.0000
10:119796714:G:GA	acceptor_gain	1.0000
10:119796714:GA:G	acceptor_gain	1.0000
10:119796714:GAC:G	acceptor_gain	1.0000
10:119796714:GACT:G	acceptor_gain	1.0000
10:119796910:GCAG:G	donor_gain	1.0000
10:119796911:CAGGT:C	donor_loss	1.0000
10:119796912:AGGTG:A	donor_loss	1.0000
10:119796914:GT:G	donor_loss	1.0000
10:119796915:T:A	donor_loss	1.0000
10:119797448:A:AG	acceptor_gain	1.0000
10:119797457:TCAGG:T	acceptor_loss	1.0000
10:119797459:A:AG	acceptor_gain	1.0000
10:119797459:AG:A	acceptor_gain	1.0000
10:119797459:AGG:A	acceptor_loss	1.0000
10:119797460:G:GG	acceptor_gain	1.0000
10:119797460:GG:G	acceptor_gain	1.0000
10:119797460:GGA:G	acceptor_gain	1.0000
10:119797460:GGAAT:G	acceptor_gain	1.0000
10:119797638:GAA:G	donor_gain	1.0000

AlphaMissense

7511 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:119751108:T:C	C44R	1.000
10:119751110:T:G	C44W	1.000
10:119797466:C:A	R292S	1.000
10:119797481:G:A	G297R	1.000
10:119797481:G:C	G297R	1.000
10:119797510:T:A	N306K	1.000
10:119797510:T:G	N306K	1.000
10:119797592:T:A	W334R	1.000
10:119797592:T:C	W334R	1.000
10:119804186:T:G	L377W	1.000
10:119804287:C:G	H411D	1.000
10:119804297:G:A	C414Y	1.000
10:119805384:C:G	C414W	1.000
10:119805398:T:G	F419C	1.000
10:119805407:T:A	V422D	1.000
10:119805416:T:C	L425P	1.000
10:119806411:T:A	N457K	1.000
10:119806411:T:G	N457K	1.000
10:119806412:T:C	C458R	1.000
10:119806414:T:G	C458W	1.000
10:119806418:G:C	D460H	1.000
10:119806419:A:C	D460A	1.000
10:119806419:A:T	D460V	1.000
10:119806421:T:C	C461R	1.000
10:119806423:C:G	C461W	1.000
10:119806427:G:C	D463H	1.000
10:119806428:A:C	D463A	1.000
10:119806428:A:G	D463G	1.000
10:119806428:A:T	D463V	1.000
10:119806429:T:A	D463E	1.000

dbSNP variants (sampled 300 via entrez): RS1000028906 (10:119738343 A>C,G,T), RS1000078702 (10:119823718 C>A,T), RS1000085545 (10:119785159 TATAAGCC>T), RS1000086805 (10:119748127 C>T), RS1000098086 (10:119780419 G>A), RS1000144646 (10:119738023 T>C), RS1000169141 (10:119737475 G>C), RS1000177072 (10:119798880 C>T), RS1000192200 (10:119744709 A>G), RS1000206590 (10:119750315 C>T), RS1000258027 (10:119732344 A>G), RS1000282212 (10:119731051 T>A), RS1000340528 (10:119725132 G>A,C), RS1000383873 (10:119805422 A>G), RS1000392883 (10:119725417 T>C)

Disease associations

OMIM: gene MIM:609389 | disease phenotypes: MIM:143890

GenCC curated gene-disease

Mondo (1): familial hypercholesterolemia (MONDO:0005439)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002544_22	Parkinson’s disease	4.000000e-13
GCST009325_4	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-28
GCST90011899_32	Aspartate aminotransferase levels	4.000000e-22

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
bisphenol A	decreases expression, decreases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
Am 580	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
scriptaid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Rosiglitazone	increases expression	1
Vorinostat	increases expression	1
Panobinostat	increases expression	1
Microplastics	decreases expression, increases abundance	1
Antimycin A	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, increases expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Hydrogen Peroxide	increases expression	1
Lead	affects expression	1
Polyethylene Terephthalates	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00655265	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Patients With Familial Hypercholesterolaemia Taking Colesevelam as add-on Therapy to Their Existing Medication
NCT00916643	PHASE4	COMPLETED	Low-Density Lipoprotein (LDL) Apheresis Using H.E.L.P. Therapy
NCT03331666	PHASE4	TERMINATED	Impact of LDL-cholesterol Lowering on Platelet Activation
NCT05465278	PHASE4	COMPLETED	Alirocumab and Plaque Burden In Familial Hypercholesterolaemia
NCT00355615	PHASE3	COMPLETED	PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
NCT00552097	PHASE3	COMPLETED	Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578)
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00827606	PHASE3	COMPLETED	Atorvastatin Three Year Pediatric Study
NCT00943306	PHASE3	COMPLETED	Long Term, Follow-on Study of Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
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)
NCT01813006	PHASE3	COMPLETED	Effect of Omega-3 Fatty Acid on Endothelial Function
NCT01841684	PHASE3	TERMINATED	Efficacy and Tolerability of Anacetrapib Added to Ongoing Lipid-Lowering Therapy in Adult Participants With Homozygous Familial Hypercholesterolemia (HoFH) (MK-0859-042)
NCT02624869	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)
NCT02748057	PHASE3	COMPLETED	A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-833)
NCT03884452	PHASE3	COMPLETED	Ezetimibe (SCH 58235) Taken With Either Atorvastatin or Simvastatin in Participants With Familial Hypercholesterolemia (MK-0653-018)
NCT04798430	PHASE3	ENROLLING_BY_INVITATION	Long-term Efficacy and Safety of OLE LIB003 in HoFH, HeFH, and High-risk CVD Patients Requiring Further LDL-C Reduction
NCT05142722	PHASE3	COMPLETED	Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT05238519	PHASE3	ACTIVE_NOT_RECRUITING	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05952856	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids
NCT05952869	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)
NCT06005597	PHASE3	COMPLETED	Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT00079846	PHASE2	TERMINATED	Implitapide in Patients With Homozygous Familial Hypercholesterolemia (HoFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00079859	PHASE2	TERMINATED	Implitapide in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00477594	PHASE2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT00751608	PHASE2	WITHDRAWN	Effect of APL180 on Endothelial Function in Familial Hypercholesterolemia Patients
NCT02597127	PHASE2	COMPLETED	Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)
NCT03060577	PHASE2	COMPLETED	An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol
NCT04455581	PHASE2	UNKNOWN	A Study to Determine the Safety, Tolerability, and Efficacy of SHR-1209 in Patients With Familial Hypercholesterolemia
NCT04941599	PHASE2	RECRUITING	2-Hydroxybenzylamine (2-HOBA) to Reduce HDL Modification and Improve HDL Function in Familial Hypercholesterolemia (FH)
NCT05261126	PHASE2	COMPLETED	A Study of the Efficacy and Safety of Enclitide Chloride (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-008)
NCT00004809	PHASE1	COMPLETED	Phase I Study of Ex Vivo Liver-Directed Gene Therapy for Familial Hypercholesterolemia
NCT02709850	PHASE1	COMPLETED	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS ANGPTL3-LRx in Healthy Volunteers With Elevated Triglycerides and Participants With Familial Hypercholesterolemia
NCT03747224	PHASE1	COMPLETED	Study of ARO-ANG3 in Healthy Volunteers and in Dyslipidemic Patients
NCT05043181	PHASE1	NOT_YET_RECRUITING	Exosome-based Nanoplatform for Ldlr mRNA Delivery in FH
NCT05851066	PHASE1	COMPLETED	A VSA003 Phase 1 Study in Chinese Adult Healthy Volunteers
NCT02048410	PHASE1/PHASE2	COMPLETED	Efficacy of a New Symbiotic Formulation in Children With Familial Hypercholesterolemia
NCT02100839	PHASE1/PHASE2	COMPLETED	Safety Study of AEM-28 to Treat Refractory Hypercholesterolemia
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results