PLCG2

Summary

PLCG2 (phospholipase C gamma 2, HGNC:9066) is a protein-coding gene on chromosome 16q24.1, encoding 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (P16885). The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.

The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3.

Source: NCBI Gene 5336 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 34
• Clinical variants (ClinVar): 1,844 total — 5 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_002661

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9066
Approved symbol	PLCG2
Name	phospholipase C gamma 2
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197943
Ensembl biotype	protein_coding
OMIM	600220
Entrez	5336

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 21 protein_coding, 15 protein_coding_CDS_not_defined, 8 retained_intron, 7 nonsense_mediated_decay

ENST00000562180, ENST00000562605, ENST00000563193, ENST00000563269, ENST00000563375, ENST00000563834, ENST00000563954, ENST00000564138, ENST00000565020, ENST00000565054, ENST00000565272, ENST00000565400, ENST00000565674, ENST00000566191, ENST00000567356, ENST00000567373, ENST00000567980, ENST00000568131, ENST00000569523, ENST00000569731, ENST00000569929, ENST00000570196, ENST00000570198, ENST00000697561, ENST00000697562, ENST00000697563, ENST00000697564, ENST00000697565, ENST00000697580, ENST00000697581, ENST00000697582, ENST00000697583, ENST00000697584, ENST00000697585, ENST00000697586, ENST00000697587, ENST00000697595, ENST00000697596, ENST00000697597, ENST00000697598, ENST00000697599, ENST00000697600, ENST00000902425, ENST00000902426, ENST00000902427, ENST00000902428, ENST00000902429, ENST00000902430, ENST00000902431, ENST00000917143, ENST00000947323

RefSeq mRNA: 4 — MANE Select: NM_002661 NM_001425749, NM_001425750, NM_001425751, NM_002661

CCDS: CCDS42204

Canonical transcript exons

ENST00000564138 — 33 exons

Exon	Start	End
ENSE00003970967	81779291	81779424
ENSE00003970980	81957956	81962685
ENSE00003971035	81946175	81946263
ENSE00003971036	81936169	81936378
ENSE00003971037	81880910	81880953
ENSE00003971038	81905403	81905507
ENSE00003971039	81870852	81870935
ENSE00003971040	81893709	81893794
ENSE00003971041	81937758	81937903
ENSE00003971042	81785943	81786182
ENSE00003971043	81869214	81869298
ENSE00003971044	81854444	81854587
ENSE00003971046	81889172	81889273
ENSE00003971047	81928558	81928624
ENSE00003971049	81891472	81891590
ENSE00003971050	81939892	81940059
ENSE00003971051	81938801	81938915
ENSE00003971053	81858263	81858356
ENSE00003971054	81956695	81956879
ENSE00003971055	81927082	81927178
ENSE00003971056	81908416	81908591
ENSE00003971057	81910520	81910720
ENSE00003971058	81859116	81859163
ENSE00003971059	81921198	81921269
ENSE00003971060	81895807	81895927
ENSE00003971061	81919484	81919664
ENSE00003971062	81883269	81883341
ENSE00003971063	81912597	81912716
ENSE00003971064	81907685	81907774
ENSE00003971065	81934429	81934531
ENSE00003971066	81931497	81931654
ENSE00003971067	81923485	81923594
ENSE00003971068	81900612	81900780

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 96.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4006 / max 907.3634, expressed in 1221 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155203	10.3075	1141
155204	5.0721	711
155202	0.6868	378
155206	0.1569	29
155210	0.1291	51
155207	0.0340	15
155205	0.0140	9
155219	0.0002	0

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal glomerulus	UBERON:0000074	96.25	gold quality
bone marrow cell	CL:0002092	96.24	gold quality
blood	UBERON:0000178	96.10	gold quality
metanephric glomerulus	UBERON:0004736	95.62	gold quality
epithelium of nasopharynx	UBERON:0001951	95.39	gold quality
spleen	UBERON:0002106	95.20	gold quality
granulocyte	CL:0000094	94.76	gold quality
endothelial cell	CL:0000115	94.54	gold quality
kidney epithelium	UBERON:0004819	94.52	gold quality
vermiform appendix	UBERON:0001154	94.24	gold quality
nephron tubule	UBERON:0001231	93.89	gold quality
lymph node	UBERON:0000029	93.82	gold quality
tonsil	UBERON:0002372	92.63	gold quality
leukocyte	CL:0000738	92.20	gold quality
monocyte	CL:0000576	92.17	gold quality
colonic epithelium	UBERON:0000397	92.05	gold quality
mononuclear cell	CL:0000842	92.03	gold quality
bone marrow	UBERON:0002371	91.76	gold quality
cortex of kidney	UBERON:0001225	91.44	gold quality
adult mammalian kidney	UBERON:0000082	91.38	gold quality
trabecular bone tissue	UBERON:0002483	90.49	gold quality
caecum	UBERON:0001153	90.48	gold quality
kidney	UBERON:0002113	90.47	gold quality
metanephros cortex	UBERON:0010533	90.08	gold quality
superficial temporal artery	UBERON:0001614	89.97	gold quality
germinal epithelium of ovary	UBERON:0001304	89.36	silver quality
metanephros	UBERON:0000081	89.12	gold quality
visceral pleura	UBERON:0002401	88.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.81	gold quality
gall bladder	UBERON:0002110	88.45	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	31907.95
E-HCAD-24	yes	6582.71
E-MTAB-9435	yes	3663.25
E-CURD-119	yes	3236.68
E-GEOD-139324	yes	2725.95
E-MTAB-8495	yes	2124.42
E-MTAB-10885	yes	891.12
E-GEOD-125970	yes	749.80
E-MTAB-6678	yes	28.00
E-ANND-3	yes	22.16
E-MTAB-9067	yes	13.72
E-CURD-114	yes	9.87
E-MTAB-8410	yes	5.98
E-MTAB-10137	no	4.69
E-MTAB-5061	no	3.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
APOC1	Activation
BCL2	Activation
CCND1	Activation
FABP5	Activation
FOS	Activation
JUN	Activation
LIPA	Activation
MYC	Activation
NFKB2	Activation

Upstream regulators (CollecTRI, top): NFATC1, NFKB

Literature-anchored findings (GeneRIF, showing 40)

• collagen receptor glycoprotein VI and alphaIIbbeta3 trigger distinct patterns of receptor signalling in platelets, leading to tyrosine phosphorylation of PLCgamma2 (integrin alphaiibbeta3) (PMID:12049640)
• Two tyrosine residues in regulating the activity of PLCgamma2 (PMID:12181444)
• full-length cDNA for human PLCgamma2 and expressed it in E. coli using the expression vector pT5T (PMID:12359094)
• PLCG2 has a signaling role in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization (PMID:12813055)
• in gastric cancer, protein translocation of PLCgamma2 and PKCalpha is critical event in the process of apoptosis induction. (PMID:14606067)
• PLC-gamma2 is phosphorylated on Y753, Y759, and Y1217 in response to engagement of the B-cell receptor (PMID:15509800)
• The PLCgamma2 is present in the majority of mediastinal B cell lymphomas. (PMID:15744341)
• PLC-gamma1 and PLC-gamma2 both regulate the functions of ITAM-containing receptors, whereas only PLC-gamma2 regulates the function of DAP10-coupled receptors. (PMID:15972651)
• novel mechanism of PLCgamma(2) activation by Rac GTPases involving neither protein tyrosine phosphorylation nor PI3K-mediated generation of PtdInsP(3) (PMID:16172125)
• observations suggest a model in which TFII-I suppresses agonist-induced calcium entry by competing with TRPC3 for binding to phospholipase C-gamma (PMID:17023658)
• intracellular mediators and pathways activated by leptin downstream of JAK2 were found to include phosphatidylinositol-3 kinase, phospholipase Cgamma2 and protein kinase C, as well as the p38 MAP kinase-phospholipase A(2) axis. (PMID:18000612)
• Plasmacytoid dendritic cells express a signalosome consisting of Lyn, Syk, Btk, Slp65 (Blnk) and PLCgamma2. Triggering CD303 leads to tyrosine phosphorylation of Syk, Slp65, PLCgamma2 & cytoskeletal proteins. (PMID:18022864)
• rac regulates its effector phospholipase Cgamma2 through interaction with a split pleckstrin homology domain (PMID:18728011)
• Data show that RTX treatment results in a time-dependent inhibition of the BCR-signaling cascade involving Lyn, Syk, PLC gamma 2, Akt, and ERK, and calcium mobilization. (PMID:19965664)
• SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. (PMID:20068106)
• Data show that bile acid reflux present in patients with BE may increase reactive oxygen species production and cell proliferation via activation of PI-PLCgamma2, ERK2 MAP kinase, and NADPH oxidase NOX5-S, thereby contributing to the development of EA. (PMID:20086178)
• Rac2 binding in the absence of lipid surfaces was not able to activate phospholipase C gamma 2. (PMID:21245382)
• Data indicate a role for PLCgamma2 and Ca(2+) signaling through the modulation of MEK/ERK in IL3/GM-csf stimulated human hematopoietic stem/progenitor cells. (PMID:21506110)
• Genomic deletions in PLCG2 cause gain of PLCgamma(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (PMID:22236196)
• PLCgamma2 participates in T cell receptor (TCR) signal transduction and plays a role in T cell selection in a transgenic mouse model. (PMID:22837484)
• Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals’ leukocytes showed clearly enhanced PLCgamma2 activity. (PMID:23000145)
• Associations between treatment response and Lyn, Syk, PLCgamma2 and ERK were not found. (PMID:23039362)
• BANK1 and BLK have roles in B-cell signaling through phospholipase C gamma 2 (PMID:23555801)
• Single-nucleotide polymorphisms in PLCG2 gene is associated with breast cancer risk after menopausal hormone replacement therapy. (PMID:24080446)
• down-regulation of PLCgamma2-beta-catenin pathway occurs in mice and humans and leads to myeloid-derived suppressor cells-mediated tumor expansion. (PMID:24127488)
• early Ca(2+) fluxing provides feed-forward signal amplification by promoting anchoring of the PLCgamma2 C2 domain to phospho-SLP65. (PMID:24166973)
• The relationship between upstream tyrosine kinase SYK and its target, PLCgamma2, is maximally predictive and sufficient to distinguish chronic lymphocytic leukemia from healthy controls. (PMID:24489640)
• amarogentin prevents platelet activation through the inhibition of PLC gamma2-PKC cascade and MAPK pathway (PMID:24868545)
• identified three distinct mutations in PLCgamma2 in two patients resistant to ibrutinib (PMID:24869598)
• Data show that phospholipase Cgamma2 (PLCgamma2) is strongly expressed in B cell non-Hodgkin lymphoma and especially in a large subset of Diffuse large B-cell lymphoma (DLBCL). (PMID:25012946)
• The autoinhibitory C-terminal SH2 domain of phospholipase C-gamma2 stabilizes B cell receptor signalosome assembly. (PMID:25227611)
• PLCG2 missense mutation is a risk factor in the development of steroid sensitive nephrotic syndrome in childhood. (PMID:25349203)
• Characterization of the effect of missense point-mutation at R665W in PLCG2 on signaling mechanisms of ibrutinib resistance in chronic lymphocytic leukemia cells. (PMID:25972157)
• The results suggest a new mechanism of PLCgamma activation with unique thermodynamic features and assign a novel regulatory role to its spPH domain. (PMID:27196803)
• Ocular manifestations of phospholipase-Cgamma2-associated antibody deficiency and immune dysregulation show mutations in the PLC[gamma]2 gene leading to aberrant function of immune cells and overproduction of interleukin-1 [beta] (IL-1[beta]). (PMID:27442322)
• R665W and L845F be referred to as allomorphic rather than hypermorphic mutations of PLCG2 Rerouting of the transmembrane signals emanating from BCR and converging on PLCgamma2 through Rac in ibrutinib-resistant CLL cells may provide novel drug treatment strategies to overcome ibrutinib resistance mediated by PLCG2 mutations or to prevent its development in ibrutinib-treated CLL patients. (PMID:27542411)
• finding that mutations or polymorphisms in two putative calcium-regulated domains of PLCG2 are associated with ibrutinib-resistant CLL adds to the evidence supporting complex regulatory shifts in the PLCG2 protein likely occurring during the development of resistance (PMID:28366935)
• Data show that protein-altering changes are in PLCG2, ABI3, and TREM2 genes highly expressed in microglia and highlight an immune-related protein-protein interaction network in Alzheimer’s disease. (PMID:28714976)
• Syk-induced signals in bone marrow stromal cell lines are mediated by phospholipase C gamma1 (PLCgamma1) in osteogenesis and PLCgamma2 in adipogenesis. (PMID:28786489)
• While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant chronic lymphocytic leukemia . Data suggest that alternative mechanisms of resistance do exist in some patients. (PMID:29381098)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	plcg2	ENSDARG00000068763
mus_musculus	Plcg2	ENSMUSG00000034330
rattus_norvegicus	Plcg2	ENSRNOG00000051986
drosophila_melanogaster	sl	FBGN0003416
drosophila_melanogaster	Plc21C	FBGN0004611
caenorhabditis_elegans		WBGENE00004038
caenorhabditis_elegans		WBGENE00004039
caenorhabditis_elegans		WBGENE00004045

Paralogs (14): PLCB4 (ENSG00000101333), PLCH1 (ENSG00000114805), PLCD4 (ENSG00000115556), PLCL1 (ENSG00000115896), PLCG1 (ENSG00000124181), PLCB2 (ENSG00000137841), PLCE1 (ENSG00000138193), PLCZ1 (ENSG00000139151), PLCH2 (ENSG00000149527), PLCB3 (ENSG00000149782), PLCL2 (ENSG00000154822), PLCD3 (ENSG00000161714), PLCB1 (ENSG00000182621), PLCD1 (ENSG00000187091)

Protein

Protein identifiers

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 — P16885 (reviewed: P16885)

Alternative names: Phosphoinositide phospholipase C-gamma-2, Phospholipase C-IV, Phospholipase C-gamma-2

All UniProt accessions (11): A0A8V8TL29, A0A8V8TL51, A0A8V8TL55, A0A8V8TLG6, A0A8V8TLH5, A0A8V8TMG4, A0A8V8TMP2, A0A8V8TMQ0, P16885, H3BMT7, H3BPZ3

UniProt curated annotations — full annotation on UniProt →

Function. The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling.

Subunit / interactions. Part of a complex composed of EEIG1, TNFRSF11A/RANK, PLCG2, GAB2, TEC and BTK; complex formation increases in the presence of TNFSF11/RANKL. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts constitutively with THEMIS2.

Subcellular location. Membrane raft.

Post-translational modifications. Phosphorylated on tyrosine residues by CSF1R. Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced activation of a variety of growth factor receptors and immune system receptors. Phosphorylation leads to increased phospholipase activity.

Disease relevance. Familial cold autoinflammatory syndrome 3 (FCAS3) [MIM:614468] An autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritis in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B-cells, defective B-cells, increased susceptibility to infection, and increased risk of autoimmune disorders. The disease is caused by variants affecting the gene represented in this entry. Autoinflammation, antibody deficiency, and immune dysregulation (APLAID) [MIM:614878] An autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (4): NP_001412678, NP_001412679, NP_001412680, NP_002652* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000909	PLipase_C_PInositol-sp_X_dom	Domain
IPR000980	SH2	Domain
IPR001192	PI-PLC_fam	Family
IPR001452	SH3_domain	Domain
IPR001711	PLipase_C_Pinositol-sp_Y	Domain
IPR001849	PH_domain	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016279	PLC-gamma	Family
IPR017946	PLC-like_Pdiesterase_TIM-brl	Homologous_superfamily
IPR035023	PLC-gamma_C-SH2	Domain
IPR035024	PLC-gamma_N-SH2	Domain
IPR035723	PLCgamma2_SH3	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR056586	EF-hand_PLCG1	Domain
IPR057061	PLCG_EF-hand_2	Domain

Pfam: PF00017, PF00018, PF00168, PF00387, PF00388, PF16457, PF23329, PF23583

Enzyme classification (BRENDA):

• EC 3.1.4.11 — phosphoinositide phospholipase C (BRENDA: 69 organisms, 175 substrates, 159 inhibitors, 27 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1-PHOSPHATIDYL-1D-MYO-INOSITOL 4,5-BISPHOSPHATE	0.006–0.45	8
PHOSPHATIDYLINOSITOL	0.012–100	7
1-PHOSPHATIDYL-1D-MYO-INOSITOL	0.058–18.7	6
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE	0.031–0.182	3
PHOSPHATIDYLINOSITOL 4-PHOSPHATE	0.031	1

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = 1D-myo-inositol 1,4,5-trisphosphate + a 1,2-diacyl-sn-glycerol + H(+) (RHEA:33179)

UniProt features (135 total): strand 55, helix 44, turn 8, domain 7, sequence variant 7, sequence conflict 6, modified residue 5, active site 2, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
2W2X	X-RAY DIFFRACTION	2.3
8T7C	X-RAY DIFFRACTION	2.55
2W2W	X-RAY DIFFRACTION	2.8
8QJU	ELECTRON MICROSCOPY	3.5
8JQG	ELECTRON MICROSCOPY	3.72
8JQI	ELECTRON MICROSCOPY	4.1
8JQH	ELECTRON MICROSCOPY	4.2
2K2J	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16885-F1	83.49	0.46

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 (2): 327; 372

Post-translational modifications (5): 753, 759, 1197, 1217, 1245

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-202433	Generation of second messenger molecules
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-2424491	DAP12 signaling
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5621480	Dectin-2 family
R-HSA-9027277	Erythropoietin activates Phospholipase C gamma (PLCG)
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers

MSigDB gene sets: 662 (showing top): PID_BCR_5PATHWAY, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, MODULE_172, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION

GO Biological Process (60): cell activation (GO:0001775), response to yeast (GO:0001878), positive regulation of receptor internalization (GO:0002092), stimulatory C-type lectin receptor signaling pathway (GO:0002223), toll-like receptor signaling pathway (GO:0002224), macrophage activation involved in immune response (GO:0002281), follicular B cell differentiation (GO:0002316), positive regulation of dendritic cell cytokine production (GO:0002732), phosphatidylinositol biosynthetic process (GO:0006661), phospholipid catabolic process (GO:0009395), positive regulation of gene expression (GO:0010628), positive regulation of epithelial cell migration (GO:0010634), programmed cell death (GO:0012501), Wnt signaling pathway (GO:0016055), regulation of lipid metabolic process (GO:0019216), calcium-mediated signaling (GO:0019722), platelet activation (GO:0030168), B cell differentiation (GO:0030183), lipopolysaccharide-mediated signaling pathway (GO:0031663), positive regulation of type I interferon production (GO:0032481), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-2 production (GO:0032743), positive regulation of interleukin-23 production (GO:0032747), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), inositol trisphosphate biosynthetic process (GO:0032959), intracellular signal transduction (GO:0035556), Fc-epsilon receptor signaling pathway (GO:0038095), B cell activation (GO:0042113), negative regulation of programmed cell death (GO:0043069), regulation of canonical NF-kappaB signal transduction (GO:0043122), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of MAPK cascade (GO:0043410), phosphatidylinositol metabolic process (GO:0046488), phosphatidylinositol-mediated signaling (GO:0048015), response to axon injury (GO:0048678), positive regulation of calcium-mediated signaling (GO:0050850), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853)

GO Molecular Function (10): phosphotyrosine residue binding (GO:0001784), phosphatidylinositol-4,5-bisphosphate phospholipase C activity (GO:0004435), C-type glycerophospholipase activity (GO:0004629), protein kinase binding (GO:0019901), scaffold protein binding (GO:0097110), phosphorylation-dependent protein binding (GO:0140031), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (9): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), ruffle membrane (GO:0032587), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), intracellular vesicle (GO:0097708), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Fc epsilon receptor (FCERI) signaling	2
C-type lectin receptors (CLRs)	2
Platelet activation, signaling and aggregation	1
Toll-like Receptor Cascades	1
Inositol phosphate metabolism	1
TCR signaling	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
DAP12 interactions	1
Signaling by Erythropoietin	1
Anti-inflammatory response favouring Leishmania parasite infection	1
SARS-CoV Infections	1
Cytokine Signaling in Immune system	1
Signaling by the B Cell Receptor (BCR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell surface receptor signaling pathway	2
intracellular anatomical structure	2
cytoplasm	2
cellular process	1
multicellular organismal process	1
response to fungus	1
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
pattern recognition receptor signaling pathway	1
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
immune response	1
macrophage activation	1
mature B cell differentiation involved in immune response	1
dendritic cell cytokine production	1
positive regulation of leukocyte mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of dendritic cell cytokine production	1
biosynthetic process	1
phosphatidylinositol metabolic process	1
phospholipid metabolic process	1
lipid catabolic process	1
organophosphate catabolic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
signal transduction	1
cell death	1
lipid metabolic process	1
regulation of primary metabolic process	1
intracellular signaling cassette	1
cell activation	1
blood coagulation	1

Protein interactions and networks

STRING

2218 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLCG2	BLNK	Q8WV28	998
PLCG2	BTK	Q06187	997
PLCG2	SYK	P43405	987
PLCG2	LCP2	Q13094	983
PLCG2	VAV1	P15498	982
PLCG2	SRC	P12931	883
PLCG2	GP6	Q9HCN6	880
PLCG2	DAPP1	Q9UN19	870
PLCG2	FCER1G	P30273	857
PLCG2	ZAP70	P43403	841
PLCG2	CD19	P15391	841
PLCG2	LYN	P07948	840
PLCG2	AKT1	P31749	770
PLCG2	PIK3CD	O00329	743
PLCG2	ITGA2	P17301	721

IntAct

99 interactions, top by confidence:

A	B	Type	Score
EGFR	PLCG2	psi-mi:“MI:0915”(physical association)	0.840
PLCG2	EGFR	psi-mi:“MI:2364”(proximity)	0.840
EGFR	PLCG2	psi-mi:“MI:0407”(direct interaction)	0.840
PLCG2	EGFR	psi-mi:“MI:0407”(direct interaction)	0.840
ERBB2	PLCG2	psi-mi:“MI:2364”(proximity)	0.570
PLCG2	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.570
PLCG2	BRAF	psi-mi:“MI:0915”(physical association)	0.550
PLCG2	BRAF	psi-mi:“MI:2364”(proximity)	0.550
PLCG2	PIK3R1	psi-mi:“MI:0915”(physical association)	0.540
PIK3R1	PLCG2	psi-mi:“MI:2364”(proximity)	0.540
PLCG2	SH2D1B	psi-mi:“MI:0407”(direct interaction)	0.520
SH2D1B	PLCG2	psi-mi:“MI:0914”(association)	0.520
FSBP	PLCG2	psi-mi:“MI:0915”(physical association)	0.510
PLCG2	PSMD3	psi-mi:“MI:0915”(physical association)	0.510
PLCG2	FSBP	psi-mi:“MI:0915”(physical association)	0.510
PLCG2	SLC35A2	psi-mi:“MI:0915”(physical association)	0.500
EPYC	PLCG2	psi-mi:“MI:0915”(physical association)	0.490
PLCG2	LHX8	psi-mi:“MI:0915”(physical association)	0.490
ELK1	PLCG2	psi-mi:“MI:0915”(physical association)	0.490
PLCG2	HSPD1	psi-mi:“MI:0915”(physical association)	0.490
PLCG2	TP53	psi-mi:“MI:0915”(physical association)	0.490
PTTG1	PLCG2	psi-mi:“MI:0915”(physical association)	0.490
LHX8	PLCG2	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (104): PLCG2 (Two-hybrid), LHX8 (Two-hybrid), PTTG1 (Two-hybrid), TP53 (Two-hybrid), ELK1 (Two-hybrid), EPYC (Two-hybrid), HSPD1 (Two-hybrid), ASB9 (Two-hybrid), C22orf29 (Two-hybrid), SETD9 (Two-hybrid), GABPB2 (Two-hybrid), KCTD17 (Two-hybrid), PSMD3 (Two-hybrid), RAD54B (Two-hybrid), RALBP1 (Two-hybrid)

ESM2 similar proteins: A0A0G2K344, A0A3Q1N1R0, E1BKH1, G3GTP0, G5EF51, O13728, O70481, P06814, P16259, P16885, P20807, P24135, P32871, P34529, P35875, P42336, P42337, P43368, P49917, P51186, P97393, Q09879, Q11208, Q13017, Q32TF8, Q32TG3, Q4V8Q1, Q5JST6, Q5JVL4, Q5R6L3, Q64691, Q6GL75, Q6GQ76, Q6J756, Q6NU25, Q758X6, Q803R5, Q8BTF7, Q8BTI9, Q8CIH5

Diamond homologs: A2AP18, A3KGF7, A5D6R3, G5EBH0, G5EFI8, O13433, O75038, O89040, P08487, P10686, P10687, P10688, P10894, P10895, P13217, P16885, P19174, P21671, P24135, P25455, P40977, P51178, P51432, Q00722, Q01970, Q02158, Q07722, Q15147, Q1RML2, Q22070, Q2VRL0, Q32NH8, Q4KWH5, Q4KWH8, Q4R6L3, Q5FX52, Q5RET0, Q62077, Q62711, Q7YRU3

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
BTK	“up-regulates activity”	PLCG2	phosphorylation
BTK	up-regulates	PLCG2	phosphorylation
CSF1R	up-regulates	PLCG2
PLCG2	up-regulates	Macrophage_differentiation
PLCG2	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
PLCG2	“down-regulates quantity”	“1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate”	“chemical modification”
PLCG2	“up-regulates quantity”	“1D-myo-inositol 1,4,5-trisphosphate”	“chemical modification”
PLCG2	“up-regulates quantity”	1,2-diacyl-sn-glycerol	“chemical modification”
INPP5D	“down-regulates activity”	PLCG2	dephosphorylation
TRPM7	“up-regulates activity”	PLCG2	phosphorylation
SYK	“up-regulates activity”	PLCG2	phosphorylation
BLK	“up-regulates activity”	PLCG2	phosphorylation
LCK	up-regulates	PLCG2	phosphorylation
PLCG2	up-regulates	Apoptosis
PLCG2	down-regulates	Proliferation
FYN	“up-regulates activity”	PLCG2	phosphorylation
HCK	“up-regulates activity”	PLCG2	phosphorylation
LYN	“up-regulates activity”	PLCG2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Signaling by ERBB2 ECD mutants	6	103.3×	2e-09
GAB1 signalosome	6	97.6×	2e-09
Constitutive Signaling by EGFRvIII	5	91.5×	1e-07
PI3K events in ERBB2 signaling	5	86.1×	1e-07
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	73.2×	3e-07
Signaling by ERBB2 KD Mutants	6	65.1×	3e-08
RET signaling	5	33.3×	1e-05
Constitutive Signaling by Aberrant PI3K in Cancer	10	32.5×	9e-11

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	9	50.7×	9e-11
cellular response to epidermal growth factor stimulus	5	36.1×	1e-04
positive regulation of MAPK cascade	6	11.0×	2e-03
positive regulation of cell migration	7	9.8×	1e-03
heart development	5	8.9×	8e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	8.9×	8e-03
positive regulation of gene expression	8	7.0×	2e-03
intracellular signal transduction	8	6.9×	2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1844 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	863
Likely benign	724
Benign	132

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
30050	NM_002661.5(PLCG2):c.1935-521_2055-1483del	Pathogenic
30051	NM_002661.5(PLCG2):c.2055-1416_2418-790del	Pathogenic
30052	NM_002661.5(PLCG2):c.1935-715_2055-2763del	Pathogenic
39696	NM_002661.5(PLCG2):c.2120C>A (p.Ser707Tyr)	Pathogenic
954960	NM_002661.5(PLCG2):c.2122G>C (p.Ala708Pro)	Pathogenic
1251962	NM_002661.5(PLCG2):c.2119T>C (p.Ser707Pro)	Likely pathogenic
1328599	NM_002661.5(PLCG2):c.3430G>A (p.Asp1144Asn)	Likely pathogenic
1339554	NM_002661.5(PLCG2):c.2095G>A (p.Gly699Ser)	Likely pathogenic
1693266	NM_002661.5(PLCG2):c.2534T>C (p.Leu845Ser)	Likely pathogenic
1719981	NM_002661.5(PLCG2):c.3420T>A (p.Asp1140Glu)	Likely pathogenic

SpliceAI

7135 predictions. Top by Δscore:

Variant	Effect	Δscore
16:81785941:A:AG	acceptor_gain	1.0000
16:81785942:G:GG	acceptor_gain	1.0000
16:81785976:T:TA	acceptor_gain	1.0000
16:81785977:G:A	acceptor_gain	1.0000
16:81786179:TTCTG:T	donor_loss	1.0000
16:81786180:TCT:T	donor_gain	1.0000
16:81786180:TCTGT:T	donor_loss	1.0000
16:81786181:CTGTG:C	donor_loss	1.0000
16:81786182:TGT:T	donor_loss	1.0000
16:81786183:G:GG	donor_gain	1.0000
16:81786183:GTGA:G	donor_loss	1.0000
16:81786184:T:G	donor_loss	1.0000
16:81786185:G:GT	donor_loss	1.0000
16:81786186:AGT:A	donor_loss	1.0000
16:81854437:A:AG	acceptor_gain	1.0000
16:81854438:T:G	acceptor_gain	1.0000
16:81854439:TTTA:T	acceptor_loss	1.0000
16:81854440:TTA:T	acceptor_loss	1.0000
16:81854441:TA:T	acceptor_loss	1.0000
16:81854442:A:AG	acceptor_gain	1.0000
16:81854442:A:C	acceptor_loss	1.0000
16:81854442:AGT:A	acceptor_gain	1.0000
16:81854442:AGTG:A	acceptor_gain	1.0000
16:81854443:G:GT	acceptor_gain	1.0000
16:81854443:GT:G	acceptor_gain	1.0000
16:81854443:GTG:G	acceptor_gain	1.0000
16:81854443:GTGG:G	acceptor_gain	1.0000
16:81854443:GTGGA:G	acceptor_gain	1.0000
16:81854583:GGCAG:G	donor_gain	1.0000
16:81854584:GCAG:G	donor_gain	1.0000

AlphaMissense

8464 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:81891565:T:G	Y321D	1.000
16:81891578:C:G	S325W	1.000
16:81891583:C:G	H327D	1.000
16:81891584:A:T	H327L	1.000
16:81891585:T:A	H327Q	1.000
16:81891585:T:G	H327Q	1.000
16:81891586:A:G	N328D	1.000
16:81891587:A:T	N328I	1.000
16:81891588:C:A	N328K	1.000
16:81891588:C:G	N328K	1.000
16:81893710:T:C	Y330H	1.000
16:81893714:T:C	L331P	1.000
16:81893727:G:C	Q335H	1.000
16:81893727:G:T	Q335H	1.000
16:81893787:C:G	C355W	1.000
16:81893792:A:T	E357V	1.000
16:81893793:A:C	E357D	1.000
16:81893793:A:T	E357D	1.000
16:81895807:T:C	L358P	1.000
16:81895809:G:C	D359H	1.000
16:81895810:A:C	D359A	1.000
16:81895810:A:G	D359G	1.000
16:81895810:A:T	D359V	1.000
16:81895811:C:A	D359E	1.000
16:81895811:C:G	D359E	1.000
16:81895814:C:G	C360W	1.000
16:81895815:T:A	W361R	1.000
16:81895815:T:C	W361R	1.000
16:81895817:G:C	W361C	1.000
16:81895817:G:T	W361C	1.000

dbSNP variants (sampled 300 via entrez): RS1000001222 (16:81926095 G>T), RS1000002678 (16:81898461 T>C), RS1000006249 (16:81829103 TTTTTA>T), RS1000009381 (16:81804663 T>G), RS1000009927 (16:81865784 C>A,T), RS1000047834 (16:81850993 C>T), RS1000052454 (16:81799603 T>A), RS1000053792 (16:81780360 G>A,C), RS1000060930 (16:81811454 C>T), RS1000070525 (16:81787512 G>A,C), RS1000103541 (16:81924245 C>G,T), RS1000105517 (16:81939796 T>C), RS1000113245 (16:81861918 A>G), RS1000138578 (16:81886140 A>G), RS1000154047 (16:81931873 G>T)

Disease associations

OMIM: gene MIM:600220 | disease phenotypes: MIM:614468, MIM:614878, MIM:120100

GenCC curated gene-disease

Disease	Classification	Inheritance
autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation	Strong	Autosomal dominant
familial cold autoinflammatory syndrome 3	Strong	Autosomal dominant

Mondo (3): familial cold autoinflammatory syndrome 3 (MONDO:0013766), autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (MONDO:0013944), familial cold autoinflammatory syndrome (MONDO:0018768)

Orphanet (3): PLCG2-associated antibody deficiency and immune dysregulation (Orphanet:300359), Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (Orphanet:324530), Familial cold urticaria (Orphanet:47045)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000403	Recurrent otitis media
HP:0000518	Cataract
HP:0000872	Hashimoto thyroiditis
HP:0000989	Pruritus
HP:0001045	Vitiligo
HP:0002099	Asthma
HP:0002720	Decreased circulating IgA concentration
HP:0002829	Arthralgia
HP:0002850	Decreased circulating total IgM
HP:0002958	Immune dysregulation
HP:0003193	Allergic rhinitis
HP:0003493	Antinuclear antibody positivity
HP:0003593	Infantile onset
HP:0004387	Enterocolitis
HP:0005425	Recurrent sinopulmonary infections
HP:0006515	Interstitial pneumonitis
HP:0010783	Erythema
HP:0011463	Childhood onset
HP:0011950	Bronchiolitis
HP:0011971	Dermatographic urticaria
HP:0012203	Onychomycosis
HP:0012393	Allergy
HP:0030388	Decreased class-switched memory B cell proportion
HP:0031972	Presyncope
HP:0100279	Ulcerative colitis
HP:0100658	Cellulitis
HP:0100665	Angioedema
HP:0200020	Corneal erosion
HP:0410135	Cold urticaria

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST002265_2	Breast cancer (menopausal hormone therapy interaction)	3.000000e-06
GCST004131_13	Inflammatory bowel disease	5.000000e-11
GCST004133_68	Ulcerative colitis	8.000000e-08
GCST004599_110	Mean platelet volume	3.000000e-26
GCST004616_68	Platelet distribution width	9.000000e-10
GCST005194_104	Coronary artery disease	1.000000e-08
GCST005195_56	Coronary artery disease	9.000000e-13
GCST005196_20	Coronary artery disease	9.000000e-13
GCST005549_9	Alzheimer’s disease (late onset)	5.000000e-10
GCST005958_20	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_30	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-06
GCST006107_5	Upper eyelid morphology	2.000000e-06
GCST006585_867	Blood protein levels	9.000000e-06
GCST008163_427	Height	3.000000e-06
GCST009030_21	Venous thromboembolism	7.000000e-13
GCST009097_16	Venous thromboembolism	2.000000e-21
GCST009267_5	Dental caries (decayed, missing and filled teeth)	2.000000e-06
GCST009391_462	Metabolite levels	9.000000e-06
GCST010121_11	Ceramide levels (C24:0)	9.000000e-06
GCST010866_70	Coronary artery disease	5.000000e-14
GCST011365_149	Myocardial infarction	4.000000e-06
GCST011939_16	Takayasu arteritis	3.000000e-06
GCST012020_157	Serum metabolite levels	9.000000e-14
GCST012021_82	Serum metabolite levels	9.000000e-14
GCST012182_1	Alzheimer’s disease	7.000000e-12
GCST90002395_223	Mean platelet volume	1.000000e-10
GCST90002395_224	Mean platelet volume	2.000000e-27
GCST90002395_225	Mean platelet volume	6.000000e-12
GCST90002395_226	Mean platelet volume	1.000000e-15
GCST90002401_112	Platelet distribution width	9.000000e-15

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0003961	hormone replacement therapy
EFO:0007984	platelet component distribution width
EFO:1001870	late-onset Alzheimers disease
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0010522	phosphoenolpyruvic acid measurement
EFO:0004309	platelet count
EFO:0007986	reticulocyte count
EFO:0010099	chronic widespread pain

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4100 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs60427389	PLCG2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphoinositide-specific phospholipase C

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

Ligand	Action	Affinity	Parameter
CCT129957	Inhibition	5.52	pIC50

ChEMBL bioactivities

14 potent at pChembl≥5 of 16 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.92	IC50	1.2	nM	CHEMBL5532458
7.96	IC50	11.05	nM	CHEMBL5404368
6.00	IC50	1000	nM	CHEMBL509134
6.00	IC50	1000	nM	CHEMBL475789
6.00	IC50	1000	nM	CHEMBL475790
5.70	IC50	2000	nM	CHEMBL455766
5.70	IC50	2000	nM	CHEMBL475623
5.70	IC50	2000	nM	CHEMBL516039
5.52	IC50	3000	nM	CHEMBL473613
5.40	IC50	4000	nM	CHEMBL475627
5.30	IC50	5000	nM	CHEMBL475466
5.10	IC50	8000	nM	CHEMBL3349802
5.02	IC50	9500	nM	CHEMBL473614
5.00	IC50	1e+04	nM	CHEMBL3349803

PubChem BioAssay actives

14 with measured affinity, of 82 total; 14 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
N-methyl-N-[3-methyl-3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxycyclobutyl]prop-2-enamide	2064207: Inhibition of PLCgamma2 phosphorylation in anti-IgM activated human Ramos cells	ic50	0.0012	uM
1-[(3R)-3-[5-(4-phenoxyanilino)-2,6,7,9,11-pentazatricyclo[6.3.1.04,12]dodeca-1,3,5,8(12),9-pentaen-7-yl]pyrrolidin-1-yl]prop-2-en-1-one	2001992: Inhibition of PLCgamma2 phosphorylation at Y1217 residue in goat F(ab’) 2 anti-human IgM stimulated human Ramos cells by Western blotting analysis	ic50	0.0111	uM
5-(3-chlorophenyl)-3-[5-(1,2-oxazol-3-yl)thiophen-2-yl]-1,2,4-oxadiazole	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	1.0000	uM
N-(4-chlorophenyl)-7-nitro-1H-indole-2-carboxamide	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	1.0000	uM
7-nitro-N-(2-phenylethyl)-1H-indole-2-carboxamide	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	1.0000	uM
5-(5-nitrothiophen-3-yl)-3-pyridin-2-yl-1,2,4-oxadiazole	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	2.0000	uM
4-chloro-N-(4-oxo-3,1-benzothiazin-2-yl)benzamide	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	2.0000	uM
4-[(E)-(5-oxo-2-phenyl-1,3-oxazol-4-ylidene)methyl]benzonitrile	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	2.0000	uM
3-(2,2-dimethyl-3,4-dihydrochromen-6-yl)-1-(4-methoxyphenyl)sulfonylpyrazole	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	3.0000	uM
6-(4-methoxyphenyl)-3-phenylthieno[2,3-e][1,2,4]triazine	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	4.0000	uM
N-(1,3-benzothiazol-2-yl)-5-methoxy-1H-indole-2-carboxamide	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	5.0000	uM
[(2R)-3-[[(1S,2S,3S,4S,5R,6S)-3-fluoro-2,4,5,6-tetrahydroxycyclohexyl]oxy-hydroxyphosphoryl]oxy-2-hexadecanoyloxypropyl] hexadecanoate	158607: In vitro inhibitory activity against bovine Phosphoinositide specific phospholipase C (PI-PLC)	ic50	8.0000	uM
2-chloro-N-[(1,1-dioxo-1-benzothiophen-6-yl)carbamoyl]benzamide	414764: Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	ic50	9.5000	uM
[(3S)-3-methoxy-4-octadecoxybutyl]-[(1R,2S,3S,4R,6R)-2,3,4,6-tetrahydroxycyclohexyl]oxyphosphinic acid	158607: In vitro inhibitory activity against bovine Phosphoinositide specific phospholipase C (PI-PLC)	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Benzo(a)pyrene	affects methylation, decreases expression	6
Aflatoxin B1	increases methylation, affects expression, decreases expression, decreases methylation	4
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases methylation, increases expression	3
ibrutinib	decreases phosphorylation, increases reaction, decreases response to substance	2
(+)-JQ1 compound	decreases phosphorylation, increases reaction, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases reaction, increases phosphorylation	2
Inositol Phosphates	decreases reaction, affects cotreatment, increases response to substance, affects binding, increases activity (+2 more)	2
Guanosine 5’-O-(3-Thiotriphosphate)	affects cotreatment, increases chemical synthesis, increases reaction, decreases response to substance, increases activity	2
Asbestos, Crocidolite	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
rilzabrutinib	decreases phosphorylation	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
honokiol	decreases reaction, increases phosphorylation	1
bis(tri-n-butyltin)oxide	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tributyltin	decreases expression	1
terbufos	increases methylation	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
methylmercury II	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1018873	Binding	Inhibition of recombinant phospholipase C gamma2 expressed in baculovirus infected Sf9 cells using [3H]PIP2 by flashplate biochemical assay	The identification of novel PLC-gamma inhibitors using virtual high throughput screening. — Bioorg Med Chem

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1YF	Abcam A-549 PLCG2 KO	Cancer cell line	Male
CVCL_D2CL	Abcam HCT 116 PLCG2 KO	Cancer cell line	Male
CVCL_D7XV	Ubigene A-549 PLCG2 KO	Cancer cell line	Male
CVCL_D8TB	Ubigene HCT 116 PLCG2 KO	Cancer cell line	Male
CVCL_D9NT	Ubigene HEK293 PLCG2 KO	Transformed cell line	Female
CVCL_E7C2	Abcam THP-1 PLCG2 KO	Cancer cell line	Male
CVCL_TE38	HAP1 PLCG2 (-) 1	Cancer cell line	Male
CVCL_TE39	HAP1 PLCG2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00288704	PHASE3	COMPLETED	Rilonacept for Treatment of Cryopyrin-Associated Periodic Syndromes (CAPS)
NCT00685373	PHASE3	COMPLETED	Efficacy and Safety of ACZ885 in Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT00991146	PHASE3	COMPLETED	Efficacy and Safety Study of Canakinumab Administered for 6 Months (24 Weeks) in Japanese Patients With Cryopyrin-associated Periodic Syndromes Followed by an Extension Phase
NCT01302860	PHASE3	COMPLETED	Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT01576367	PHASE3	COMPLETED	Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT04868968	PHASE2	COMPLETED	Study of Safety, Tolerability and Efficacy of DFV890 in Participants With Familial Cold Auto-inflammatory Syndrome (FCAS)
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes