PLCG1

Summary

PLCG1 (phospholipase C gamma 1, HGNC:9065) is a protein-coding gene on chromosome 20q12, encoding 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (P19174). Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).

The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RasGRP1 to translocate to the Golgi, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5335 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immune dysregulation, autoimmunity, and autoinflammation (Moderate, ClinGen)
• GWAS associations: 12
• Clinical variants (ClinVar): 185 total — 1 pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• MANE Select transcript: NM_002660

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9065
Approved symbol	PLCG1
Name	phospholipase C gamma 1
Location	20q12
Locus type	gene with protein product
Status	Approved
Aliases	PLC148, PLC-II, PLCgamma1, NCKAP3
Ensembl gene	ENSG00000124181
Ensembl biotype	protein_coding
OMIM	172420
Entrez	5335

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 8 protein_coding, 8 retained_intron, 7 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000244007, ENST00000373271, ENST00000423733, ENST00000461641, ENST00000465571, ENST00000470528, ENST00000473632, ENST00000477870, ENST00000483175, ENST00000483646, ENST00000490253, ENST00000492148, ENST00000599785, ENST00000607954, ENST00000608689, ENST00000608885, ENST00000609257, ENST00000609821, ENST00000612731, ENST00000617873, ENST00000619272, ENST00000630423, ENST00000685551, ENST00000896054, ENST00000896055, ENST00000896056, ENST00000930632

RefSeq mRNA: 2 — MANE Select: NM_002660 NM_002660, NM_182811

CCDS: CCDS13313, CCDS13314

Canonical transcript exons

ENST00000685551 — 32 exons

Exon	Start	End
ENSE00000844725	41162452	41162536
ENSE00000844726	41162642	41162725
ENSE00000844727	41162958	41162992
ENSE00000844728	41163203	41163275
ENSE00000844731	41163921	41164006
ENSE00000844732	41164081	41164201
ENSE00000844733	41164933	41165101
ENSE00000844734	41165245	41165367
ENSE00000844736	41165639	41165826
ENSE00000844737	41166194	41166394
ENSE00000844739	41166679	41166859
ENSE00000844740	41167852	41167929
ENSE00000844744	41170112	41170269
ENSE00000844745	41172193	41172289
ENSE00000844751	41174124	41174311
ENSE00003478726	41169079	41169175
ENSE00003501961	41173923	41174011
ENSE00003506117	41169457	41169526
ENSE00003510568	41165450	41165551
ENSE00003523330	41172421	41172645
ENSE00003545839	41163378	41163479
ENSE00003547317	41168767	41168870
ENSE00003551169	41173652	41173813
ENSE00003569415	41173420	41173534
ENSE00003580465	41160106	41160153
ENSE00003597994	41159870	41159963
ENSE00003625082	41172729	41172877
ENSE00003628943	41163715	41163833
ENSE00003667490	41166476	41166595
ENSE00003669633	41159606	41159758
ENSE00003769760	41174467	41177626
ENSE00003925672	41137543	41137858

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.9702 / max 280.6363, expressed in 1744 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184634	27.8973	1707
184633	9.6959	1623
184632	0.5468	341
209112	0.4620	286
184635	0.2280	88
184642	0.1402	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.02	gold quality
cerebellar hemisphere	UBERON:0002245	98.90	gold quality
cerebellar cortex	UBERON:0002129	98.79	gold quality
right lobe of thyroid gland	UBERON:0001119	98.72	gold quality
ganglionic eminence	UBERON:0004023	98.62	gold quality
left lobe of thyroid gland	UBERON:0001120	98.57	gold quality
right ovary	UBERON:0002118	98.38	gold quality
ventricular zone	UBERON:0003053	98.36	gold quality
endocervix	UBERON:0000458	98.24	gold quality
body of uterus	UBERON:0009853	98.16	gold quality
left ovary	UBERON:0002119	98.08	gold quality
stromal cell of endometrium	CL:0002255	97.98	gold quality
thyroid gland	UBERON:0002046	97.92	gold quality
sural nerve	UBERON:0015488	97.92	gold quality
nerve	UBERON:0001021	97.88	gold quality
tibial nerve	UBERON:0001323	97.88	gold quality
ectocervix	UBERON:0012249	97.85	gold quality
right lung	UBERON:0002167	97.79	gold quality
mucosa of stomach	UBERON:0001199	97.78	gold quality
cerebellum	UBERON:0002037	97.74	gold quality
metanephros cortex	UBERON:0010533	97.52	gold quality
skin of leg	UBERON:0001511	97.40	gold quality
apex of heart	UBERON:0002098	97.38	gold quality
granulocyte	CL:0000094	97.37	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.36	gold quality
gall bladder	UBERON:0002110	97.28	gold quality
right frontal lobe	UBERON:0002810	97.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.22	gold quality
lower esophagus	UBERON:0013473	97.21	gold quality
cortical plate	UBERON:0005343	97.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, GATA1, GATA2, STAT1, TAL1, TXK, VDR

miRNA regulators (miRDB)

34 targeting PLCG1, 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-5193	100.00	67.26	1744
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-4700-3P	97.74	68.64	1014
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-4296	96.35	63.55	1233

Literature-anchored findings (GeneRIF, showing 40)

• Pharmacological and molecular inhibition of phospholipase C-gamma1 inhibits growth factor receptor-mediated invasion of breast and prostate tumor cells through Matrigel in vitro. (PMID:10473113)
• Interaction of elongation factor-1alpha and pleckstrin homology domain of phospholipase C-gamma 1 with activating its activity (PMID:11886851)
• Translocation of PKC[theta] in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C (PMID:11956228)
• Leukotriene D4 induces association of active RhoA with phospholipase C-gamma1 in intestinal epithelial cells. (PMID:12071848)
• Phospholipase C gamma 1 is essential for NF-kappa B activation and lipid raft translocation of protein kinase C theta and the I kappa B kinase complex. (PMID:12496421)
• activation of Src kinase by depletion of glucosylceramide-based glycosphingolipids in cultured ECV304 cells is a critical up-stream event in the activation of phospholipase C-gamma1. (PMID:12771140)
• Stabilizes F-actin, preventing oxidative stress disruption of intestinal barrier. Essential for cellular prevention of oxidative stress of iNOS. Ability to suppress iNOS-driven reactions and cytoskeletal oxidation and disassembly. (PMID:12788694)
• in response to Src-dependent activation of phospholipase Cgamma1, the Ras guanine nucleotide exchange factor RasGRP1 translocated to the Golgi where it activated Ras (PMID:12845332)
• PLC gamma-dependent component of Fc epsilon RI-mediated calcium flux leading to degranulation of mast cells is independent of PI 3-kinase (PMID:13129935)
• PLCgamma function and activation are mediated by GIT1 through c-Src, which integrates signal transduction by GPCRs and TKRs (PMID:14523024)
• tr-kit promotes the formation of a multimolecular complex composed of Fyn, PLCgamma1 and Sam68, which allows phosphorylation of PLCgamma1 by Fyn, and may modulate RNA metabolism. (PMID:14647465)
• T-cell receptor activation of Rap1 depends on phospholipase C-gamma1 (PMID:14702343)
• Treatment of cells of a carcinoma cell line with cysteine proteinase inhibitors results in increasing PLC1 intracellular level. Iyt is concluded that PLC1 is ubiquitinated and degraded by proteasomes. (PMID:14989173)
• Data suggest that hyaluronan-CD44 interaction with Rac1-protein kinase N gamma plays a pivotal role in phospholipase C gamma1-regulated calcium signaling and cortactin-cytoskeleton function required for keratinocyte cell-cell adhesion and differentiation. (PMID:15123640)
• LAB resembled a LAT molecule unable to bind phospholipase C-gamma1. (PMID:15153499)
• Tyr-783 phosphorylation of of phospholipase C-gamma 1 is not sufficient for enzyme activation (PMID:15161916)
• SHP-2 has a role in regulating IL-1-induced Ca2+ flux and ERK activation via phosphorylation of PLCgamma1 (PMID:15563458)
• SLP-76 need not interact with SH3(PLC) to activate PLC-gamma1, and the P-I region of SLP-76 serves a structural role that is sequence-independent and is not directly related to protein-protein interactions (PMID:15623534)
• activation of store operated channels in keratinocytes depends, at least partly, on the interaction of TRPC with PLCgamma1 and IP3R (PMID:15654973)
• calcium activates PLC-gamma1 via increased PIP3 formation mediated by c-src- and fyn-activated PI3K (PMID:15872086)
• PLCgamma1 in cell motility, functioning as a mediator of both growth factor and integrin-initiated signals (PMID:15944397)
• 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)
• PLCgamma1 plays a pivotal role in the migration of human colorectal cancer cells, and the upregulation of NF-kappaB binding activity and downregulation of Hsp70 expression in LoVo cells. (PMID:15996687)
• Data show that membrane transport of p42(IP4) induced by epidermal growth factor is inhibited by stimulation of phospholipase C-coupled thrombin receptor. (PMID:16341594)
• phospholipase C-gamma1 interaction with villin regulates epithelial cell migration (PMID:16921170)
• 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)
• High phosphatidylcholine-specific phospholipase C expression on the cell membrane surface is apparently involved in the ability of natural killer (NK) cytolytic cells to lyse sensitive target cells. (PMID:17111345)
• We show that Fas-mediated apoptosis requires endoplasmic reticulum-mediated calcium release in a mechanism dependent on phospholipase C-gamma1 (PLC-gamma1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. (PMID:17130290)
• Phospholipase C-gamma1 (PLC-gamma1) activation depends on a heterotrimeric complex of adaptor proteins such as SLP76. (PMID:17148460)
• the recruitment of PI3K to the E-cadherin/beta-catenin/p120-catenin complex via beta-catenin at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and, ultimately, keratinocyte differentiation (PMID:17242406)
• Review discusses how the interaction between PLC-gamma1 and effector proteins plays a key role in on- or off-regulating PLC-gamma1-mediated cellular proliferation independent of its enzymatic activity. (PMID:17336371)
• corecruitment of c-Cbl and PLCgamma1 to VEGFR-2 serves as a mechanism to fine-tune the angiogenic signal relay of VEGFR-2 (PMID:17372230)
• Results demonstrate that the gamma 1 isoform of phospholipase C associates with nuclear promyelocytic leukemia protein. (PMID:17419608)
• Cellular knockdown of protein kinase Cepsilon (PKCepsilon) leads to decreased activation of PLCgamma1 by epidermal growth factor (EGF). EGF induces tyrosine phosphorylation of PKCepsilon as well as its association with EGF receptor and PLCgamma1. (PMID:17561374)
• Results suggest that a PLCgamma-STAT1 pathway mediates apoptotic signaling by FGFR3 in genetic dwarfism and chondrogenic cell lines. (PMID:17561467)
• The association of PLCgamma1 with complexes containing GIT1 and beta-Pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, PLCgamma1 is also involved in the activation of Cdc42 and Rac1. (PMID:17562871)
• PLCgamma-mediated activation of PKCepsilon and PKCbetaI and intracellular calcium is involved in EGF-mediated protection of tight junctions from acetaldehyde-induced insult (PMID:17991733)
• Controls tumor cell adhesion by controlling the RAP guanine nucleotide exchange factor (RAPGEF) molecular switch. (PMID:18037957)
• HDAC8-selective inhibitors have a unique mechanism of action involving PLCgamma1 activation and calcium-induced apoptosis (PMID:18256683)
• tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases are regulated by phosphorylation (PMID:18467332)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	plcg1	ENSDARG00000038442
mus_musculus	Plcg1	ENSMUSG00000016933
rattus_norvegicus	Plcg1	ENSRNOG00000051490
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), PLCB2 (ENSG00000137841), PLCE1 (ENSG00000138193), PLCZ1 (ENSG00000139151), PLCH2 (ENSG00000149527), PLCB3 (ENSG00000149782), PLCL2 (ENSG00000154822), PLCD3 (ENSG00000161714), PLCB1 (ENSG00000182621), PLCD1 (ENSG00000187091), PLCG2 (ENSG00000197943)

Protein

Protein identifiers

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 — P19174 (reviewed: P19174)

Alternative names: PLC-148, Phosphoinositide phospholipase C-gamma-1, Phospholipase C-II, Phospholipase C-gamma-1

All UniProt accessions (6): A0A0D9SEK2, P19174, M0QX77, V9GY63, V9GY71, V9GYH5

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, EGFR, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganization and cell migration. Guanine nucleotide exchange factor that binds the GTPase DNM1 and catalyzes the dissociation of GDP, allowing a GTP molecule to bind in its place, therefore enhancing DNM1-dependent endocytosis.

Subunit / interactions. Interacts with AGAP2 via its SH3 domain. Interacts (via SH2 domain) with RET. Interacts with FLT1 (tyrosine-phosphorylated). Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK. Interacts with AXL, FLT4 and KIT. Interacts with RALGPS1. Interacts (via the SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C. Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with SYK; activates PLCG1. Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes. Interacts with TESPA1; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome. Interacts (via C-terminal proline-rich domain (PRD)) with PLCG1 (via SH3 domain); this interaction leads to guanine nucleotide exchange from PlCG1 to DNM1 and enhances DNM1-dependent endocytosis. (Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein.

Subcellular location. Cell projection. Lamellipodium. Ruffle.

Post-translational modifications. Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA. Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases, in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. May be dephosphorylated by PTPRJ. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells. Ubiquitinated by CBLB in activated T-cells.

Disease relevance. Immune dysregulation, autoimmunity, and autoinflammation (IDAA) [MIM:620514] An autosomal dominant disorder characterized by anemia and thrombocytopenia associated with circulating autoantibodies, positive Coombs test, immune dysregulation, and increased levels of proinflammatory cytokines. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphorylation on tyrosine residues.

Domain organisation. The SH3 domain mediates interaction with CLNK. The SH3 domain also mediates interaction with RALGPS1.

Isoforms (2)

UniProt ID	Names	Canonical?
P19174-1	1	yes
P19174-2	2

RefSeq proteins (2): NP_002651, NP_877963 (=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
IPR002048	EF_hand_dom	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
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR035023	PLC-gamma_C-SH2	Domain
IPR035024	PLC-gamma_N-SH2	Domain
IPR035724	PLCgamma1_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, PF00169, PF00387, PF00388, 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), 2 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)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + H2O = 1D-myo-inositol 1-phosphate + a 1,2-diacyl-sn-glycerol + H(+) (RHEA:43484)

UniProt features (69 total): strand 20, modified residue 13, domain 10, helix 7, binding site 5, sequence variant 5, region of interest 2, active site 2, turn 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7NXE	X-RAY DIFFRACTION	2.1
4FBN	X-RAY DIFFRACTION	2.4
4EY0	X-RAY DIFFRACTION	2.8
1HSQ	SOLUTION NMR
2HSP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19174-F1	83.22	0.57

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): 335; 380

Ligand- & substrate-binding residues (5): 165; 167; 169; 171; 176

Post-translational modifications (13): 2, 506, 771, 775, 783, 977, 1221, 1227, 1233, 1248, 1253, 1263, 1222

Function

Pathways and Gene Ontology

Reactome pathways

35 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1251932	PLCG1 events in ERBB2 signaling
R-HSA-1489509	DAG and IP3 signaling
R-HSA-167021	PLC-gamma1 signalling
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-186763	Downstream signal transduction
R-HSA-201556	Signaling by ALK
R-HSA-202433	Generation of second messenger molecules
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-210990	PECAM1 interactions
R-HSA-212718	EGFR interacts with phospholipase C-gamma
R-HSA-2424491	DAP12 signaling
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-418890	Role of second messengers in netrin-1 signaling
R-HSA-5218921	VEGFR2 mediated cell proliferation
R-HSA-5637810	Constitutive Signaling by EGFRvIII
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654227	Phospholipase C-mediated cascade; FGFR3
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
R-HSA-5655253	Signaling by FGFR2 in disease
R-HSA-5655291	Signaling by FGFR4 in disease
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-5655332	Signaling by FGFR3 in disease
R-HSA-8853659	RET signaling
R-HSA-9026527	Activated NTRK2 signals through PLCG1
R-HSA-9027277	Erythropoietin activates Phospholipase C gamma (PLCG)
R-HSA-9034793	Activated NTRK3 signals through PLCG1

