PIK3C2G

Summary

PIK3C2G (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma, HGNC:8973) is a protein-coding gene on chromosome 12p12.3, encoding Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (O75747). Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers.

The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5288 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 296 total — 9 pathogenic, 5 likely-pathogenic
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001288772

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8973
Approved symbol	PIK3C2G
Name	phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma
Location	12p12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000139144
Ensembl biotype	protein_coding
OMIM	609001
Entrez	5288

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000433979, ENST00000535651, ENST00000536967, ENST00000538458, ENST00000538779, ENST00000546003, ENST00000675017, ENST00000676171, ENST00000852955, ENST00000852956

RefSeq mRNA: 3 — MANE Select: NM_001288772 NM_001288772, NM_001288774, NM_004570

CCDS: CCDS44839, CCDS73452

Canonical transcript exons

ENST00000538779 — 33 exons

Exon	Start	End
ENSE00001121910	18282004	18282759
ENSE00002220291	18647876	18648416
ENSE00003458713	18371180	18371311
ENSE00003462014	18491451	18491558
ENSE00003483709	18423945	18424039
ENSE00003490041	18290855	18291012
ENSE00003503214	18293901	18294015
ENSE00003504724	18546323	18546432
ENSE00003510165	18594494	18594569
ENSE00003513434	18640429	18640554
ENSE00003516351	18563377	18563498
ENSE00003522369	18497619	18497748
ENSE00003523964	18505292	18505461
ENSE00003525681	18381766	18381880
ENSE00003530068	18343327	18343360
ENSE00003546157	18503281	18503417
ENSE00003549948	18391122	18391252
ENSE00003553733	18609535	18609629
ENSE00003561004	18362764	18362886
ENSE00003561625	18538156	18538312
ENSE00003569755	18399659	18399847
ENSE00003590307	18325035	18325098
ENSE00003599493	18338426	18338548
ENSE00003599820	18313962	18314064
ENSE00003616361	18488449	18488629
ENSE00003627921	18320962	18321032
ENSE00003629600	18562703	18562892
ENSE00003649241	18420941	18421034
ENSE00003656514	18496062	18496154
ENSE00003671251	18346641	18346836
ENSE00003674889	18566949	18567057
ENSE00003744419	18286847	18286929
ENSE00003897624	18261518	18261577

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 88.79.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7433 / max 105.1497, expressed in 107 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124559	0.2295	47
124553	0.1131	19
124558	0.0959	18
124554	0.0903	15
124555	0.0767	13
124560	0.0703	27
124557	0.0552	22
124552	0.0123	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	88.79	gold quality
hair follicle	UBERON:0002073	82.53	gold quality
upper leg skin	UBERON:0004262	80.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.30	gold quality
skin of abdomen	UBERON:0001416	79.49	gold quality
right lobe of liver	UBERON:0001114	79.48	gold quality
gall bladder	UBERON:0002110	78.77	gold quality
stomach	UBERON:0000945	78.68	gold quality
liver	UBERON:0002107	78.18	gold quality
body of stomach	UBERON:0001161	78.12	gold quality
seminal vesicle	UBERON:0000998	77.83	gold quality
zone of skin	UBERON:0000014	77.21	gold quality
skin of leg	UBERON:0001511	77.13	gold quality
pylorus	UBERON:0001166	76.37	gold quality
cauda epididymis	UBERON:0004360	76.22	gold quality
buccal mucosa cell	CL:0002336	75.91	silver quality
mammalian vulva	UBERON:0000997	74.67	gold quality
parotid gland	UBERON:0001831	74.32	gold quality
cardia of stomach	UBERON:0001162	73.89	gold quality
skin of hip	UBERON:0001554	73.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.91	gold quality
fundus of stomach	UBERON:0001160	71.31	gold quality
sperm	CL:0000019	70.45	gold quality
esophagus mucosa	UBERON:0002469	68.99	gold quality
male germ cell	CL:0000015	68.86	gold quality
metanephros cortex	UBERON:0010533	67.84	gold quality
epithelium of mammary gland	UBERON:0003244	66.21	gold quality
adult mammalian kidney	UBERON:0000082	65.52	gold quality
mammary duct	UBERON:0001765	64.59	gold quality
lower esophagus mucosa	UBERON:0035834	64.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1879.50
E-CURD-119	yes	1821.87
E-CURD-135	yes	921.32
E-MTAB-8221	yes	367.35
E-ANND-3	yes	6.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting PIK3C2G, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-1244	99.33	68.38	832
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-4650-3P	99.01	68.39	1062
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-10A-5P	98.89	69.85	712
HSA-MIR-10B-5P	98.89	69.86	711

Literature-anchored findings (GeneRIF, showing 4)

• The associations of five SNPs (SNPs1-5: A-5468G, A-3333G, C-1794T, C437T and T9148C) of the class II phosphoinositide 3-kinase gamma-subunit (PIK3C2G) gene with type 2 diabetes were examined. (PMID:17991425)
• Data indicate substituents of benzensulfonamide and pyrazine as phosphoinositide 3-kinase-C2gamma (PI3K-C2GAMMA) inhibitors. (PMID:24983663)
• The molecular mechanisms mediating class II PI 3-kinase function in cell physiology. (PMID:33387369)
• Class II phosphatidylinositol 3-kinase isoforms in vesicular trafficking. (PMID:33666217)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pik3c2g	ENSDARG00000099803
mus_musculus	Pik3c2g	ENSMUSG00000030228
rattus_norvegicus	Pik3c2g	ENSRNOG00000034228
drosophila_melanogaster	Pi3K68D	FBGN0015278
drosophila_melanogaster	Pi3K92E	FBGN0015279
caenorhabditis_elegans		WBGENE00000090
caenorhabditis_elegans		WBGENE00009552

Paralogs (9): PIK3C2A (ENSG00000011405), PIK3CB (ENSG00000051382), PIK3C3 (ENSG00000078142), PIK3CG (ENSG00000105851), PIK3CA (ENSG00000121879), PIK3C2B (ENSG00000133056), PI4KB (ENSG00000143393), PIK3CD (ENSG00000171608), PI4KA (ENSG00000241973)

Protein

Protein identifiers

Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma — O75747 (reviewed: O75747)

Alternative names: Phosphoinositide 3-kinase-C2-gamma

All UniProt accessions (4): O75747, A0A087WV31, F5GWG6, F5H7Y7

UniProt curated annotations — full annotation on UniProt →

Function. Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. May play a role in SDF1A-stimulated chemotaxis.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in liver, prostate and testis. Lower levels in small intestine, kidney and pancreas.

Similarity. Belongs to the PI3/PI4-kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75747-1	1	yes
O75747-2	2

RefSeq proteins (3): NP_001275701, NP_001275703, NP_004561 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000341	PI3K_Ras-bd_dom	Domain
IPR000403	PI3/4_kinase_cat_dom	Domain
IPR001263	PI3K_accessory_dom	Domain
IPR001683	PX_dom	Domain
IPR002420	PI3K-type_C2_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015433	PI3/4_kinase	Family
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018936	PI3/4_kinase_CS	Conserved_site
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036871	PX_dom_sf	Homologous_superfamily
IPR036940	PI3/4_kinase_cat_sf	Homologous_superfamily
IPR037707	PI3-kinase_C2_gamma_cat	Domain
IPR042236	PI3K_accessory_sf	Homologous_superfamily

Pfam: PF00168, PF00454, PF00613, PF00787, PF00792, PF00794

Enzyme classification (BRENDA):

• EC 2.7.1.137 — phosphatidylinositol 3-kinase (BRENDA: 29 organisms, 131 substrates, 146 inhibitors, 16 Km, 0 kcat entries)
• EC 2.7.1.154 — phosphatidylinositol-4-phosphate 3-kinase (BRENDA: 7 organisms, 22 substrates, 53 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.03–44	7
ATP	0.015–0.12	5
PHOSPHATIDYLINOSITOL	0.034–64	3
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE	0.004–15	2
PHOSPHATIDYLINOSITOL 4-PHOSPHATE	0.009–10	2
PHOSPHATIDYLINOSITOL	0.064–0.122	2
1,2-DIOCTANOYLPHOSPHATIDYLINOSITOL 4,5-DIPHOSPHA	0.05	1
PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE	0.011	1
PHOSPHATIDYLINOSITOL 4-PHOSPHATE	0.025	1

Catalyzed reactions (Rhea), 2 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H(+) (RHEA:12709)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + ADP + H(+) (RHEA:18373)

UniProt features (31 total): domain 6, sequence conflict 6, sequence variant 5, helix 5, strand 3, region of interest 3, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2WWE	X-RAY DIFFRACTION	1.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75747-F1	73.97	0.27

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane

MSigDB gene sets: 129 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, BIOCARTA_FMLP_PATHWAY, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_3_PHOSPHATE_BIOSYNTHETIC_PROCESS, DING_LUNG_CANCER_BY_MUTATION_RATE, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_TAXIS, BOYAULT_LIVER_CANCER_SUBCLASS_G12_DN, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (8): chemotaxis (GO:0006935), cell migration (GO:0016477), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), host-mediated perturbation of viral process (GO:0044788), phosphatidylinositol-mediated signaling (GO:0048015), lipid metabolic process (GO:0006629), phosphatidylinositol phosphate biosynthetic process (GO:0046854)

GO Molecular Function (8): ATP binding (GO:0005524), 1-phosphatidylinositol-3-kinase activity (GO:0016303), 1-phosphatidylinositol-4-phosphate 3-kinase activity (GO:0035005), phosphatidylinositol binding (GO:0035091), phosphatidylinositol kinase activity (GO:0052742), nucleotide binding (GO:0000166), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
phosphatidylinositol kinase activity	2
response to chemical	1
taxis	1
cell motility	1
phosphatidylinositol phosphate biosynthetic process	1
intracellular signaling cassette	1
host-mediated perturbation of symbiont process	1
intracellular signal transduction	1
primary metabolic process	1
glycerophospholipid biosynthetic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
phosphatidylinositol-3-phosphate biosynthetic process	1
anion binding	1
lipid kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIK3C2G	PIK3C2B	O00750	688
PIK3C2G	EPO	P01588	648
PIK3C2G	PIK3R5	Q8WYR1	576
PIK3C2G	PIK3R4	Q99570	530
PIK3C2G	PIK3R2	O00459	507
PIK3C2G	PIK3C2A	O00443	504
PIK3C2G	PIK3CA	P42336	497
PIK3C2G	PIK3CB	P42338	483
PIK3C2G	PIK3R3	Q92569	474
PIK3C2G	PIK3R1	P27986	450
PIK3C2G	PIK3R6	Q5UE93	419
PIK3C2G	RERGL	Q9H628	418
PIK3C2G	BPGM	P07738	418
PIK3C2G	INPP4B	O15327	418
PIK3C2G	CYRIA	Q9H0Q0	411

IntAct

0 interactions, top by confidence:

BioGRID (3): PIK3C2G (Affinity Capture-MS), BANP (Two-hybrid), PIK3C2G (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GW35, A6QNM3, B0R034, B1ANS9, B9EK06, D2KC46, D3ZY60, F1MS15, F1P065, F1REV3, O00522, O15091, O75747, P10911, P58069, Q008S8, Q14449, Q14D04, Q15283, Q32NR9, Q45GW3, Q4R366, Q4R6T7, Q5H9U9, Q5K651, Q5PQS3, Q5XGX5, Q5XIZ9, Q5ZLD2, Q60862, Q63713, Q69Z37, Q6DCF6, Q6S5J6, Q6TNJ1, Q75PQ8, Q80W71, Q86VD1, Q86YR7, Q8C5W4

Diamond homologs: A0A0G2K344, O00329, O00443, O00750, O02697, O35904, O70167, O70173, O75747, P32871, P42336, P42337, P42338, P48736, P50520, P54673, P54674, P54675, P54676, Q0WPX9, Q22258, Q54UC0, Q5RAY1, Q61194, Q8BTI9, Q8WN22, Q9C680, Q9FMJ0, Q9JHG7, Q9VK45, Q9Z1L0, A4IID4, A4QPH2, A9X1A0, B0KWC1, B1MTG7, B2KI64, B3EX61, B4UT09, E9Q3L2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	5
Uncertain significance	242
Likely benign	22
Benign	3

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
2069975	NM_033123.4(PLCZ1):c.1662del (p.Phe554fs)	Pathogenic
2148203	NM_033123.4(PLCZ1):c.957_960del (p.Asn319fs)	Pathogenic
2578004	NM_033123.4(PLCZ1):c.1174+3A>C	Pathogenic
2578005	NM_033123.4(PLCZ1):c.1274A>G (p.Asn425Ser)	Pathogenic
2578006	NM_033123.4(PLCZ1):c.136-1G>C	Pathogenic
2578007	NM_033123.4(PLCZ1):c.1358G>A (p.Gly453Asp)	Pathogenic
978089	NM_033123.4(PLCZ1):c.588C>A (p.Cys196Ter)	Pathogenic
978090	NM_033123.4(PLCZ1):c.1048T>C (p.Ser350Pro)	Pathogenic
978091	NM_033123.4(PLCZ1):c.736C>T (p.Leu246Phe)	Pathogenic
1324931	NM_033123.4(PLCZ1):c.193C>T (p.Arg65Ter)	Likely pathogenic
271283	NM_033123.4(PLCZ1):c.1465A>T (p.Ile489Phe)	Likely pathogenic
4531235	NM_033123.4(PLCZ1):c.949+1G>A	Likely pathogenic
4796511	NM_033123.4(PLCZ1):c.590G>A (p.Arg197His)	Likely pathogenic
916567	NM_001288772.2(PIK3C2G):c.761+2T>C	Likely pathogenic

SpliceAI

6051 predictions. Top by Δscore:

Variant	Effect	Δscore
12:18293899:A:AG	acceptor_gain	1.0000
12:18293900:G:GG	acceptor_gain	1.0000
12:18293900:GCT:G	acceptor_gain	1.0000
12:18293900:GCTA:G	acceptor_gain	1.0000
12:18294011:CAAAA:C	donor_gain	1.0000
12:18294012:AAAA:A	donor_gain	1.0000
12:18294013:AAA:A	donor_gain	1.0000
12:18294013:AAAGT:A	donor_loss	1.0000
12:18294014:AA:A	donor_gain	1.0000
12:18294015:AG:A	donor_loss	1.0000
12:18294016:G:GG	donor_gain	1.0000
12:18294017:TAA:T	donor_loss	1.0000
12:18325034:GACA:G	acceptor_gain	1.0000
12:18346636:TCTA:T	acceptor_loss	1.0000
12:18346638:TAG:T	acceptor_loss	1.0000
12:18346639:A:AG	acceptor_gain	1.0000
12:18346639:AGG:A	acceptor_loss	1.0000
12:18346640:G:A	acceptor_loss	1.0000
12:18346640:G:GA	acceptor_gain	1.0000
12:18346640:GGCTT:G	acceptor_gain	1.0000
12:18362887:G:GG	donor_gain	1.0000
12:18381765:GAA:G	acceptor_gain	1.0000
12:18381880:GGTA:G	donor_loss	1.0000
12:18381881:G:GC	donor_loss	1.0000
12:18381882:T:A	donor_loss	1.0000
12:18391117:TTCA:T	acceptor_loss	1.0000
12:18391118:TCAG:T	acceptor_loss	1.0000
12:18391119:CAG:C	acceptor_loss	1.0000
12:18391120:A:AG	acceptor_gain	1.0000
12:18391120:A:C	acceptor_loss	1.0000

AlphaMissense

9944 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:18496154:G:C	K921N	0.998
12:18496154:G:T	K921N	0.998
12:18497682:T:A	W943R	0.998
12:18497682:T:C	W943R	0.998
12:18505320:C:A	A1020D	0.998
12:18538252:C:G	C1099W	0.998
12:18546387:T:C	L1141P	0.998
12:18546426:T:C	F1154S	0.998
12:18505323:G:A	G1021D	0.997
12:18505325:T:A	W1022R	0.997
12:18505325:T:C	W1022R	0.997
12:18505395:G:A	G1045D	0.997
12:18538169:T:C	F1072L	0.997
12:18538171:C:A	F1072L	0.997
12:18538171:C:G	F1072L	0.997
12:18505328:T:C	C1023R	0.996
12:18505375:T:A	N1038K	0.996
12:18505375:T:G	N1038K	0.996
12:18505383:T:C	L1041P	0.996
12:18505404:T:C	F1048S	0.996
12:18505414:C:A	D1051E	0.996
12:18505414:C:G	D1051E	0.996
12:18546413:G:C	A1150P	0.996
12:18505330:T:G	C1023W	0.995
12:18505361:C:A	R1034S	0.995
12:18505413:A:T	D1051V	0.995
12:18538156:G:C	R1067S	0.995
12:18538156:G:T	R1067S	0.995
12:18538275:G:C	R1107T	0.995
12:18538276:A:C	R1107S	0.995

dbSNP variants (sampled 300 via entrez): RS1000001323 (12:18368930 G>C,T), RS1000008783 (12:18412005 T>A), RS1000014623 (12:18392373 G>A), RS1000015208 (12:18264856 T>C), RS1000017843 (12:18660102 G>A), RS1000025537 (12:18578678 T>A), RS1000029820 (12:18496329 G>A), RS1000036670 (12:18469858 C>T), RS1000040106 (12:18546054 A>T), RS1000040908 (12:18694667 G>C), RS1000042639 (12:18672324 C>A,G,T), RS1000043252 (12:18470977 T>C), RS1000049302 (12:18454371 G>A), RS1000056870 (12:18476478 G>C), RS1000060387 (12:18547369 T>A)

Disease associations

OMIM: gene MIM:609001 | disease phenotypes: MIM:617214, MIM:189960

GenCC curated gene-disease

Mondo (2): spermatogenic failure 17 (MONDO:0014970), esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (1): Esophageal atresia (Orphanet:1199)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002203_3	Gray matter volume (schizophrenia interaction)	3.000000e-06
GCST002805_10	Body mass index	6.000000e-07
GCST002816_1	Colorectal cancer (aspirin and/or NSAID use interaction)	5.000000e-09
GCST004865_8	Itch intensity from mosquito bite adjusted by bite size	7.000000e-06
GCST009391_51	Metabolite levels	9.000000e-06
GCST010423_1	Diastolic blood pressure x educational attainment (graduated college) interaction (2df)	4.000000e-08
GCST010423_2	Diastolic blood pressure x educational attainment (graduated college) interaction (2df)	3.000000e-07
GCST011696_9	Alzheimer’s disease	1.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0005420	grey matter volume measurement
EFO:0005937	longitudinal BMI measurement
EFO:0007010	drug use measurement
EFO:0007012	NSAID use measurement
EFO:0007013	aspirin use measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0010473	cyclic adenosine monophosphate measurement
EFO:0004784	self reported educational attainment
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163120 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 84,907 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL554	LAPATINIB	4	69,326
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL603469	LESTAURTINIB	3
CHEMBL230011	TG100-115	2	1,504
CHEMBL4558527	AZD-8154	2	19
CHEMBL521851	PICTILISIB	2	6,071
CHEMBL3112866	SAR-260301	1	728

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylinositol kinases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
SAR260301	Inhibition	5.42	pIC50

ChEMBL bioactivities

46 potent at pChembl≥5 of 53 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL3979343
8.70	IC50	2	nM	CHEMBL3942643
8.70	IC50	2	nM	CHEMBL3959351
8.49	Kd	3.2	nM	TG100-115
8.40	IC50	4	nM	CHEMBL3904942
7.70	IC50	20	nM	CHEMBL3889977
7.53	IC50	29.3	nM	CHEMBL3898901
7.52	IC50	30	nM	CHEMBL3950648
7.41	IC50	39	nM	CHEMBL3907932
7.40	Kd	40	nM	CHEMBL1474834
7.39	IC50	41	nM	CHEMBL3922919
7.39	Kd	41	nM	PI-103
7.31	IC50	49	nM	CHEMBL1673047
7.29	IC50	50.7	nM	CHEMBL3986648
7.20	IC50	63.1	nM	AZD-8154
7.12	IC50	75.9	nM	CHEMBL3913941
7.02	IC50	96	nM	CHEMBL3926951
6.91	IC50	123	nM	CHEMBL3918001
6.82	Kd	150	nM	CHEMBL1241674
6.80	Kd	160	nM	CHEMBL2153266
6.64	IC50	231	nM	CHEMBL3979343
6.64	Kd	230	nM	LESTAURTINIB
6.52	Kd	300	nM	PICTILISIB
6.47	IC50	340	nM	CHEMBL3360227
6.37	Kd	430	nM	STAUROSPORINE
6.36	IC50	438	nM	CHEMBL3935895
6.24	Kd	570	nM	MIDOSTAURIN
6.08	IC50	822	nM	CHEMBL3932938
6.07	IC50	858	nM	CHEMBL5400057
6.00	IC50	1000	nM	CHEMBL3785311
6.00	IC50	1000	nM	CHEMBL3786230
5.58	IC50	2610	nM	CHEMBL3948672
5.50	IC50	3162	nM	CHEMBL4126156
5.47	IC50	3410	nM	CHEMBL3360219
5.44	IC50	3610	nM	CHEMBL3360221
5.42	IC50	3812	nM	SAR-260301
5.26	IC50	5500	nM	CHEMBL6048246
5.26	IC50	5500	nM	CHEMBL5838658
5.26	IC50	5500	nM	CHEMBL5754550
5.26	IC50	5500	nM	CHEMBL6051914
5.26	IC50	5500	nM	CHEMBL6035982
5.15	Kd	7110	nM	CHEMBL4445812
5.12	Kd	7500	nM	LAPATINIB

PubChem BioAssay actives

22 with measured affinity, of 236 total; 20 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
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	624958: Binding constant for PIK3C2G kinase domain	kd	0.0032	uM
6-(1,3-benzodioxol-5-yl)-N-methyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]quinazolin-4-amine	594088: Binding affinity to human PIK3C2G	kd	0.0400	uM
3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol	624958: Binding constant for PIK3C2G kinase domain	kd	0.0410	uM
2-[(1S)-1-cyclopropylethyl]-5-[4-methyl-2-[[6-(2-oxopyrrolidin-1-yl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]-7-methylsulfonyl-3H-isoindol-1-one	1807064: Inhibition of PIK3C2G (unknown origin) assessed as reduction in substrate phosphorylation by FRET Adapta assay	ic50	0.0631	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624958: Binding constant for PIK3C2G kinase domain	kd	0.1500	uM
4-quinolin-3-yl-1H-imidazo[4,5-c]pyridin-2-amine	693121: Binding affinity to PIK3C2G	kd	0.1600	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507673: Binding affinity to PIK3C2G	kd	0.2300	uM
4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine	624958: Binding constant for PIK3C2G kinase domain	kd	0.3000	uM
3-amino-N-[3-(3,5-dimethoxyanilino)pyrazin-2-yl]benzenesulfonamide	1181871: Inhibition of human GDT-fused recombinant PI3K-C2gamma assessed as residual activity by nonradiometric ADP-Glo assay	ic50	0.3400	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624958: Binding constant for PIK3C2G kinase domain	kd	0.4300	uM
Midostaurin	507673: Binding affinity to PIK3C2G	kd	0.5700	uM
2-[4-oxo-3-(2-phenylethyl)pteridin-2-yl]sulfanyl-N-(1,3-thiazol-2-yl)acetamide	2019681: Inhibition of PI3KC2gamma (unknown origin) in the presence of 10 uM ATP by Adapta universal kinase assay	ic50	0.8580	uM
N-[5-[3-[(4-hydroxyphenyl)sulfamoyl]-4-methoxyphenyl]-4-methyl-1,3-thiazol-2-yl]cyclopentanecarboxamide	1290192: Inhibition of N-terminal GST-tagged recombinant human full length PI3KC2gamma expressed in baculovirus infected Sf21 insect cells preincubated for 15 mins followed by addition of cold ATP/gamma32P-ATP measured after 15 mins	ic50	1.0000	uM
N-[5-[3-[(4-hydroxyphenyl)sulfamoyl]-4-methoxyphenyl]-4-methyl-1,3-thiazol-2-yl]-2,2-dimethylpropanamide	1290192: Inhibition of N-terminal GST-tagged recombinant human full length PI3KC2gamma expressed in baculovirus infected Sf21 insect cells preincubated for 15 mins followed by addition of cold ATP/gamma32P-ATP measured after 15 mins	ic50	1.0000	uM
N-[5-[2-[(1S)-1-cyclopropylethyl]-7-methylsulfonyl-1-oxo-3H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl]acetamide	1497520: Inhibition of PI3KC2gamma (unknown origin)	ic50	3.1623	uM
N-[3-[[3-(2,5-dimethoxyanilino)pyrazin-2-yl]sulfamoyl]phenyl]acetamide	1181871: Inhibition of human GDT-fused recombinant PI3K-C2gamma assessed as residual activity by nonradiometric ADP-Glo assay	ic50	3.4100	uM
3-[[3-(2,5-dimethoxyanilino)pyrazin-2-yl]sulfamoyl]benzoic acid	1181871: Inhibition of human GDT-fused recombinant PI3K-C2gamma assessed as residual activity by nonradiometric ADP-Glo assay	ic50	3.6100	uM
2-[2-[(2S)-2-methyl-2,3-dihydroindol-1-yl]-2-oxoethyl]-4-morpholin-4-yl-1H-pyrimidin-6-one	1068534: Inhibition of PI3KC2gamma (unknown origin)	ic50	3.8120	uM
6-[(3,4-dichlorobenzoyl)amino]-N-(1,3-thiazol-2-yl)naphthalene-2-carboxamide	1577086: Binding affinity to wild-type human partial length PIK3C2G (M1 to I1446 residues) expressed in mammalian expression system measured after 1 hr by kinomescan method	kd	7.1100	uM
Lapatinib	624958: Binding constant for PIK3C2G kinase domain	kd	7.5000	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects cotreatment, decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression	3
Acetaminophen	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Chenodeoxycholic Acid	affects cotreatment, decreases expression	2
Deoxycholic Acid	affects cotreatment, decreases expression	2
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	2
Glycocholic Acid	affects cotreatment, decreases expression	2
Glycodeoxycholic Acid	decreases expression, affects cotreatment	2
Nickel	decreases expression	2
methyleugenol	decreases expression	1
aflatoxin B2	increases methylation	1
nefazodone	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol S	affects methylation	1
Atazanavir Sulfate	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Tartrazine	affects cotreatment, decreases expression	1
Triclosan	affects cotreatment, decreases expression	1
Valproic Acid	decreases expression, decreases methylation	1
Isotretinoin	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

123 unique, capped per target: 123 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1166620	Binding	Inhibition of PIK3C2G at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair