PLCH2

Summary

PLCH2 (phospholipase C eta 2, HGNC:29037) is a protein-coding gene on chromosome 1p36.32, encoding 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 (O75038). 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.

PLCH2 is a member of the PLC-eta family of the phosphoinositide-specific phospholipase C (PLC) superfamily of enzymes that cleave PtdIns(4,5) P2 to generate second messengers inositol 1,4,5-trisphosphate and diacylglycerol (Zhou et al., 2005 [PubMed 16107206]).

Source: NCBI Gene 9651 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 318 total
• MANE Select transcript: NM_014638

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29037
Approved symbol	PLCH2
Name	phospholipase C eta 2
Location	1p36.32
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0450, PLCeta2, RP3-395M20.1, PLC-eta2
Ensembl gene	ENSG00000149527
Ensembl biotype	protein_coding
OMIM	612836
Entrez	9651

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 retained_intron

ENST00000278878, ENST00000343889, ENST00000378486, ENST00000419816, ENST00000449969, ENST00000462379, ENST00000473964, ENST00000609981

RefSeq mRNA: 3 — MANE Select: NM_014638 NM_001303012, NM_001303013, NM_014638

CCDS: CCDS59959

Canonical transcript exons

ENST00000378486 — 22 exons

Exon	Start	End
ENSE00001477685	2480183	2480312
ENSE00001477687	2479734	2479977
ENSE00003465003	2486907	2487000
ENSE00003466854	2498744	2498828
ENSE00003472793	2484448	2484618
ENSE00003472855	2489207	2489378
ENSE00003516954	2496828	2497010
ENSE00003517403	2489760	2489867
ENSE00003535221	2495488	2495570
ENSE00003552203	2487598	2487718
ENSE00003559057	2496607	2496704
ENSE00003571083	2499084	2499230
ENSE00003582994	2491192	2491335
ENSE00003596489	2502112	2502409
ENSE00003609797	2499641	2499720
ENSE00003616922	2497502	2497609
ENSE00003653363	2498523	2498647
ENSE00003684947	2494856	2494948
ENSE00003688902	2487173	2487376
ENSE00003847390	2503922	2505532
ENSE00003849320	2476289	2476712
ENSE00003890286	2478476	2478622

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 96.69.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2377 / max 130.3551, expressed in 226 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
228	0.7228	120
217	0.2873	97
230	0.1488	8
229	0.0788	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.69	gold quality
skin of abdomen	UBERON:0001416	96.51	gold quality
cerebellar hemisphere	UBERON:0002245	96.17	gold quality
cerebellar cortex	UBERON:0002129	96.15	gold quality
cerebellum	UBERON:0002037	96.08	gold quality
zone of skin	UBERON:0000014	95.83	gold quality
skin of leg	UBERON:0001511	95.41	gold quality
lower esophagus mucosa	UBERON:0035834	95.21	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.10	gold quality
esophagus mucosa	UBERON:0002469	91.33	gold quality
right frontal lobe	UBERON:0002810	91.15	gold quality
anterior cingulate cortex	UBERON:0009835	89.16	gold quality
primary visual cortex	UBERON:0002436	88.79	gold quality
Ammon’s horn	UBERON:0001954	88.78	gold quality
granulocyte	CL:0000094	88.45	gold quality
superior frontal gyrus	UBERON:0002661	88.39	gold quality
frontal cortex	UBERON:0001870	88.31	gold quality
minor salivary gland	UBERON:0001830	87.91	gold quality
cerebral cortex	UBERON:0000956	87.75	gold quality
saliva-secreting gland	UBERON:0001044	87.61	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.46	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.03	gold quality
prefrontal cortex	UBERON:0000451	86.62	gold quality
brain	UBERON:0000955	86.61	gold quality
right uterine tube	UBERON:0001302	86.48	gold quality
prostate gland	UBERON:0002367	86.11	gold quality
vagina	UBERON:0000996	86.06	gold quality
substantia nigra	UBERON:0002038	85.45	gold quality
temporal lobe	UBERON:0001871	84.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	11.92
E-ANND-3	no	2.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting PLCH2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-4475	97.36	66.95	761

Literature-anchored findings (GeneRIF, showing 6)

• molecular cloning of PLC-eta1 and PLC-eta2 (PMID:15583837)
• PLC(eta)2 is a neuron-specific isozyme that may be important for the formation and/or maintenance of the neuronal network in the postnatal brain (PMID:15899900)
• The molecular cloning and sequencing of phospholipase C eta2 are reported. (PMID:16107206)
• Purified Gbeta 1gamma 2 stimulated the activity of purified PLC-eta2 in a concentration-dependent manner similar to that observed with purified PLC-beta2. (PMID:18361507)
• The researchers investigated the D1S80 minisatellite and associated single nucelotide polymorphisms in a Tamil population in India. (PMID:20649401)
• PLCH2 might be a putative candidate gene for the neurodevelopmental delay observed in patients bearing 1p36.3 deletions. (PMID:21474938)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	plch2b	ENSDARG00000056805
danio_rerio	plch2a	ENSDARG00000059960
mus_musculus	Plch2	ENSMUSG00000029055
rattus_norvegicus	Plch2	ENSRNOG00000014226
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), PLCB3 (ENSG00000149782), PLCL2 (ENSG00000154822), PLCD3 (ENSG00000161714), PLCB1 (ENSG00000182621), PLCD1 (ENSG00000187091), PLCG2 (ENSG00000197943)

Protein

Protein identifiers

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2 — O75038 (reviewed: O75038)

Alternative names: Phosphoinositide phospholipase C-eta-2, Phosphoinositide phospholipase C-like 4, Phospholipase C-eta-2

All UniProt accessions (3): O75038, B9DI82, V9GY64

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. This phospholipase activity is very sensitive to calcium. May be important for formation and maintenance of the neuronal network in the postnatal brain.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in retina and kidney.

Activity regulation. Activity is stimulated by GNB1:GNG2.

Isoforms (5)

UniProt ID	Names	Canonical?
O75038-1	1	yes
O75038-2	2
O75038-3	3
O75038-4	4
O75038-5	5

RefSeq proteins (3): NP_001289941, NP_001289942, NP_055453* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000909	PLipase_C_PInositol-sp_X_dom	Domain
IPR001192	PI-PLC_fam	Family
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
IPR015359	PLC_EF-hand-like	Domain
IPR017946	PLC-like_Pdiesterase_TIM-brl	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028393	PLC-eta2_cat	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR046971	PLC-eta2_EFh	Domain

Pfam: PF00168, PF00387, PF00388, PF09279, PF16457

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 (56 total): binding site 19, splice variant 8, compositionally biased region 7, domain 6, region of interest 5, modified residue 4, sequence conflict 4, active site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75038-F1	63.21	0.26

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): 341; 385

Ligand- & substrate-binding residues (19): 182; 184; 186; 188; 193; 342; 371; 373; 420; 469; 471; 653 …

Post-translational modifications (4): 487, 491, 595, 605

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol

MSigDB gene sets: 114 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, MODULE_66, GOBP_MAINTENANCE_OF_LOCATION, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, MODULE_88, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_PHOSPHOLIPASE_C_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_LIPID_CATABOLIC_PROCESS, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT

GO Biological Process (8): phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), lipid catabolic process (GO:0016042), phosphatidylinositol metabolic process (GO:0046488), phosphatidylinositol-mediated signaling (GO:0048015), release of sequestered calcium ion into cytosol (GO:0051209), lipid metabolic process (GO:0006629), signal transduction (GO:0007165), intracellular signal transduction (GO:0035556)

GO Molecular Function (6): phosphatidylinositol-4,5-bisphosphate phospholipase C activity (GO:0004435), calcium ion binding (GO:0005509), C-type glycerophospholipase activity (GO:0004629), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Inositol phosphate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
G protein-coupled receptor signaling pathway	1
phospholipase C activator activity	1
lipid metabolic process	1
catabolic process	1
phosphorus metabolic process	1
intracellular signal transduction	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
primary metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
C-type glycerophospholipase activity	1
metal ion binding	1
glycerophospholipase activity	1
phosphoric diester hydrolase activity	1
phosphoric ester hydrolase activity	1
catalytic activity	1
cation binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLCH2	GNG2	P59768	614
PLCH2	GNB1	P04697	592
PLCH2	GNAQ	P50148	567
PLCH2	TMEM182	Q6ZP80	448
PLCH2	PLCXD1	Q9NUJ7	432
PLCH2	SUCLG1	P53597	426
PLCH2	USP53	Q70EK8	422
PLCH2	PRDX6	P30041	393
PLCH2	RHOA	P06749	392
PLCH2	PLEK2	Q9NYT0	374
PLCH2	PLEK	P08567	371
PLCH2	PRDX2	P31945	362
PLCH2	PLBD2	Q8NHP8	356
PLCH2	TTC28	Q96AY4	355
PLCH2	PARD6A	Q9NPB6	353
PLCH2	NOVA2	Q9UNW9	353

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TNKS	PLCH2	psi-mi:“MI:0407”(direct interaction)	0.440
PLCH2	HNRNPU	psi-mi:“MI:0915”(physical association)	0.400
PLCH2	AGTR1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (11): PLCH2 (Affinity Capture-MS), PLCH2 (Reconstituted Complex), HNRNPU (Proximity Label-MS), PLCH2 (Two-hybrid), PLCH2 (Affinity Capture-MS), PLCH2 (Affinity Capture-MS), PLCH2 (Protein-peptide), PLCH2 (Cross-Linking-MS (XL-MS)), PLCH2 (Cross-Linking-MS (XL-MS)), PLCH2 (Cross-Linking-MS (XL-MS)), PLCH2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0R4IMY7, A0JPA0, A2AP18, A8DYE2, J9SQF3, O00329, O35904, O75038, P0C1Q3, P0C588, P19687, P33402, P48736, P97557, Q02108, Q09M05, Q148L1, Q1LWG4, Q2TV84, Q2WEA5, Q3USB7, Q4ZHS0, Q502J0, Q5EBA1, Q60565, Q62688, Q69ZF7, Q6P4Q7, Q6PA06, Q7L5N7, Q7TN37, Q7Z2W7, Q7Z4N2, Q80YD1, Q8BTI9, Q8BYI6, Q8BZN2, Q8CIR4, Q8NHH9, Q8R455

Diamond homologs: A2AP18, A3KGF7, A5D6R3, G5EBH0, G5EFI8, O75038, O89040, P10687, P10688, P10894, P10895, P21671, P25455, P51178, P51432, Q00722, Q01970, Q07722, Q15111, Q15147, Q1RML2, Q2VRL0, Q32NH8, Q3USB7, Q4KWH5, Q4KWH8, Q4R6L3, Q5FX52, Q5RET0, Q62688, Q62711, Q6NMA7, Q7YRU3, Q86YW0, Q8K2J0, Q8K394, Q8K3R3, Q8K4D7, Q8K4S1, Q8L706

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	250
Likely benign	31
Benign	14

Top pathogenic / likely-pathogenic (0)

SpliceAI

4715 predictions. Top by Δscore:

Variant	Effect	Δscore
1:2478474:A:AG	acceptor_gain	1.0000
1:2478475:G:GG	acceptor_gain	1.0000
1:2478475:GTGGA:G	acceptor_gain	1.0000
1:2478621:GA:G	donor_gain	1.0000
1:2478623:GTGA:G	donor_gain	1.0000
1:2479726:C:G	acceptor_gain	1.0000
1:2479729:CGCA:C	acceptor_loss	1.0000
1:2479732:A:AC	acceptor_loss	1.0000
1:2479732:A:AG	acceptor_gain	1.0000
1:2479733:G:GA	acceptor_gain	1.0000
1:2479733:GT:G	acceptor_gain	1.0000
1:2479733:GTCT:G	acceptor_gain	1.0000
1:2479733:GTCTC:G	acceptor_gain	1.0000
1:2479972:G:GT	donor_gain	1.0000
1:2479973:G:T	donor_gain	1.0000
1:2480311:GG:G	donor_gain	1.0000
1:2480312:GG:G	donor_gain	1.0000
1:2484615:GAAG:G	donor_gain	1.0000
1:2484616:AAGG:A	donor_loss	1.0000
1:2484617:AG:A	donor_loss	1.0000
1:2487163:C:CA	acceptor_gain	1.0000
1:2487168:TGCA:T	acceptor_loss	1.0000
1:2487169:GCAG:G	acceptor_loss	1.0000
1:2487170:CA:C	acceptor_loss	1.0000
1:2487171:A:AG	acceptor_gain	1.0000
1:2487171:AG:A	acceptor_gain	1.0000
1:2487172:G:GA	acceptor_gain	1.0000
1:2487172:GG:G	acceptor_gain	1.0000
1:2487172:GGC:G	acceptor_gain	1.0000
1:2487172:GGCT:G	acceptor_gain	1.0000

AlphaMissense

9246 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:2478589:T:A	W80R	1.000
1:2478589:T:C	W80R	1.000
1:2478591:G:C	W80C	0.999
1:2478591:G:T	W80C	0.999
1:2479827:T:C	F122S	0.999
1:2479866:T:C	L135P	0.999
1:2479898:T:A	W146R	0.999
1:2479898:T:C	W146R	0.999
1:2487281:C:T	S340F	0.999
1:2487283:C:G	H341D	0.999
1:2487288:C:A	N342K	0.999
1:2487288:C:G	N342K	0.999
1:2487296:T:C	L345P	0.999
1:2487601:A:C	D373A	0.999
1:2487601:A:T	D373V	0.999
1:2489221:T:C	L417P	0.999
1:2489230:A:T	E420V	0.999
1:2489234:C:A	N421K	0.999
1:2489234:C:G	N421K	0.999
1:2489240:C:G	C423W	0.999
1:2489255:G:C	Q428H	0.999
1:2489255:G:T	Q428H	0.999
1:2489275:T:C	L435P	0.999
1:2489371:T:C	L467P	0.999
1:2489378:G:C	K469N	0.999
1:2489378:G:T	K469N	0.999
1:2496970:C:A	N692K	0.999
1:2496970:C:G	N692K	0.999
1:2496989:T:A	W699R	0.999
1:2496989:T:C	W699R	0.999

dbSNP variants (sampled 300 via entrez): RS1000008176 (1:2495235 A>T), RS1000013219 (1:2492334 C>T), RS1000056375 (1:2429251 C>G,T), RS1000066170 (1:2490945 C>A,T), RS1000075363 (1:2462101 C>G), RS1000145523 (1:2462502 G>C), RS1000174643 (1:2415062 C>T), RS1000189242 (1:2416959 C>T), RS1000274143 (1:2456872 C>T), RS1000282061 (1:2474205 A>T), RS1000288458 (1:2482266 C>A,T), RS1000301819 (1:2503181 G>A), RS1000308807 (1:2433653 G>A), RS1000331867 (1:2440813 C>T), RS1000338378 (1:2495023 C>T)

Disease associations

OMIM: gene MIM:612836 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000964_38	Ulcerative colitis	3.000000e-09
GCST001728_20	Ulcerative colitis	3.000000e-12
GCST002539_27	Schizophrenia	9.000000e-10
GCST005951_35	Body mass index	4.000000e-08
GCST006803_89	Schizophrenia	7.000000e-12
GCST006941_50	Irritable mood	2.000000e-08
GCST010002_374	Refractive error	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0009594	irritability measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphoinositide-specific phospholipase C

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	affects cotreatment, increases methylation, decreases expression	2
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
sodium arsenite	increases expression	2
Cyclosporine	decreases methylation, increases expression	2
Particulate Matter	increases expression, affects cotreatment, increases abundance	2
GSK-J4	decreases expression	1
OTX015	decreases expression	1
mivebresib	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
tricetin	increases expression	1
quinocetone	increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants	increases abundance, increases expression	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
DEET	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Phthalic Acids	increases methylation	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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