MSigDB gene sets: 544 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, PID_S1P_S1P1_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, PID_NETRIN_PATHWAY, REACTOME_SIGNALING_BY_FGFR, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, HALMOS_CEBPA_TARGETS_UP

GO Biological Process (23): negative regulation of inflammatory response to antigenic stimulus (GO:0002862), epidermal growth factor receptor signaling pathway (GO:0007173), phospholipid catabolic process (GO:0009395), positive regulation of epithelial cell migration (GO:0010634), cell migration (GO:0016477), calcium-mediated signaling (GO:0019722), Fc-epsilon receptor signaling pathway (GO:0038095), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of angiogenesis (GO:0045766), phosphatidylinositol metabolic process (GO:0046488), phosphatidylinositol-mediated signaling (GO:0048015), T cell receptor signaling pathway (GO:0050852), release of sequestered calcium ion into cytosol (GO:0051209), positive regulation of release of sequestered calcium ion into cytosol (GO:0051281), cellular response to epidermal growth factor stimulus (GO:0071364), positive regulation of vascular endothelial cell proliferation (GO:1905564), positive regulation of endothelial cell apoptotic process (GO:2000353), lipid metabolic process (GO:0006629), signal transduction (GO:0007165), lipid catabolic process (GO:0016042), intracellular signal transduction (GO:0035556), antigen receptor-mediated signaling pathway (GO:0050851), obsolete regulation of sequestering of calcium ion (GO:0051282)

GO Molecular Function (12): phosphatidylinositol-4,5-bisphosphate phospholipase C activity (GO:0004435), C-type glycerophospholipase activity (GO:0004629), guanyl-nucleotide exchange factor activity (GO:0005085), neurotrophin TRKA receptor binding (GO:0005168), calcium ion binding (GO:0005509), protein kinase binding (GO:0019901), obsolete calcium-dependent phospholipase C activity (GO:0050429), phosphatidylinositol phospholipase C activity (GO:0120548), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (8): ruffle (GO:0001726), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), COP9 signalosome (GO:0008180), lamellipodium (GO:0030027), ruffle membrane (GO:0032587), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-19 pathways:

Category	Pathways
Fc epsilon receptor (FCERI) signaling	2
Antimicrobial mechanism of IFN-stimulated genes	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Signaling by ERBB2	1
Intracellular signaling by second messengers	1
Signaling by NTRK1 (TRKA)	1
Inositol phosphate metabolism	1
Signaling by PDGF	1
Signaling by Receptor Tyrosine Kinases	1
TCR signaling	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Cell surface interactions at the vascular wall	1
Signaling by EGFR	1
DAP12 interactions	1
Netrin-1 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
C-type glycerophospholipase activity	2
cell leading edge	2
plasma membrane bounded cell projection	2
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
ERBB signaling pathway	1
phospholipid metabolic process	1
lipid catabolic process	1
organophosphate catabolic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
cell motility	1
intracellular signaling cassette	1
Fc receptor signaling pathway	1
positive regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
phosphorus metabolic process	1
intracellular signal transduction	1
antigen receptor-mediated signaling pathway	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol	1
positive regulation of calcium ion transmembrane transport	1
response to epidermal growth factor	1
cellular response to growth factor stimulus	1
positive regulation of endothelial cell proliferation	1
vascular endothelial cell proliferation	1
regulation of vascular endothelial cell proliferation	1
positive regulation of apoptotic process	1
endothelial cell apoptotic process	1
regulation of endothelial cell apoptotic process	1

Protein interactions and networks

STRING

2622 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLCG1	GRAP2	O75791	996
PLCG1	LAT	O43561	992
PLCG1	LCP2	Q13094	989
PLCG1	GRB2	P29354	982
PLCG1	VAV1	P15498	964
PLCG1	ITK	Q08881	954
PLCG1	NCK1	P16333	951
PLCG1	PDGFRB	P09619	914
PLCG1	CBL	P22681	899
PLCG1	LCK	P06239	877
PLCG1	FGFR1	P11362	868
PLCG1	TRPC3	Q13507	854
PLCG1	ZAP70	P43403	816
PLCG1	LAT2	Q9GZY6	816
PLCG1	EGFR	P00533	804

IntAct

413 interactions, top by confidence:

A	B	Type	Score
FGFR1	PLCG1	psi-mi:“MI:0217”(phosphorylation reaction)	0.900
PLCG1	FGFR1	psi-mi:“MI:0407”(direct interaction)	0.900
FGFR1	PLCG1	psi-mi:“MI:0407”(direct interaction)	0.900
PLCG1	PDGFRB	psi-mi:“MI:0407”(direct interaction)	0.850
PLCG1	LAT	psi-mi:“MI:0407”(direct interaction)	0.810
PLCG1	LAT	psi-mi:“MI:0915”(physical association)	0.810
FGFR2	PLCG1	psi-mi:“MI:0915”(physical association)	0.700
PLCG1	FGFR2	psi-mi:“MI:0915”(physical association)	0.700
FGFR2	PLCG1	psi-mi:“MI:0407”(direct interaction)	0.700
FGFR2	PLCG1	psi-mi:“MI:0914”(association)	0.700
CD244	SH2D1B	psi-mi:“MI:0914”(association)	0.690
PLCG1	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.690
PLCG1	SOS1	psi-mi:“MI:0407”(direct interaction)	0.670
SOS1	PLCG1	psi-mi:“MI:0915”(physical association)	0.670
PLCG1	MAP4K1	psi-mi:“MI:0915”(physical association)	0.660
MAP4K1	PLCG1	psi-mi:“MI:0407”(direct interaction)	0.660
MAP4K1	PLCG1	psi-mi:“MI:0915”(physical association)	0.660
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
PLCG1	VIL1	psi-mi:“MI:0915”(physical association)	0.630
VIL1	PLCG1	psi-mi:“MI:2364”(proximity)	0.630

BioGRID (429): PLCG1 (Affinity Capture-RNA), PLCG1 (Affinity Capture-Western), AKT1 (Affinity Capture-Western), PLCG1 (Reconstituted Complex), PLCG1 (Biochemical Activity), PLCG1 (Affinity Capture-Western), PLCG1 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), CTPS1 (Co-fractionation), MCMBP (Co-fractionation), NPEPL1 (Co-fractionation)

ESM2 similar proteins: A0A131MCZ8, A0JN54, A7T1N0, D3ZEY4, F2Y4A3, F4IDQ6, F4INY4, O14159, O35646, O88501, O88673, P08487, P10686, P16885, P19174, P20192, P23743, P24135, P27730, P49619, P49620, P49621, P51556, P91550, Q03603, Q22036, Q22949, Q39017, Q45EK7, Q4V339, Q5JTY5, Q5RIA9, Q618H8, Q62077, Q6DNF3, Q6NS52, Q6P5E8, Q7YTB0, Q8CIH5, Q8IUF1

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

55 interactions.

A	Effect	B	Mechanism
PTPRJ	down-regulates	PLCG1	dephosphorylation
GIT1	up-regulates	PLCG1	binding
ALK	up-regulates	PLCG1	binding
KDR	up-regulates	PLCG1	binding
PLCG1	up-regulates	RAC1
ITK	up-regulates	PLCG1	phosphorylation
PLCG1	up-regulates	ITPRIPL1
PLCG1	up-regulates	1,2-diacyl-sn-glycerol	“chemical modification”
PLCG1	up-regulates	“1D-myo-inositol 1,4,5-trisphosphate”	“chemical modification”
PRKACA	down-regulates	PLCG1	phosphorylation
PRKCA	down-regulates	PLCG1	phosphorylation
GNB1	up-regulates	PLCG1
GNB2	up-regulates	PLCG1
GNB3	up-regulates	PLCG1	binding
GNG2	up-regulates	PLCG1	binding
GNG3	up-regulates	PLCG1	binding
GNGT1	up-regulates	PLCG1	binding
ERBB2	up-regulates	PLCG1	binding
EGFR	up-regulates	PLCG1	phosphorylation
LAT	“up-regulates activity”	PLCG1	binding
SYK	“up-regulates activity”	PLCG1	phosphorylation
PTPRJ	unknown	PLCG1	dephosphorylation
PRKD1	“down-regulates activity”	PLCG1	phosphorylation
PLCG1	“up-regulates quantity”	1,2-diacyl-sn-glycerol	“chemical modification”
STOML2	“up-regulates activity”	PLCG1	binding
PLCG1	“up-regulates quantity by stabilization”	CDKN1A	phosphorylation
TNK1	“up-regulates quantity”	PLCG1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 165 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
Interleukin-2 family signaling	6	32.5×	1e-06
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	7	31.1×	3e-07
Tie2 Signaling	5	25.7×	4e-05
Role of LAT2/NTAL/LAB on calcium mobilization	5	25.7×	4e-05
DAP12 signaling	8	25.2×	1e-07
Interleukin receptor SHC signaling	7	24.4×	1e-06
Downstream signal transduction	7	22.8×	1e-06
Nephrin family interactions	5	20.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	8	22.5×	1e-06
epidermal growth factor receptor signaling pathway	9	14.9×	3e-06
cell surface receptor protein tyrosine kinase signaling pathway	12	13.9×	5e-08
B cell receptor signaling pathway	5	13.4×	4e-03
positive regulation of neuron projection development	13	11.9×	5e-08
fibroblast growth factor receptor signaling pathway	6	11.4×	2e-03
protein autophosphorylation	10	9.7×	2e-05
T cell receptor signaling pathway	9	9.1×	1e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — ANGS, LGGNOS, RCC, SOFT_TISSUE.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	131
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2580883	NM_002660.3(PLCG1):c.3062C>T (p.Ser1021Phe)	Pathogenic

SpliceAI

5271 predictions. Top by Δscore:

Variant	Effect	Δscore
20:41137854:GGCCA:G	donor_gain	1.0000
20:41137855:GCCA:G	donor_gain	1.0000
20:41137855:GCCAG:G	donor_gain	1.0000
20:41137859:G:GG	donor_gain	1.0000
20:41159602:CTAG:C	acceptor_loss	1.0000
20:41159603:TAGTT:T	acceptor_loss	1.0000
20:41159604:A:AG	acceptor_gain	1.0000
20:41159604:AGTT:A	acceptor_gain	1.0000
20:41159604:AGTTG:A	acceptor_loss	1.0000
20:41159605:G:GA	acceptor_gain	1.0000
20:41159605:GT:G	acceptor_gain	1.0000
20:41159605:GTT:G	acceptor_gain	1.0000
20:41159605:GTTG:G	acceptor_gain	1.0000
20:41159605:GTTGA:G	acceptor_gain	1.0000
20:41159746:C:G	donor_gain	1.0000
20:41160102:CCAG:C	acceptor_loss	1.0000
20:41160103:CA:C	acceptor_loss	1.0000
20:41160104:A:AG	acceptor_gain	1.0000
20:41160105:G:A	acceptor_loss	1.0000
20:41160105:G:GG	acceptor_gain	1.0000
20:41160149:GATCG:G	donor_gain	1.0000
20:41160150:ATCG:A	donor_gain	1.0000
20:41160151:TCG:T	donor_gain	1.0000
20:41160152:CG:C	donor_gain	1.0000
20:41160153:GG:G	donor_gain	1.0000
20:41160154:G:GG	donor_gain	1.0000
20:41160154:G:T	donor_loss	1.0000
20:41160155:T:A	donor_loss	1.0000
20:41162450:A:AG	acceptor_gain	1.0000
20:41162451:G:GG	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000149471 (20:41149923 G>A), RS1000160546 (20:41137930 C>T), RS1000250868 (20:41173384 A>G), RS1000313515 (20:41143814 T>C), RS1000381163 (20:41138069 C>A), RS1000388997 (20:41142895 T>A), RS1000390638 (20:41156768 C>A), RS1000440541 (20:41137621 G>GCCGCCC), RS1000454639 (20:41143454 C>A,T), RS1000524141 (20:41154616 G>A,C), RS1000546601 (20:41168711 G>A), RS1000602468 (20:41174831 G>C), RS1000674794 (20:41162230 T>G), RS1000700898 (20:41161330 G>A), RS1000760236 (20:41167983 G>A)

Disease associations

OMIM: gene MIM:172420 | disease phenotypes: MIM:620514, MIM:131100

GenCC curated gene-disease

Disease	Classification	Inheritance
immune dysregulation, autoimmunity, and autoinflammation	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immune dysregulation, autoimmunity, and autoinflammation	Moderate	AD

Mondo (3): immune dysregulation, autoimmunity, and autoinflammation (MONDO:0957790), multiple endocrine neoplasia type 1 (MONDO:0007540), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (2): Multiple endocrine neoplasia type 1 (Orphanet:652), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000967	Petechiae
HP:0001903	Anemia
HP:0003493	Antinuclear antibody positivity
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0005421	Decreased circulating complement C3 concentration
HP:0011463	Childhood onset
HP:0025289	Cervical lymphadenopathy
HP:0030783	Increased circulating interleukin 6 concentration
HP:0031364	Ecchymosis
HP:0032436	Abnormal circulating C-reactive protein concentration
HP:0033178	Increased circulating interleukin 8 concentration
HP:0034751	Inguinal lymphadenopathy
HP:0045042	Decreased circulating complement C4 concentration

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST004615_128	Hemoglobin concentration	8.000000e-09
GCST006041_26	Major depressive disorder	3.000000e-07
GCST006661_160	Male-pattern baldness	2.000000e-15
GCST008362_42	Birth weight	3.000000e-09
GCST010002_67	Refractive error	7.000000e-10
GCST010083_140	Hemoglobin levels	2.000000e-07
GCST010243_200	Apolipoprotein B levels	7.000000e-24
GCST010244_161	Triglyceride levels	2.000000e-11
GCST010245_141	LDL cholesterol levels	7.000000e-22
GCST010703_20	Brain morphology (MOSTest)	1.000000e-09
GCST90020025_1661	Waist-to-hip ratio adjusted for BMI	7.000000e-10
GCST90020027_333	Waist-hip index	4.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004344	birth weight
EFO:0004615	apolipoprotein B measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D018761	Multiple Endocrine Neoplasia Type 1	C04.588.322.400.500; C04.651.600.500; C04.700.630.500; C16.320.700.630.500; C19.344.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3964 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 27,787 (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
CHEMBL1541	CEFIXIME	4	27,787

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2228246	Toxicity	3	acetaminophen;aspirin;diclofenac;propionic acid derivatives;Pyrazolones

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2228246	PLCG1	3	2.50	1	acetaminophen;aspirin;diclofenac;propionic acid derivatives;Pyrazolones

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
compound 5 [PMID: 10869194]	Inhibition	5.02	pIC50

Binding affinities (BindingDB)

166 measured of 228 human assays (240 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-cyclopentylidene-2-sulfanylidene-1,3-thiazolidin-4-one	IC50	240 nM
4-[(E)-[3-(2-methylanilino)-4-oxo-1-naphthalenylidene]amino]sulfonylbenzoic acid	IC50	522 nM
(NZ)-N-[3-(4-hydroxyanilino)-4-keto-1-naphthylidene]thiophene-2-sulfonamide	IC50	656 nM
4-({(4Z)-1-oxo-4-[(phenylsulfonyl)imino]-1,4-dihydronaphthalen-2-yl}amino)benzoic acid	IC50	967 nM
3-(2-{(E)-[1-(4-chlorophenyl)-2,5-dioxoimidazolidin-4-ylidene]methyl}-1H-pyrrol-1-yl)benzoic acid	IC50	1230 nM
2,3,4,5-tetrahydroxy-6-benzo[7]annulenone	IC50	1230 nM
(2Z)-1,3-diketo-2-[(5-methyl-2-furyl)methylene]indane-5-carboxylic acid	IC50	1650 nM
(5Z)-5-[(E)-3-(2-furanyl)prop-2-enylidene]-3-(4-hydroxyphenyl)-2-sulfanylidene-4-thiazolidinone	IC50	1720 nM
1,6-dimethyl-3-propyl-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1770 nM
5-[(E)-3-(5-Nitro-furan-2-yl)-prop-2-en-(Z)-ylidene]-2-thioxo-thiazolidin-4-one	IC50	1920 nM
N-[3-(3-quinolin-4-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-[1-(2-hydroxy-2-methylpropyl)-6-oxo-3-pyridinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(1H-indol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-(3-hydroxypentan-3-yl)-5-[3-(2-methoxy-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
(E)-4-(dimethylamino)-N-[3-(3-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]but-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-[6-(cyclopropylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
(E)-2-cyano-3-[3-(3-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-(3-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(2-methoxy-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-N-methylprop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
(E)-4-morpholin-4-yl-N-[3-(3-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]but-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(2-methoxy-6-methyl-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(6-methoxy-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
(E)-2-cyano-3-[3-[3-(2-methyl-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
(E)-4-(dimethylamino)-N-[3-[3-(2-methoxy-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]but-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(6-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(5-chloro-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[4-[3-(2-methoxy-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6-propan-2-yloxy-2-pyridinyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-[6-(methylamino)-3-pyridinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-[6-(methylamino)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
N-[3-[3-(6-methoxy-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5-(trifluoromethyl)phenyl]prop-2-enamide	IC50	3000 nM	US-9695200: Heterocyclic ITK inhibitors for treating inflammation and cancer
2-Methyl-8-morpholin-4-yl-5,6-dioxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester	IC50	3210 nM
MLS000334119	IC50	3440 nM
1,6-dimethyl-3-(2-pyridinyl)pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione	IC50	10200 nM
4-[(5Z)-5-[(E)-3-(2-furanyl)prop-2-enylidene]-4-oxo-2-sulfanylidene-3-thiazolidinyl]butanoic acid	IC50	19300 nM
1-[[(E)-(2,3-dihydroxy-4-keto-cyclohexa-2,5-dien-1-ylidene)methyl]amino]-3-(3-pyridyl)thiourea	IC50	19500 nM
cid_360404	IC50	40800 nM
3-[(2Z)-2-(3-formyl-4-oxo-1-cyclohexa-2,5-dienylidene)hydrazinyl]benzoic acid	IC50	42500 nM
SMR003100911	IC50	45100 nM
MLS004342426	IC50	47200 nM
SMR003287627	IC50	55400 nM
cid_60159071	IC50	61900 nM
cid_616832	IC50	102000 nM
cid_340219	IC50	122000 nM
SMR000114997	IC50	122000 nM
cid_240739	IC50	122000 nM
cid_46742345	IC50	122000 nM

ChEMBL bioactivities

38 potent at pChembl≥5 of 80 total, top 38 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.75	IC50	180	nM	CHEMBL3355737
6.27	IC50	540	nM	CHEMBL3355726
5.92	IC50	1212	nM	CEFIXIME
5.69	IC50	2026	nM	CHEMBL3188921
5.66	IC50	2198	nM	PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER
5.58	IC50	2600	nM	CHEMBL3355311
5.57	IC50	2696	nM	CHEMBL1878086
5.52	IC50	3000	nM	CHEMBL6057221
5.52	IC50	3000	nM	CHEMBL5760366
5.52	IC50	3000	nM	CHEMBL6001427
5.52	IC50	3000	nM	CHEMBL5984588
5.52	IC50	3000	nM	CHEMBL5857792
5.52	IC50	3000	nM	CHEMBL5967236
5.52	IC50	3000	nM	CHEMBL6048232
5.52	IC50	3000	nM	CHEMBL5856985
5.52	IC50	3000	nM	CHEMBL5831797
5.52	IC50	3000	nM	CHEMBL5894586
5.52	IC50	3000	nM	CHEMBL5741756
5.52	IC50	3000	nM	CHEMBL5886687
5.52	IC50	3000	nM	CHEMBL5849481
5.52	IC50	3000	nM	CHEMBL6062454
5.52	IC50	3000	nM	CHEMBL5786708
5.52	IC50	3000	nM	CHEMBL5928954
5.52	IC50	3000	nM	CHEMBL5894403
5.52	IC50	3000	nM	CHEMBL5787115
5.52	IC50	3000	nM	CHEMBL5764742
5.52	IC50	3000	nM	CHEMBL5860389
5.52	IC50	3000	nM	CHEMBL5765895
5.52	IC50	3000	nM	CHEMBL5978031
5.52	IC50	3000	nM	CHEMBL6051261
5.52	IC50	3000	nM	CHEMBL5947369
5.52	IC50	3000	nM	CHEMBL5917546
5.40	IC50	3969	nM	CHEMBL1464200
5.36	IC50	4359	nM	CHEMBL1594374
5.29	IC50	5138	nM	CHEMBL417727
5.20	IC50	6372	nM	9,10-PHENANTHRENEQUINONE
5.06	IC50	8715	nM	CHEMBL3392220
5.02	IC50	9500	nM	CHEMBL503874

PubChem BioAssay actives

4 with measured affinity, of 28 total; 4 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
4-[[4-(benzenesulfonyl)-6-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]amino]cyclohexan-1-ol	1173758: Inhibition of PLC gamma-1 phosphorylation in human Jurkat T cells after 30 mins	ic50	0.1800	uM
4-[[4-(benzenesulfonyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]amino]cyclohexan-1-ol	1173758: Inhibition of PLC gamma-1 phosphorylation in human Jurkat T cells after 30 mins	ic50	0.5400	uM
4-[[4-benzyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]cyclohexan-1-ol	1173758: Inhibition of PLC gamma-1 phosphorylation in human Jurkat T cells after 30 mins	ic50	2.6000	uM
(1S,2R,4aS,6aR,6aR,6bR,8aR,10S,12aR,14bS)-10-hydroxy-6a-[(E)-4-(4-hydroxyphenyl)-2-oxobut-3-enyl]-1,2,6b,9,9,12a-hexamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid	380378: Inhibition of PLCgamma1	ic50	9.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases localization	2
Resveratrol	decreases reaction, increases cleavage, increases degradation, decreases expression	2
Benzo(a)pyrene	increases expression, increases mutagenesis	2
Cadmium Chloride	decreases expression, increases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
anemoside B4	decreases phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases reaction, decreases expression	1
trigonelline	decreases reaction, increases phosphorylation	1
tributyltin	decreases expression	1
benzo(a)pyrene-3,6-quinone	increases phosphorylation	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	decreases expression	1
oxophenylarsine	affects localization	1
benzo(a)pyrene-1,6-quinone	increases phosphorylation	1
methylmercury II	decreases expression	1
triadimefon	increases expression	1
chrysin	decreases reaction, increases degradation	1
iodixanol	decreases reaction, increases phosphorylation	1
dinitrophenyl-human serum albumin conjugate	affects cotreatment, decreases phosphorylation	1
1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione	decreases reaction, increases phosphorylation	1
N-acetylsphingosine	decreases reaction, increases degradation	1
platycodin D	decreases phosphorylation	1

ChEMBL screening assays

13 unique, capped per target: 12 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3215176	Binding	PubChem BioAssay. Counterscreen for inhibitors of phospholipase C isozymes (PLC-B3): Fluorescence-based biochemical high throughput dose response assay to identify inhibitors of phospholipase C isozymes (PLC-gamma1). (Class of assay: conf	PubChem BioAssay data set
CHEMBL4354390	ADMET	Effect on PLCgamma1 phosphorylation in BDNF-induced human SH-SY5Y cells up to 2 uM preincubated for 6 hrs followed by BDNF addition and measured after 30 mins by Western blot analysis	Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors. — Eur J Med Chem

Cellosaurus cell lines

16 cell lines: 14 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6411	J.gamma1.WT	Cancer cell line	Male
CVCL_A1SD	CY-6	Cancer cell line
CVCL_B3DZ	Abcam HEK293T PLCG1 KO	Transformed cell line	Female
CVCL_B7YV	Abcam Raji PLCG1 KO	Cancer cell line	Male
CVCL_B9ZL	Abcam THP-1 PLCG1 KO	Cancer cell line	Male
CVCL_C7BA	Abcam PC-3 PLCG1 KO	Cancer cell line	Male
CVCL_D7XU	Ubigene A-549 PLCG1 KO	Cancer cell line	Male
CVCL_D8TA	Ubigene HCT 116 PLCG1 KO	Cancer cell line	Male
CVCL_D9NS	Ubigene HEK293 PLCG1 KO	Transformed cell line	Female
CVCL_E0L8	Ubigene HeLa PLCG1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00001277	PHASE2	COMPLETED	Studies of Elevated Parathyroid Activity
NCT00454363	PHASE2	COMPLETED	Pazopanib Hydrochloride in Treating Patients With Advanced Neuroendocrine Cancer
NCT02101918	PHASE2	COMPLETED	Ziv-Aflibercept in Treating and Computed Tomography Perfusion Imaging in Predicting Response in Patients With Pancreatic Neuroendocrine Tumors That Are Metastatic or Cannot Be Removed by Surgery
NCT03950609	PHASE2	ACTIVE_NOT_RECRUITING	Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT02831179	PHASE1	WITHDRAWN	Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03001349	EARLY_PHASE1	TERMINATED	68Ga-DOTA-TOC PET/CT in Imaging Participants With Neuroendocrine Tumors
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01794676	Not specified	COMPLETED	Genetic Evaluation of Families With Endocrine Cancers
NCT03043508	Not specified	UNKNOWN	Overall and Disease Specific Survival in Patients With Confirmed MEN1 With or Without PNET (Pancreatic Neuroendocrine Tumors)
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03966612	Not specified	RECRUITING	Study and Monitoring of Multiple Endocrine Neoplasia Type 1
NCT05037461	Not specified	RECRUITING	Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients
NCT05061784	Not specified	COMPLETED	Routine Transcervical Thymectomy in MEN-1 Patients
NCT05554744	Not specified	UNKNOWN	EUS-FNI for MEN1-related Pancreatic Neuroendocrine Tumors
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT06790251	Not specified	NOT_YET_RECRUITING	Institution of an Italian Multicenter Database of Patients With Multiple Endocrine Neoplasia Type 1 (MENNET1 Database)
NCT07272187	Not specified	RECRUITING	Endoscopic Ultrasound-guided Radiofrequency Ablation for Upper Gastrointestinal Tract Lesions
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk