PIK3R4

Summary

PIK3R4 (phosphoinositide-3-kinase regulatory subunit 4, HGNC:8982) is a protein-coding gene on chromosome 3q22.1, encoding Phosphoinositide 3-kinase regulatory subunit 4 (Q99570). Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of…. It is a selective cancer dependency (DepMap: 38.9% of cell lines).

Predicted to enable protein serine/threonine kinase activity. Involved in several processes, including early endosome to late endosome transport; phosphatidylinositol 3-kinase/protein kinase B signal transduction; and phosphatidylinositol-3-phosphate biosynthetic process. Located in ciliary basal body; intercellular bridge; and late endosome. Part of phosphatidylinositol 3-kinase complex, class III.

Source: NCBI Gene 30849 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 189 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 38.9% of screened cell lines
• MANE Select transcript: NM_014602

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8982
Approved symbol	PIK3R4
Name	phosphoinositide-3-kinase regulatory subunit 4
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	VPS15, p150
Ensembl gene	ENSG00000196455
Ensembl biotype	protein_coding
OMIM	602610
Entrez	30849

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000356763, ENST00000504834, ENST00000507330, ENST00000508273, ENST00000511760, ENST00000512362, ENST00000512430, ENST00000512677, ENST00000893859, ENST00000893860, ENST00000954554

RefSeq mRNA: 1 — MANE Select: NM_014602 NM_014602

CCDS: CCDS3067

Canonical transcript exons

ENST00000356763 — 20 exons

Exon	Start	End
ENSE00000778202	130735869	130736002
ENSE00000778205	130728463	130728684
ENSE00000778207	130718389	130718534
ENSE00000778208	130716396	130716599
ENSE00000778209	130708291	130708492
ENSE00000778210	130706948	130707135
ENSE00000778211	130705561	130705771
ENSE00000778212	130703723	130703888
ENSE00000778213	130690490	130690654
ENSE00001048139	130733548	130734130
ENSE00001078058	130744486	130745264
ENSE00001151964	130730308	130730442
ENSE00001151979	130746318	130746829
ENSE00001431034	130678934	130679485
ENSE00003473754	130723414	130723587
ENSE00003491621	130684250	130684381
ENSE00003605957	130681491	130681591
ENSE00003670145	130680613	130680721
ENSE00003672366	130680977	130681065
ENSE00003684151	130686211	130686422

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 92.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2763 / max 238.3430, expressed in 1803 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44577	17.5527	1802
44578	0.5468	328
44575	0.1184	42
44576	0.0584	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	92.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.34	gold quality
adenohypophysis	UBERON:0002196	91.93	gold quality
colonic epithelium	UBERON:0000397	91.59	gold quality
right lobe of thyroid gland	UBERON:0001119	91.33	gold quality
pituitary gland	UBERON:0000007	91.31	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.98	gold quality
epithelium of nasopharynx	UBERON:0001951	90.57	gold quality
ventricular zone	UBERON:0003053	90.52	gold quality
mucosa of transverse colon	UBERON:0004991	90.44	gold quality
left lobe of thyroid gland	UBERON:0001120	90.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.14	gold quality
upper lobe of left lung	UBERON:0008952	90.01	gold quality
right lung	UBERON:0002167	89.88	gold quality
tibial nerve	UBERON:0001323	89.85	gold quality
thyroid gland	UBERON:0002046	89.76	gold quality
upper lobe of lung	UBERON:0008948	89.67	gold quality
skin of abdomen	UBERON:0001416	89.62	gold quality
skin of leg	UBERON:0001511	89.53	gold quality
right frontal lobe	UBERON:0002810	89.49	gold quality
liver	UBERON:0002107	89.42	gold quality
right ovary	UBERON:0002118	89.41	gold quality
right coronary artery	UBERON:0001625	89.28	gold quality
right adrenal gland	UBERON:0001233	89.22	gold quality
right adrenal gland cortex	UBERON:0035827	89.18	gold quality
ectocervix	UBERON:0012249	89.15	gold quality
caudate nucleus	UBERON:0001873	89.10	gold quality
corpus epididymis	UBERON:0004359	89.07	gold quality
putamen	UBERON:0001874	89.06	gold quality
right uterine tube	UBERON:0001302	88.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.13
E-MTAB-7249	no	145.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting PIK3R4, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
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-4789-5P	99.98	70.76	2721
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-605-5P	98.79	68.24	1161

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 38.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells (PMID:18957027)
• A specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis, whereas ATG14L, a PI3K-III subunit involved in autophagy, is not required. (PMID:20643123)
• High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia. (PMID:25840748)
• A missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype is identified. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts. (PMID:27882921)
• Both Danon Disease and glycogen storage disease type II show accumulation and altered localization of VPS15 in autophagy-incompetent fibers. However, TFEB displays a different pattern between these two lysosomal storage diseases (PMID:28102838)
• The mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. (PMID:29311744)
• Phosphoproteomic identification of ULK substrates reveals VPS15-dependent ULK/VPS34 interplay in the regulation of autophagy. (PMID:34121209)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pik3r4	ENSDARG00000060469
mus_musculus	Pik3r4	ENSMUSG00000032571
rattus_norvegicus	Pik3r4	ENSRNOG00000013669
drosophila_melanogaster	Vps15	FBGN0260935
caenorhabditis_elegans		WBGENE00014151

Protein

Protein identifiers

Phosphoinositide 3-kinase regulatory subunit 4 — Q99570 (reviewed: Q99570)

Alternative names: PI3-kinase p150 subunit, Phosphoinositide 3-kinase adaptor protein

All UniProt accessions (4): D6RAC3, D6RBB7, D6RJ98, Q99570

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2.

Subunit / interactions. Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxiliary subunits to form alternative complex forms. Alternative complex forms containing a fourth regulatory subunit in a mutually exclusive manner are PI3K complex I (PI3KC3-C1) containing ATG14, and PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1, AMBRA1 and NRBF2. PI3KC3-C1 probably associates with PIK3CB. Interacts with RAB7A in the presence of PIK3C3/VPS34. Interacts with NRBF2. Interacts with ARMC3.

Subcellular location. Late endosome. Cytoplasmic vesicle. Autophagosome. Membrane.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Myristoylated. Probably autophosphorylated.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.

RefSeq proteins (1): NP_055417* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001680	WD40_rpt	Repeat
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR021133	HEAT_type_2	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR045162	Vps15-like	Family
IPR055231	PIK3R4-like_middle	Domain

Pfam: PF00069, PF00400, PF22956

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (148 total): helix 57, strand 45, turn 11, repeat 10, sequence variant 8, modified residue 5, region of interest 2, binding site 2, sequence conflict 2, initiator methionine 1, chain 1, compositionally biased region 1, active site 1, domain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9MHF	ELECTRON MICROSCOPY	2.73
9RX5	ELECTRON MICROSCOPY	3.15
9MHG	ELECTRON MICROSCOPY	3.2
9RX6	ELECTRON MICROSCOPY	3.52
13BV	ELECTRON MICROSCOPY	3.77
9RX8	ELECTRON MICROSCOPY	3.87
9RX9	ELECTRON MICROSCOPY	3.99
9RXA	ELECTRON MICROSCOPY	4
9RXB	ELECTRON MICROSCOPY	4.03
9MHH	ELECTRON MICROSCOPY	4.5
9C82	ELECTRON MICROSCOPY	6.84
7BL1	ELECTRON MICROSCOPY	9.8
9S47	ELECTRON MICROSCOPY	9.88
8SOR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99570-F1	78.47	0.33

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): 148 (proton acceptor)

Ligand- & substrate-binding residues (2): 32–40; 53

Post-translational modifications (6): 808, 813, 853, 865, 1316, 2

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1632852	Macroautophagy
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-9679504	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC
R-HSA-9920951	Dengue virus modulates apoptosis

MSigDB gene sets: 251 (showing top): E2F_Q4_01, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_LYSOSOMAL_TRANSPORT, GU_PDEF_TARGETS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT

GO Biological Process (15): pexophagy (GO:0000425), protein phosphorylation (GO:0006468), protein targeting to lysosome (GO:0006622), protein targeting to vacuole (GO:0006623), regulation of autophagy (GO:0010506), regulation of macroautophagy (GO:0016241), regulation of cytokinesis (GO:0032465), receptor catabolic process (GO:0032801), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), cellular response to glucose starvation (GO:0042149), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), early endosome to late endosome transport (GO:0045022), late endosome to vacuole transport (GO:0045324), autophagosome maturation (GO:0097352), macroautophagy (GO:0016236)

GO Molecular Function (8): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (18): late endosome (GO:0005770), autophagosome (GO:0005776), cytosol (GO:0005829), cilium (GO:0005929), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), phagocytic vesicle membrane (GO:0030670), phosphatidylinositol 3-kinase complex, class III, type I (GO:0034271), phosphatidylinositol 3-kinase complex, class III, type II (GO:0034272), phosphatidylinositol 3-kinase complex, class III (GO:0035032), ciliary basal body (GO:0036064), intercellular bridge (GO:0045171), nucleus-vacuole junction (GO:0071561), cytoplasm (GO:0005737), endosome (GO:0005768), cytoskeleton (GO:0005856), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
PI Metabolism	3
IRS-mediated signalling	1
Autophagy	1
Toll-like Receptor Cascades	1
RHO GTPase Effectors	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
SARS-CoV-2-host interactions	1
Class I MHC mediated antigen processing & presentation	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
macroautophagy	3
cytoplasm	3
vacuolar transport	2
autophagy	2
protein kinase activity	2
cytoskeleton	2
phosphatidylinositol 3-kinase complex, class III	2
autophagy of peroxisome	1
phosphorylation	1
protein modification process	1
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
protein targeting	1
intracellular protein transport	1
protein localization to vacuole	1
establishment of protein localization to vacuole	1
regulation of catabolic process	1
regulation of autophagy	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
macromolecule catabolic process	1
receptor metabolic process	1
phosphatidylinositol phosphate biosynthetic process	1
cellular response to starvation	1
intracellular signaling cassette	1
vesicle-mediated transport between endosomal compartments	1
intercellular transport	1
vesicle-mediated transport	1
protein-containing complex disassembly	1
autophagosome assembly	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1

Protein interactions and networks

STRING

2004 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3R4	ATG14	Q6ZNE5	999
PIK3R4	PIK3C3	Q8NEB9	999
PIK3R4	UVRAG	Q9P2Y5	999
PIK3R4	BECN1	Q14457	999
PIK3R4	AMBRA1	Q9C0C7	996
PIK3R4	NRBF2	Q96F24	995
PIK3R4	RUBCN	Q92622	980
PIK3R4	BECN2	A8MW95	978
PIK3R4	SH3GLB1	Q9Y371	945
PIK3R4	ATG7	O95352	930
PIK3R4	ATG13	O75143	916
PIK3R4	ATG5	Q9H1Y0	893
PIK3R4	ATG16L1	Q676U5	880
PIK3R4	BNIP1	Q12981	876
PIK3R4	RB1CC1	Q8TDY2	872

IntAct

139 interactions, top by confidence:

A	B	Type	Score
ATG14	BECN1	psi-mi:“MI:0915”(physical association)	0.980
ATG14	BECN1	psi-mi:“MI:0914”(association)	0.980
UVRAG	BECN1	psi-mi:“MI:0915”(physical association)	0.970
BECN1	PIK3C3	psi-mi:“MI:0915”(physical association)	0.970
UVRAG	BECN1	psi-mi:“MI:0914”(association)	0.970
BECN1	PIK3C3	psi-mi:“MI:0914”(association)	0.970
PIK3C3	BECN1	psi-mi:“MI:0914”(association)	0.970
ATG14	PIK3C3	psi-mi:“MI:0914”(association)	0.950
RUBCN	BECN1	psi-mi:“MI:0914”(association)	0.920
NRBF2	PIK3R4	psi-mi:“MI:0915”(physical association)	0.920
NRBF2	BECN1	psi-mi:“MI:0914”(association)	0.860
NRBF2	PIK3C3	psi-mi:“MI:0914”(association)	0.850
PIK3C3	NRBF2	psi-mi:“MI:0914”(association)	0.850

BioGRID (196): PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-RNA), PIK3R4 (Affinity Capture-RNA), PIK3R4 (Affinity Capture-Western), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Co-fractionation), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS), PIK3R4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IB93, A0A2R8QPS5, A1Z7K9, A2QW83, A4RF51, A5DAD0, A6QR55, B0X2V9, F6V6I0, F6Z5C0, O13046, O17468, P0C0R5, P0C581, P35123, P53015, Q05B30, Q09798, Q0J7U6, Q0WV90, Q10NY2, Q13107, Q1E873, Q20059, Q27GK7, Q4WHP6, Q5NBT9, Q5R4F4, Q5R9I3, Q5RCD3, Q5ZMV9, Q6CMN5, Q6DIP5, Q754X1, Q7ZVL2, Q7ZX22, Q84JM4, Q8R5H1, Q8VD65, Q94AI7

Diamond homologs: A8X5H5, F4ICB6, F4JY12, G4NH08, O14132, O42900, P0C0R5, P18265, P18266, P18431, P22219, P43292, P49840, P49841, P51136, P51137, P54665, P54685, Q00534, Q09499, Q10452, Q12222, Q2NL51, Q2V419, Q38774, Q388M1, Q3S406, Q40518, Q54XJ4, Q5R9I3, Q5YJC2, Q64261, Q6BRY2, Q6CCB0, Q6FRH8, Q6I5Y0, Q6ZAG3, Q7XQP4, Q8SW92, Q8VD65

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
NRBF2	“down-regulates activity”	PIK3R4	binding
PIK3R4	up-regulates	PIK3C3	binding
RAB5A	“up-regulates activity”	PIK3R4	binding
PIK3R4	“up-regulates activity”	PIK3C3	binding
PIK3R4	“form complex”	“Vps34 Complex I”	binding
PIK3R4	“form complex”	“Vps34 Complex II”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 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
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	5	22.1×	3e-04
Intrinsic Pathway for Apoptosis	5	16.4×	8e-04
Macroautophagy	11	14.3×	1e-07
SARS-CoV-2-host interactions	8	10.7×	2e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	10.4×	1e-03
Autophagy	6	10.0×	1e-03
SARS-CoV-1-host interactions	5	9.9×	4e-03
SARS-CoV-1 Infection	6	9.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	7	21.6×	8e-06
autophagosome assembly	9	17.7×	7e-07
mitophagy	6	16.7×	3e-04
cellular response to glucose starvation	5	14.8×	2e-03
macroautophagy	5	10.6×	9e-03
autophagy	8	7.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	153
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

3192 predictions. Top by Δscore:

Variant	Effect	Δscore
3:130679497:T:TC	acceptor_gain	1.0000
3:130680608:AGTAC:A	donor_loss	1.0000
3:130680609:GTA:G	donor_loss	1.0000
3:130680612:C:CA	donor_loss	1.0000
3:130680720:ACC:A	acceptor_loss	1.0000
3:130680722:CTAGG:C	acceptor_loss	1.0000
3:130680723:T:A	acceptor_loss	1.0000
3:130681067:T:C	acceptor_gain	1.0000
3:130684245:CTTAC:C	donor_loss	1.0000
3:130684246:TTACC:T	donor_loss	1.0000
3:130684248:ACCT:A	donor_loss	1.0000
3:130684249:C:CG	donor_loss	1.0000
3:130684249:CCTG:C	donor_gain	1.0000
3:130684377:TGTAC:T	acceptor_gain	1.0000
3:130684379:TAC:T	acceptor_gain	1.0000
3:130684379:TACC:T	acceptor_loss	1.0000
3:130684380:AC:A	acceptor_gain	1.0000
3:130684381:CC:C	acceptor_gain	1.0000
3:130684382:C:CC	acceptor_gain	1.0000
3:130684382:C:T	acceptor_gain	1.0000
3:130684382:CTTA:C	acceptor_loss	1.0000
3:130684383:T:C	acceptor_gain	1.0000
3:130684383:T:TC	acceptor_gain	1.0000
3:130690485:GATA:G	donor_loss	1.0000
3:130690486:ATAC:A	donor_loss	1.0000
3:130690487:TACC:T	donor_loss	1.0000
3:130690488:ACC:A	donor_loss	1.0000
3:130690489:CCTG:C	donor_gain	1.0000
3:130690531:AGAAG:A	donor_gain	1.0000
3:130690650:TAGAT:T	acceptor_gain	1.0000

AlphaMissense

8975 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:130679323:A:G	W1357R	1.000
3:130679323:A:T	W1357R	1.000
3:130679338:C:A	G1352W	1.000
3:130680717:A:G	W1268R	1.000
3:130680717:A:T	W1268R	1.000
3:130681562:A:G	W1213R	1.000
3:130681562:A:T	W1213R	1.000
3:130684341:G:C	F1172L	1.000
3:130684341:G:T	F1172L	1.000
3:130684342:A:C	F1172C	1.000
3:130684342:A:G	F1172S	1.000
3:130684343:A:C	F1172V	1.000
3:130684343:A:G	F1172L	1.000
3:130684343:A:T	F1172I	1.000
3:130684344:C:A	R1171S	1.000
3:130684344:C:G	R1171S	1.000
3:130684345:C:A	R1171M	1.000
3:130684345:C:G	R1171T	1.000
3:130684350:G:C	D1169E	1.000
3:130684350:G:T	D1169E	1.000
3:130684351:T:A	D1169V	1.000
3:130684351:T:C	D1169G	1.000
3:130684351:T:G	D1169A	1.000
3:130684352:C:G	D1169H	1.000
3:130684355:A:G	W1168R	1.000
3:130684355:A:T	W1168R	1.000
3:130684381:C:T	G1159D	1.000
3:130686219:A:G	L1156P	1.000
3:130686289:A:G	W1133R	1.000
3:130686289:A:T	W1133R	1.000

dbSNP variants (sampled 300 via entrez): RS1000021511 (3:130685019 A>G), RS1000101900 (3:130704703 T>C), RS1000128103 (3:130732073 G>C,T), RS1000165057 (3:130703167 G>T), RS1000182024 (3:130742308 A>C), RS1000280003 (3:130697552 G>C,T), RS1000282514 (3:130742551 G>A,C), RS1000291649 (3:130690346 A>C), RS1000325158 (3:130711701 A>G), RS1000361252 (3:130724980 T>C), RS1000392843 (3:130737077 A>G), RS1000473057 (3:130739202 G>A,C), RS1000489583 (3:130729148 A>C), RS1000526314 (3:130743693 C>T), RS1000594975 (3:130691568 T>C)

Disease associations

OMIM: gene MIM:602610 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009091_5	Abdominal aortic calcification levels	5.000000e-07
GCST010002_439	Refractive error	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010272	abdominal aortic calcification measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2189144 (SINGLE PROTEIN), CHEMBL5483084 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol kinases

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.60	IC50	25	nM	CHEMBL3913746

PubChem BioAssay actives

2 with measured affinity, of 6 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
1-[[5-[2-[(2-chloro-4-pyridinyl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol	2017597: Inhibition of recombinant human Vps34-Vps15 complex expressed in insect cells assessed as reduction in PtdIns phosphorylation in presence of gamma32P-ATP by radioactive assay	ic50	0.0250	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
zinc chloride	increases expression	1
sodium arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	decreases expression	1
mesotrione	affects methylation, increases abundance	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	decreases expression	1
Doxorubicin	decreases expression	1
Herbicides	affects methylation, increases abundance	1
Ivermectin	decreases expression	1
Mercury	increases expression	1
Nickel	decreases expression	1
Piroxicam	decreases expression	1
Ribonucleotides	affects binding	1
Thiram	decreases expression	1
Zinc	increases expression	1
Cyclosporine	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2211984	Binding	Inhibition of PIK3R4	Discovery of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide (CZC24758), as a potent, orally bioavailable and selective inhibitor of PI3K for the treatment of inflammatory disease. — Bioorg Med Chem Lett

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7YS	Abcam Raji PIK3R4 KO	Cancer cell line	Male
CVCL_B9ZH	Abcam THP-1 PIK3R4 KO	Cancer cell line	Male
CVCL_C7B6	Abcam PC-3 PIK3R4 KO	Cancer cell line	Male
CVCL_E3KC	HeLa S3 PIK3R4 KO clone #89	Cancer cell line	Female

Clinical trials (associated diseases)

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