PPP3CA

Summary

PPP3CA (protein phosphatase 3 catalytic subunit alpha, HGNC:9314) is a protein-coding gene on chromosome 4q24, encoding Protein phosphatase 3 catalytic subunit alpha (Q08209). Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals.

Enables several functions, including ATPase binding activity; calmodulin binding activity; and calmodulin-dependent protein phosphatase activity. Involved in several processes, including calcineurin-NFAT signaling cascade; negative regulation of angiotensin-activated signaling pathway; and peptidyl-serine dephosphorylation. Located in cytoplasm; cytoplasmic side of plasma membrane; and dendritic spine. Part of calcineurin complex. Implicated in developmental and epileptic encephalopathy 91. Biomarker of cholangiocarcinoma; focal segmental glomerulosclerosis; and schizophrenia.

Source: NCBI Gene 5530 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 608 total — 23 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 90
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_000944

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9314
Approved symbol	PPP3CA
Name	protein phosphatase 3 catalytic subunit alpha
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	CNA1, PPP2B
Ensembl gene	ENSG00000138814
Ensembl biotype	protein_coding
OMIM	114105
Entrez	5530

Gene structure

Transcript identifiers

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

ENST00000323055, ENST00000394853, ENST00000394854, ENST00000492351, ENST00000507176, ENST00000510292, ENST00000512215, ENST00000525819, ENST00000529324, ENST00000964807

RefSeq mRNA: 3 — MANE Select: NM_000944 NM_000944, NM_001130691, NM_001130692

CCDS: CCDS34037, CCDS47113, CCDS47114

Canonical transcript exons

ENST00000394854 — 14 exons

Exon	Start	End
ENSE00000934972	101032267	101032364
ENSE00000970136	101080532	101080626
ENSE00001080695	101040482	101040566
ENSE00001080697	101061087	101061161
ENSE00001284009	101023418	101026061
ENSE00001720711	101083186	101083263
ENSE00001781830	101063232	101063357
ENSE00001896251	101346739	101347526
ENSE00002484240	101029166	101029195
ENSE00003490016	101093776	101093915
ENSE00003530483	101195916	101196116
ENSE00003577022	101108954	101109078
ENSE00003589120	101099611	101099722
ENSE00003637761	101098367	101098512

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.4067 / max 645.9126, expressed in 1764 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53354	17.2293	1741
53346	3.2488	921
53355	1.6230	957
53348	1.1244	227
53347	0.7693	380
53350	0.7658	154
53335	0.5362	132
53351	0.5237	86
53353	0.4097	189
203299	0.2156	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.83	gold quality
endothelial cell	CL:0000115	99.76	gold quality
middle temporal gyrus	UBERON:0002771	99.72	gold quality
CA1 field of hippocampus	UBERON:0003881	99.52	gold quality
postcentral gyrus	UBERON:0002581	99.51	gold quality
parietal lobe	UBERON:0001872	99.49	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.43	gold quality
entorhinal cortex	UBERON:0002728	99.38	gold quality
orbitofrontal cortex	UBERON:0004167	99.30	gold quality
lateral globus pallidus	UBERON:0002476	99.28	gold quality
pons	UBERON:0000988	98.96	gold quality
superior frontal gyrus	UBERON:0002661	98.85	gold quality
cartilage tissue	UBERON:0002418	98.41	gold quality
oocyte	CL:0000023	98.34	gold quality
occipital lobe	UBERON:0002021	98.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.21	gold quality
putamen	UBERON:0001874	98.16	gold quality
primary visual cortex	UBERON:0002436	97.92	gold quality
nucleus accumbens	UBERON:0001882	97.85	gold quality
caudate nucleus	UBERON:0001873	97.77	gold quality
secondary oocyte	CL:0000655	97.75	gold quality
synovial joint	UBERON:0002217	97.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.59	gold quality
seminal vesicle	UBERON:0000998	97.54	gold quality
parotid gland	UBERON:0001831	97.53	gold quality
calcaneal tendon	UBERON:0003701	97.47	gold quality
cortical plate	UBERON:0005343	97.37	gold quality
urethra	UBERON:0000057	97.32	gold quality
cauda epididymis	UBERON:0004360	97.30	gold quality
Ammon’s horn	UBERON:0001954	97.19	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-89232	yes	3588.81
E-HCAD-5	yes	655.73
E-HCAD-25	yes	79.07
E-HCAD-35	yes	35.35
E-CURD-119	yes	22.28
E-GEOD-125970	yes	14.00
E-GEOD-75140	no	1136.84
E-MTAB-6819	no	1108.44
E-CURD-89	no	372.46
E-MTAB-7606	no	104.06
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
HAND2	Activation
IL6	Activation
MCM7	Repression

Upstream regulators (CollecTRI, top): CREB1, SMAD4, SRF, TAL1

miRNA regulators (miRDB)

247 targeting PPP3CA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-499A-5P	99.98	70.79	1323

Literature-anchored findings (GeneRIF, showing 40)

• The functional differences conferred upon CaN by the alpha or beta catalytic subunit isoforms suggest that the alpha:beta and CaN:substrate ratios may determine the levels of CaN phosphatase activity toward specific substrates. (PMID:12135494)
• Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes. (PMID:12218175)
• involvement of PKA and PPP2B in the regulation of NF-kappaB in human monocytes (PMID:12586544)
• there is a 13-amino acid region within CN that is essential for the interaction with NFAT and with two other CN-binding proteins, AKAP79 and Cabin-1 (PMID:15671033)
• The activation of calcineurin by calpain I in the brain of patients with Alzheimer’s disease is reported. (PMID:16150694)
• These results indicate that calcineurin mediates acetylcholinesterase expression during apoptosis. (PMID:17320203)
• activation of calcineurin is required for lytic granule exocytosis but it is not the sole Ca2+-dependent step (PMID:17478429)
• analysis of the secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin binding (PMID:18296442)
• CHP2 has a role in tumorigenesis and as an activator of the calcineurin/NFAT signaling pathway (PMID:18815128)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• Study demonstrates that all CaN isoforms display the same cytoplasmic subcellular distribution and are expressed in each tested cell line, differences in substrate specificities may determine specific physiological functions of the distinct isoforms. (PMID:19154138)
• A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants. (PMID:19285944)
• SFRP2 is a novel stimulator of angiogenesis that stimulates angiogenesis via a calcineurin/NFAT pathway and may be a favorable target for the inhibition of angiogenesis in solid tumors. (PMID:19458075)
• Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. (PMID:19492085)
• calcineurin has a role in the heart and in cardiac disease (PMID:19879877)
• Data suggest an association between polymorphisms in PPP3CA, PPP3R1 and PPP3R2 and baseline levels or trainability of endurance phenotype traits. (PMID:20107831)
• CN mediates the Ang II-induced aldosterone synthesis through up-regulation of the CYP11B2 transcription. (PMID:20413672)
• CnAalpha, was significantly overexpressed in lung cancer tissues with bone metastasis as compared to tumors with non-bone metastases. (PMID:20422345)
• PP2B is an important target of the aberrant acinar cell Ca(2+) rise associated with pathological protease activation and pancreatitis. (PMID:20501444)
• Data show that in patients with CHF, calpain upregulation was associated with an increase in cleavage of cain/cabin1 and the activation of CaN. (PMID:20514436)
• data underscore the importance of calcineurin gene in the molecular mechanism of addiction and Alzheimer’s diseases (PMID:20590401)
• two new complementary roles for calcineurin in the regulation of the early UPR (Unfolded Protein Responses) (PMID:20700529)
• The C allele of protein phosphatase 3 subunit alpha rs3804358 polymorphism was overrepresented in athletes compared with controls, whereas the T allele of protein phosphatase 3 subunit beta rs3763679 polymorphism was underrepresented in athletes. (PMID:21233773)
• Findings demonstrate that CaN functions as a critical signaling molecule during Th cell activation, regulating Bcl-10 phosphorylation and NF-kappaB activation. (PMID:21674474)
• High calcineurin A alpha protein is associated with bone metastasis in small-cell lung cancer. (PMID:21785830)
• The authors demonstrate that the regulatory domain within calcineurin is unstructured and that it folds upon binding calmodulin, ousting the autoinhibitory domain from the catalytic site. (PMID:22100452)
• Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway (PMID:22164265)
• suggest that CaMKII and calcineurin provide a switch-like mechanism that controls Ca-dependent LIMK1, SSH1L and cofilin activation, and subsequently actin cytoskeletal reorganization (PMID:22270398)
• Alterations in calcineurin signaling in the caudate nucleus contribute to the pathogenesis of schizophrenia. (PMID:22285318)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Even though an association of the polymorphisms rs2850328 and rs2395 and breast cancer was not detected in our case-control study population, other variants within the PPP3CA and MARK4 genes may still be associated with breast cancer. (PMID:22506312)
• NHE1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy (PMID:22688515)
• calcineurin crystal of trypsin-resistant catalytic domain belonged to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 161.6, b = 87.4, c = 112.0 A (PMID:22691791)
• Present findings indicate that downregulation of hemoxygenase-1 expression in neutrophils from hypertensive subjects is likely mediated by CN, which acts by hindering translocation to the nucleus of the transcription factor NRF2. (PMID:22739212)
• PPP3CA down-regulation is associated with hepatocellular carcinoma infected with hepatitis C virus. (PMID:23317196)
• Bile-induced NF-kappaB activation and acinar cell injury are mediated by calcineurin. (PMID:23744075)
• Dephosphorylation of Aly1 by calcineurin serves as a regulatory switch to promote Aly1-mediated trafficking to the vacuole. (PMID:23824189)
• lower expression of PPP3CA and PPP3CB genes in atrium myocardium can be related to expressed postinfarction LV remodeling. (PMID:23888774)
• Mutations on the hydrophobic face of Calcineurin distal helix disrupt the structure gained upon CaM binding. (PMID:24191726)
• PKCepsilon may negatively regulate adverse myocardial remodeling by cooperating with calcineurin to downregulate fibrosis and induce transcription of cardioprotective wound healing genes, including COX-2 (PMID:24298017)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ppp3ca	ENSMUSG00000028161
rattus_norvegicus	Ppp3ca	ENSRNOG00000009882
drosophila_melanogaster	PpD5	FBGN0005778
drosophila_melanogaster	Pp1-Y1	FBGN0261399
caenorhabditis_elegans		WBGENE00001748
caenorhabditis_elegans		WBGENE00007354
caenorhabditis_elegans		WBGENE00007699
caenorhabditis_elegans		WBGENE00007700
caenorhabditis_elegans		WBGENE00007763
caenorhabditis_elegans		WBGENE00008124
caenorhabditis_elegans	F22D6.9	WBGENE00009054
caenorhabditis_elegans		WBGENE00009079
caenorhabditis_elegans		WBGENE00009101
caenorhabditis_elegans		WBGENE00009893
caenorhabditis_elegans		WBGENE00010265
caenorhabditis_elegans		WBGENE00011133
caenorhabditis_elegans		WBGENE00012008
caenorhabditis_elegans		WBGENE00012741
caenorhabditis_elegans		WBGENE00013476
caenorhabditis_elegans		WBGENE00014158
caenorhabditis_elegans		WBGENE00016010
caenorhabditis_elegans		WBGENE00016081
caenorhabditis_elegans	F26B1.5	WBGENE00017817
caenorhabditis_elegans		WBGENE00018359
caenorhabditis_elegans		WBGENE00018410
caenorhabditis_elegans		WBGENE00019951
caenorhabditis_elegans	W03D8.2	WBGENE00020985
caenorhabditis_elegans		WBGENE00022617
caenorhabditis_elegans		WBGENE00022710
caenorhabditis_elegans	Y71G12B.30	WBGENE00044347

Paralogs (12): PPP5C (ENSG00000011485), PPEF1 (ENSG00000086717), PPP2CB (ENSG00000104695), PPP3CB (ENSG00000107758), PPP2CA (ENSG00000113575), PPP6C (ENSG00000119414), PPP3CC (ENSG00000120910), PPP4C (ENSG00000149923), PPEF2 (ENSG00000156194), PPP1CA (ENSG00000172531), PPP1CC (ENSG00000186298), PPP1CB (ENSG00000213639)

Protein

Protein identifiers

Protein phosphatase 3 catalytic subunit alpha — Q08209 (reviewed: Q08209)

Alternative names: CAM-PRP catalytic subunit, Calcineurin A alpha, Calmodulin-dependent calcineurin A subunit alpha isoform, Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform

All UniProt accessions (7): Q08209, A0A0S2Z4B5, A0A0S2Z4C6, E7ETC2, E9PK68, E9PPC8, H0YAB4

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Many of the substrates contain a PxIxIT motif and/or a LxVP motif. In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation. In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion. Positively regulates the CACNA1B/CAV2.2-mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals. Dephosphorylates heat shock protein HSPB1. Dephosphorylates and activates transcription factor NFATC1. In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32. May dephosphorylate CRTC2 at ‘Ser-171’ resulting in CRTC2 dissociation from 14-3-3 proteins. Dephosphorylates transcription factor TFEB at ‘Ser-211’ following Coxsackievirus B3 infection, promoting nuclear translocation. Required for postnatal development of the nephrogenic zone and superficial glomeruli in the kidneys, cell cycle homeostasis in the nephrogenic zone, and ultimately normal kidney function. Plays a role in intracellular AQP2 processing and localization to the apical membrane in the kidney, may thereby be required for efficient kidney filtration. Required for secretion of salivary enzymes amylase, peroxidase, lysozyme and sialic acid via formation of secretory vesicles in the submandibular glands. Required for calcineurin activity and homosynaptic depotentiation in the hippocampus. Required for normal differentiation and survival of keratinocytes and therefore required for epidermis superstructure formation. Positively regulates osteoblastic bone formation, via promotion of osteoblast differentiation. Positively regulates osteoclast differentiation, potentially via NFATC1 signaling. May play a role in skeletal muscle fiber type specification, potentially via NFATC1 signaling. Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB. Required for antigen-specific T-cell proliferation response. Dephosphorylates KLHL3, promoting the interaction between KLHL3 and WNK4 and subsequent degradation of WNK4. Negatively regulates SLC9A1 activity.

Subunit / interactions. Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2). In response to an increase in Ca(2+) intracellular levels, forms a complex composed of PPP3CA/calcineurin A, calcineurin B and calmodulin. Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B. Interacts (via calmodulin-binding domain) with CALM1/calmodulin; the interaction depends on calmodulin binding to Ca(2+) (PubMed:18384083, PubMed:19404396, PubMed:25144868, Ref.34). Forms a complex composed of MYOZ2 and ACTN1. Within the complex interacts with MYOZ2. Interacts with MYOZ1. Interacts with MYOZ3. Interacts with CIB1; the interaction increases upon cardiomyocyte hypertrophy. Interacts with CHP1 and CHP2. Interacts with CRTC1. Interacts with CRTC2. Interacts with DNM1L; the interaction dephosphorylates DNM1L and promotes its translocation to mitochondria. Interacts with CMYA5; this interaction represses calcineurin activity in muscle. Interacts (constitutively active form) with SYNPO2. Interacts with scaffold protein AKAP5 (via IAIIIT motif); the interaction recruits PPP3CA to the plasma membrane following L-type Ca(2+)-channel activation. Interacts with NFATC2. Interacts with RCAN3. Interacts with PPIA. Interacts with RCAN1. Interacts with UNC119. Interacts with C16orf74 (via PxIxIT motif, when phosphorylated on ‘Thr-44’). Interacts (via N-terminus) with MAP3K14/NIK (via C-terminus and kinase domain). Interacts with TRAF3. Interacts with SPATA33 (via PQIIIT motif).

Subcellular location. Cytoplasm. Cell membrane. Sarcolemma. Myofibril. Sarcomere. Z line. Cell projection. Dendritic spine.

Tissue specificity. Expressed in keratinocytes (at protein level). Expressed in lymphoblasts (at protein level).

Disease relevance. Epileptic encephalopathy, infantile or early childhood, 1 (IECEE1) [MIM:617711] A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. IECEE1 is an autosomal dominant condition with onset of seizures between the first weeks and first years of life. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID) [MIM:618265] An autosomal dominant disease characterized by moderate to severe intellectual disability, craniosynostosis, cleft palate, micrognathia, arthrogryposis, and short stature. Some patients may present bone abnormalities and generalized seizures. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A. The subsequent binding of Ca(2+)-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A. Inhibited by immunosuppressant drug FK506 (tacrolimus) in complex with FKBP12 and also by immunosuppressant drug cyclosporin A (CsA) in complex with PPIA/cyclophilin A; the inhibition is Ca(2+)-dependent.

Cofactor. Binds 1 Fe(3+) ion per subunit. Binds 1 zinc ion per subunit.

Domain organisation. The autoinhibitory domain prevents access to the catalytic site. The autoinhibitory segment prevents access to the substrate binding site. Possible isomerization of Pro-309 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.

Miscellaneous. Although African swine fever virus infects pigs and not humans, human PPP3CA has been used for the crystallization. PPP3CA interacts with African swine fever virus Mal-047/A238L (via PKIIIT and FLCVK motifs); the interaction does not block catalytic activity per se but inhibits PPP3CA function by blocking the access to the two substrate recognition sites.

Similarity. Belongs to the PPP phosphatase family. PP-2B subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q08209-1	1	yes
Q08209-2	2
Q08209-3	3
Q08209-4	4
Q08209-5	5

RefSeq proteins (3): NP_000935, NP_001124163, NP_001124164 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004843	Calcineurin-like_PHP	Domain
IPR006186	Ser/Thr-sp_prot-phosphatase	Domain
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR041751	MPP_PP2B	Domain
IPR043360	PP2B	Family

Pfam: PF00149

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)

Substrate kinetics (BRENDA)

59 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
P-NITROPHENYL PHOSPHATE	3–200	11
RRAPTVA	0.058–1.954	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3
PHOSPHORYLATED MYOSIN LIGHT CHAIN PEPTIDE	0.01–0.11	3
PHOSPHOSERINE-MYELIN BASIC PROTEIN	0.0004–0.022	3
DLDVPIPGRFDRRVSVAAE	0.0006–0.0138	2
DLDVPIPGRFDRRVY(P)VAAE	0.0025–0.023	2
PHOSPHORYLASE A	0.004–0.021	2
RRA(PT)VA	0.0536–0.308	2
80S-RIBOSOME	0.0027	1
AAAPTVA	0.206	1
AGPALSPVPPV	0.357	1

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (85 total): strand 18, helix 17, sequence variant 10, binding site 7, region of interest 7, turn 6, modified residue 4, splice variant 4, mutagenesis site 4, compositionally biased region 3, initiator methionine 1, chain 1, active site 1, site 1, short sequence motif 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
2W73	X-RAY DIFFRACTION	1.45
4F0Z	X-RAY DIFFRACTION	1.7
6UUQ	X-RAY DIFFRACTION	1.85
2R28	X-RAY DIFFRACTION	1.86
6NUC	X-RAY DIFFRACTION	1.9
6NUF	X-RAY DIFFRACTION	1.9
4Q5U	X-RAY DIFFRACTION	1.95
3LL8	X-RAY DIFFRACTION	2
9NXE	X-RAY DIFFRACTION	2.09
1AUI	X-RAY DIFFRACTION	2.1
9NXN	X-RAY DIFFRACTION	2.1
2P6B	X-RAY DIFFRACTION	2.3
6NUU	X-RAY DIFFRACTION	2.3
5SVE	X-RAY DIFFRACTION	2.6
1M63	X-RAY DIFFRACTION	2.8
1MF8	X-RAY DIFFRACTION	3.1
9NXF	X-RAY DIFFRACTION	3.13
5C1V	X-RAY DIFFRACTION	3.35
9B9G	ELECTRON MICROSCOPY	3.5
2JOG	SOLUTION NMR
2JZI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08209-F1	86.24	0.61

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): 151 (proton donor); 352 (interaction with pxvp motif in substrate)

Ligand- & substrate-binding residues (7): 90; 92; 118; 118; 150; 199; 281

Post-translational modifications (4): 2, 224, 469, 492

Mutagenesis-validated functional residues (4):

Position	Phenotype
288	partial loss of ca(2+)-mediated transcription factor nfat activation; when associated with f-341.
288	loss of ca(2+)-mediated transcription factor nfat activation; when associated with f-341.
328–332	loss of ca(2+)-mediated transcription factor nfat activation; when associated with f-341.
341	resistant to cyclosporin a-mediated inhibition. loss of ca(2+)-mediated transcription factor nfat activation; when assoc

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-180024	DARPP-32 events
R-HSA-2025928	Calcineurin activates NFAT
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-4086398	Ca2+ pathway
R-HSA-5607763	CLEC7A (Dectin-1) induces NFAT activation

MSigDB gene sets: 907 (showing top): PID_BCR_5PATHWAY, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_DIGESTION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, BIOCARTA_FMLP_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, MODY_HIPPOCAMPUS_POSTNATAL, REACTOME_INNATE_IMMUNE_SYSTEM

GO Biological Process (49): G1/S transition of mitotic cell cycle (GO:0000082), protein dephosphorylation (GO:0006470), protein import into nucleus (GO:0006606), calcium ion transport (GO:0006816), epidermis development (GO:0008544), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), transition between fast and slow fiber (GO:0014883), cardiac muscle hypertrophy in response to stress (GO:0014898), dephosphorylation (GO:0016311), negative regulation of signaling (GO:0023057), keratinocyte differentiation (GO:0030216), positive regulation of cell migration (GO:0030335), calcineurin-NFAT signaling cascade (GO:0033173), multicellular organismal response to stress (GO:0033555), wound healing (GO:0042060), positive regulation of activated T cell proliferation (GO:0042104), T cell activation (GO:0042110), skeletal muscle tissue regeneration (GO:0043403), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of cell adhesion (GO:0045785), positive regulation of endocytosis (GO:0045807), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of saliva secretion (GO:0046878), skeletal muscle fiber development (GO:0048741), dendrite morphogenesis (GO:0048813), negative regulation of dendrite morphogenesis (GO:0050774), modulation of chemical synaptic transmission (GO:0050804), response to calcium ion (GO:0051592), excitatory postsynaptic potential (GO:0060079), regulation of cell proliferation involved in kidney morphogenesis (GO:0061006), peptidyl-serine dephosphorylation (GO:0070262), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), positive regulation of glomerulus development (GO:0090193), renal filtration (GO:0097205), calcineurin-mediated signaling (GO:0097720), postsynaptic modulation of chemical synaptic transmission (GO:0099170), negative regulation of angiotensin-activated signaling pathway (GO:0110062), positive regulation of calcium ion-dependent exocytosis of neurotransmitter (GO:1903235)

GO Molecular Function (11): protein serine/threonine phosphatase activity (GO:0004722), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), enzyme binding (GO:0019899), calmodulin-dependent protein phosphatase activity (GO:0033192), protein dimerization activity (GO:0046983), ATPase binding (GO:0051117), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (19): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), calcineurin complex (GO:0005955), protein serine/threonine phosphatase complex (GO:0008287), extrinsic component of plasma membrane (GO:0019897), Z disc (GO:0030018), sarcolemma (GO:0042383), dendritic spine (GO:0043197), Schaffer collateral - CA1 synapse (GO:0098685), glutamatergic synapse (GO:0098978), nucleus (GO:0005634), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Opioid Signalling	1
Downstream signaling events of B Cell Receptor (BCR)	1
Fc epsilon receptor (FCERI) signaling	1
Beta-catenin independent WNT signaling	1
CLEC7A (Dectin-1) signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein binding	3
plasma membrane	3
synapse	3
gene expression	2
regulation of gene expression	2
tissue regeneration	2
cytoplasm	2
intracellular membrane-bounded organelle	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
dephosphorylation	1
protein modification process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
metal ion transport	1
tissue development	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of skeletal muscle adaptation	1
muscle hypertrophy in response to stress	1
cardiac muscle hypertrophy	1
cardiac muscle adaptation	1
phosphate-containing compound metabolic process	1
regulation of signaling	1
signaling	1
negative regulation of biological process	1
epidermal cell differentiation	1
skin development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
calcineurin-mediated signaling	1
response to stress	1
multicellular organismal process	1
response to wounding	1
positive regulation of T cell proliferation	1

Protein interactions and networks

STRING

4142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP3CA	PPP3R1	P06705	999
PPP3CA	CALM1	P02593	983
PPP3CA	CALML3	P27482	971
PPP3CA	CALML5	Q9NZT1	971
PPP3CA	CALML4	Q96GE6	970
PPP3CA	CALML6	Q8TD86	969
PPP3CA	PPP3CB	P16298	868
PPP3CA	NFATC1	O95644	851
PPP3CA	KERA	O60938	800
PPP3CA	FKBP1A	P20071	778
PPP3CA	RCAN1	P53805	761
PPP3CA	AKAP5	P24588	695
PPP3CA	PPP3R2	Q96LZ3	685
PPP3CA	PPP3CC	P48454	661
PPP3CA	SERPINH1	P29043	657

IntAct

106 interactions, top by confidence:

A	B	Type	Score
PPP3R1	PPP3CA	psi-mi:“MI:0915”(physical association)	0.900
PPP3CA	PPP3R1	psi-mi:“MI:0915”(physical association)	0.900
PPP3CA	PPP3R1	psi-mi:“MI:0407”(direct interaction)	0.900
PPP3R1	PPP3CA	psi-mi:“MI:2364”(proximity)	0.900
PPP3CA	PPP3R1	psi-mi:“MI:0914”(association)	0.900
PABIR1	PPP2R1A	psi-mi:“MI:0914”(association)	0.880
GSK3A	AXIN1	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PPP3CA	GRB2	psi-mi:“MI:0915”(physical association)	0.680
PPP3CA	C16orf74	psi-mi:“MI:0915”(physical association)	0.670
C16orf74	PPP3CA	psi-mi:“MI:0915”(physical association)	0.670
RCAN1	PPP3CB	psi-mi:“MI:0914”(association)	0.660
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
KLRG2	GLRX3	psi-mi:“MI:0914”(association)	0.640
PPP3CA	Cacng8	psi-mi:“MI:0915”(physical association)	0.540
Cacng8	PPP3CA	psi-mi:“MI:0407”(direct interaction)	0.540
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530

BioGRID (238): JUN (Biochemical Activity), PPP3CA (Affinity Capture-Western), PPP3CA (Reconstituted Complex), JUN (Affinity Capture-Western), PPP3R1 (Two-hybrid), C16orf74 (Two-hybrid), PPP3CA (Affinity Capture-Western), PPP3CA (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), RCAN1 (Affinity Capture-MS), NFATC4 (Affinity Capture-MS), SIK3 (Affinity Capture-MS)

ESM2 similar proteins: A0A365, A0QHM5, A0QX51, A1KIW9, A4FIS6, B1W5F4, B8ZR76, O88956, P00165, P16298, P20651, P31350, P37273, P48452, P48453, P63328, P63329, P65263, P9WK98, P9WK99, Q06GW7, Q06RA2, Q08209, Q0G9I9, Q0G9T2, Q0ZIY9, Q1KXS9, Q2KJ61, Q2PMQ5, Q332U7, Q33C02, Q3C1M5, Q4R7Q7, Q4VZI6, Q5HZM6, Q5RIC0, Q5ZHS1, Q68RX7, Q6ENT4, Q6EW22

Diamond homologs: A0C1E4, A0CCD2, A0DJ90, G5EBX9, O04858, O14829, O14830, O35385, O35655, O74789, P14747, P16298, P20604, P20651, P23287, P26570, P32345, P32838, P32945, P33329, P34430, P36614, P40421, P48452, P48453, P48454, P48455, P48456, P48457, P48528, P48529, P49576, P53043, P63328, P63329, Q05681, Q08209, Q09496, Q0G819, Q10298

SIGNOR signaling

47 interactions.

A	Effect	B	Mechanism
CALM1	up-regulates	PPP3CA	binding
“cyclosporin A”	down-regulates	PPP3CA	“chemical inhibition”
“tacrolimus (anhydrous)”	down-regulates	PPP3CA	“chemical inhibition”
PPP3CA	up-regulates	NFATC1	dephosphorylation
PPP3CA	down-regulates	FLNA	dephosphorylation
calcium(2+)	up-regulates	PPP3CA	“chemical activation”
PPP3CA	up-regulates	NFATC2	dephosphorylation
PPP3CA	up-regulates	NFATC3	dephosphorylation
PPP3CA	up-regulates	NFATC4	dephosphorylation
PPP3CA	“up-regulates activity”	DNM1L	dephosphorylation
PPP3CA	“up-regulates activity”	NFATC2	dephosphorylation
PPP3CA	“up-regulates activity”	BAD	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 100 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
FCERI mediated Ca+2 mobilization	5	26.6×	2e-04
Infectious disease	11	4.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
calcineurin-NFAT signaling cascade	5	48.4×	2e-05
positive regulation of neuron apoptotic process	5	15.6×	1e-03
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	5	12.1×	3e-03
response to endoplasmic reticulum stress	5	9.6×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	19
Uncertain significance	243
Likely benign	249
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064702	NM_000944.5(PPP3CA):c.1299dup (p.Ser434fs)	Pathogenic
1064703	NM_000944.5(PPP3CA):c.1417G>T (p.Ala473Ser)	Pathogenic
1366464	NM_000944.5(PPP3CA):c.1251_1254del (p.Ser417fs)	Pathogenic
1703173	NM_000944.5(PPP3CA):c.1251_1252del (p.Ser417fs)	Pathogenic
2504846	NM_000944.5(PPP3CA):c.451C>G (p.His151Asp)	Pathogenic
2760879	NM_000944.5(PPP3CA):c.917T>G (p.Phe306Cys)	Pathogenic
2817196	NM_000944.5(PPP3CA):c.432_433del (p.Leu146fs)	Pathogenic
2819282	NM_000944.5(PPP3CA):c.1340-1G>C	Pathogenic
3236340	NM_000944.5(PPP3CA):c.1308_1312dup (p.Ser438fs)	Pathogenic
3252473	NM_000944.5(PPP3CA):c.274C>G (p.His92Asp)	Pathogenic
3727465	NM_000944.5(PPP3CA):c.1411G>T (p.Glu471Ter)	Pathogenic
3900639	NM_000944.5(PPP3CA):c.1354_1356delinsCAATA (p.Ile452fs)	Pathogenic
3900641	NM_000944.5(PPP3CA):c.1284_1287dup (p.Gly430fs)	Pathogenic
3900642	NM_000944.5(PPP3CA):c.1333_1336dup (p.Ser446fs)	Pathogenic
3900643	NM_000944.5(PPP3CA):c.1338dup (p.Ala447fs)	Pathogenic
3900644	NM_000944.5(PPP3CA):c.1255_1258dup (p.Val420fs)	Pathogenic
441271	NM_000944.5(PPP3CA):c.1333C>T (p.Gln445Ter)	Pathogenic
496636	NM_000944.5(PPP3CA):c.1255_1256del (p.Ser419fs)	Pathogenic
522802	NM_000944.5(PPP3CA):c.1308_1311dup (p.Ser438fs)	Pathogenic
599239	NM_000944.5(PPP3CA):c.1290dup (p.Met431fs)	Pathogenic
599240	NM_000944.5(PPP3CA):c.1408T>C (p.Phe470Leu)	Pathogenic
599241	NM_000944.5(PPP3CA):c.1417G>A (p.Ala473Thr)	Pathogenic
802080	NM_000944.5(PPP3CA):c.1311_1315del (p.Ser438fs)	Pathogenic
1343236	NM_000944.5(PPP3CA):c.34_43del (p.Ser12fs)	Likely pathogenic
1481076	NM_000944.5(PPP3CA):c.259+1G>T	Likely pathogenic
1525729	NM_000944.5(PPP3CA):c.1240A>G (p.Arg414Gly)	Likely pathogenic
1675951	NM_000944.5(PPP3CA):c.760A>G (p.Arg254Gly)	Likely pathogenic
1694451	NM_000944.5(PPP3CA):c.530C>G (p.Ala177Gly)	Likely pathogenic
2584523	NM_000944.5(PPP3CA):c.1341_1344del (p.Thr448fs)	Likely pathogenic
3340564	NM_000944.5(PPP3CA):c.480C>A (p.Phe160Leu)	Likely pathogenic

SpliceAI

4556 predictions. Top by Δscore:

Variant	Effect	Δscore
4:101040477:CCCA:C	donor_loss	1.0000
4:101040478:CCA:C	donor_loss	1.0000
4:101040479:CACCT:C	donor_loss	1.0000
4:101040480:ACC:A	donor_loss	1.0000
4:101040481:C:CG	donor_loss	1.0000
4:101040567:C:A	acceptor_loss	1.0000
4:101040576:C:CT	acceptor_gain	1.0000
4:101061076:AAG:A	donor_gain	1.0000
4:101061081:TCTTA:T	donor_loss	1.0000
4:101061082:CTTA:C	donor_loss	1.0000
4:101061083:TTA:T	donor_loss	1.0000
4:101061084:TAC:T	donor_loss	1.0000
4:101061085:A:AC	donor_gain	1.0000
4:101061085:A:AG	donor_loss	1.0000
4:101061085:AC:A	donor_gain	1.0000
4:101061086:C:CC	donor_gain	1.0000
4:101061086:CC:C	donor_gain	1.0000
4:101061086:CCAT:C	donor_gain	1.0000
4:101061157:AGTCA:A	acceptor_gain	1.0000
4:101061158:GTCA:G	acceptor_gain	1.0000
4:101061159:TCA:T	acceptor_gain	1.0000
4:101061159:TCAC:T	acceptor_loss	1.0000
4:101061160:CA:C	acceptor_gain	1.0000
4:101061160:CAC:C	acceptor_gain	1.0000
4:101061161:ACT:A	acceptor_loss	1.0000
4:101061162:C:CC	acceptor_gain	1.0000
4:101061162:CTA:C	acceptor_loss	1.0000
4:101061176:C:CT	acceptor_gain	1.0000
4:101080527:CTTA:C	donor_loss	1.0000
4:101080528:TTAC:T	donor_loss	1.0000

AlphaMissense

3449 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:101032311:A:T	L432H	1.000
4:101032338:A:G	L423P	1.000
4:101032364:T:A	R414S	1.000
4:101032364:T:G	R414S	1.000
4:101040485:A:G	L413P	1.000
4:101040485:A:T	L413H	1.000
4:101040493:G:C	F410L	1.000
4:101040493:G:T	F410L	1.000
4:101040495:A:G	F410L	1.000
4:101040503:G:T	A407D	1.000
4:101040504:C:G	A407P	1.000
4:101040506:A:C	M406R	1.000
4:101040506:A:T	M406K	1.000
4:101040512:C:T	G404D	1.000
4:101040515:A:T	I403K	1.000
4:101040519:C:G	A402P	1.000
4:101040521:C:G	R401P	1.000
4:101040524:A:C	I400S	1.000
4:101040524:A:G	I400T	1.000
4:101040524:A:T	I400N	1.000
4:101040526:C:A	K399N	1.000
4:101040526:C:G	K399N	1.000
4:101040528:T:C	K399E	1.000
4:101040536:A:T	I396K	1.000
4:101061137:A:G	L369P	1.000
4:101061137:A:T	L369H	1.000
4:101061149:A:G	L365P	1.000
4:101061149:A:T	L365Q	1.000
4:101061152:A:C	M364R	1.000
4:101061152:A:T	M364K	1.000

dbSNP variants (sampled 300 via entrez): RS1000024573 (4:101348336 A>G), RS1000027306 (4:101194572 T>C), RS1000037151 (4:101087055 A>C,G), RS1000038684 (4:101034811 A>G), RS1000051180 (4:101110285 T>G), RS1000053809 (4:101269142 C>T), RS1000059869 (4:101194774 C>A), RS1000064200 (4:101124394 A>G), RS1000079949 (4:101218721 G>A), RS1000083003 (4:101236215 A>G), RS1000084291 (4:101067192 A>C), RS1000090025 (4:101327834 T>C), RS1000092647 (4:101303277 T>C), RS1000092886 (4:101349407 C>T), RS1000103015 (4:101109960 A>C)

Disease associations

OMIM: gene MIM:114105 | disease phenotypes: MIM:617711, MIM:618265

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 91	Strong	Autosomal dominant
arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development	Strong	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
developmental and epileptic encephalopathy	Definitive	AD

Mondo (6): developmental and epileptic encephalopathy 91 (MONDO:0020630), arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (MONDO:0032642), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (3): Craniosynostosis-microretrognathia-severe intellectual disability syndrome (Orphanet:565858), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

90 total (30 of 90 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0000883	Thin ribs
HP:0000954	Single transverse palmar crease
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001261_5	Corneal structure	4.000000e-06
GCST001598_1	Blood pressure	9.000000e-07
GCST001598_2	Blood pressure	8.000000e-08
GCST002354_2	Anorexia nervosa	6.000000e-06
GCST004785_14	Vitiligo	3.000000e-08
GCST007576_161	Chronotype	3.000000e-09
GCST008154_71	Trunk fat mass	6.000000e-06
GCST008524_17	Bitter non-alcoholic beverage consumption	2.000000e-06
GCST010988_231	Adult body size	5.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0010093	bitter non-alcoholic beverage consumption measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4445 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 846,504 (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
CHEMBL1200679	ZINC CHLORIDE	4	411,454
CHEMBL160	CYCLOSPORINE	4	168,247
CHEMBL269732	TACROLIMUS ANHYDROUS	4	95,168
CHEMBL83	TAMOXIFEN	4	171,635

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3730251	PPP3CA		0.00	0

ChEMBL bioactivities

36 potent at pChembl≥5 of 38 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.55	IC50	2.8	nM	CHEMBL407332
8.40	Kd	4	nM	CYCLOSPORINE
8.40	IC50	3.96	nM	CHEMBL266705
8.38	IC50	4.17	nM	CHEMBL268110
8.31	IC50	4.93	nM	CHEMBL405917
8.23	IC50	5.85	nM	CHEMBL412791
8.14	IC50	7.25	nM	CHEMBL65863
8.14	IC50	7.2	nM	CHEMBL406186
8.13	IC50	7.32	nM	CHEMBL264568
8.10	IC50	7.91	nM	CHEMBL275103
8.06	IC50	8.7	nM	CHEMBL305081
8.06	IC50	8.65	nM	CHEMBL431368
7.85	IC50	14	nM	CHEMBL263032
7.83	IC50	14.8	nM	TACROLIMUS ANHYDROUS
7.70	Kd	20	nM	TACROLIMUS ANHYDROUS
7.31	IC50	49	nM	CHEMBL1213211
7.12	IC50	75	nM	CHEMBL1213211
7.05	IC50	89	nM	CHEMBL1213210
6.87	IC50	135	nM	CHEMBL1213210
6.85	IC50	140	nM	CHEMBL1213205
6.74	IC50	183	nM	CYCLOSPORINE
6.52	Kd	300	nM	CHEMBL407550
6.46	Kd	350	nM	CHEMBL421507
6.46	IC50	348	nM	CHEMBL412946
6.45	IC50	358	nM	CHEMBL1213205
6.44	IC50	363	nM	CHEMBL269260
6.24	IC50	581	nM	CHEMBL384316
6.20	IC50	636	nM	CHEMBL413883
6.13	IC50	742	nM	CHEMBL387036
6.08	IC50	840	nM	CHEMBL405486
6.05	IC50	890	nM	CHEMBL411789
5.96	IC50	1100	nM	ZINC CHLORIDE
5.85	IC50	1400	nM	CHEMBL1213210
5.81	IC50	1539	nM	CHEMBL216652
5.72	IC50	1916	nM	CHEMBL387036
5.67	IC50	2147	nM	CHEMBL412946

PubChem BioAssay actives

31 with measured affinity, of 79 total; 25 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
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-1-[(3R,4R)-4-[(2S)-2-hydroxy-2-naphthalen-2-ylethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0028	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(3R,4R)-4-[(2R)-2-(1-benzothiophen-2-yl)-2-hydroxyethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0040	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(3R,4R)-4-[(2S)-2-(1-benzothiophen-2-yl)-2-hydroxyethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0042	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-1-[(3R,4R)-4-[(2S)-2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0049	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-1-[(3R,4R)-4-[(2R)-2-hydroxy-2-[3-(trifluoromethyl)phenyl]ethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0059	uM
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-12-[(E)-1-[(1R,3R,4R)-3-methoxy-4-(2-phenylethoxy)cyclohexyl]prop-1-en-2-yl]-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45443: Concentration required for inhibition of serine/threonine protein phosphatase calcineurin (CAN)	ic50	0.0072	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-1-[(3R,4R)-4-[(2R)-2-hydroxy-2-naphthalen-2-ylethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0073	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(3R,4R)-4-[(2S)-2-(3,4-difluorophenyl)-2-hydroxyethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0073	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(3R,4R)-4-[(2S)-2-(3,5-dimethylphenyl)-2-hydroxyethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0079	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(3R,4R)-4-[(2R)-2-(3,4-difluorophenyl)-2-hydroxyethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0086	uM
(1R,9S,12S,13R,14R,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(3R,4R)-4-[(2R)-2-(3,5-dimethylphenyl)-2-hydroxyethoxy]-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0087	uM
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-12-[(E)-1-[(1R,3R,4R)-3-methoxy-4-(3-phenylpropoxy)cyclohexyl]prop-1-en-2-yl]-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone	45443: Concentration required for inhibition of serine/threonine protein phosphatase calcineurin (CAN)	ic50	0.0140	uM
Tacrolimus	45444: Inhibitory activity against Calcineurin (CaN phosphatase)	ic50	0.0148	uM
2-[[(2R,5S,8S,11S,14S,17S,23S,26S,29S,32S)-17-ethyl-14-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-4,7,10,13,19,22,28,32-octamethyl-5,8,23,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-11,26-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]methoxy]-N-(4-phenyldiazenylphenyl)acetamide	497678: Inhibition of calcineurin-mediated NFAT activation in human Jurkat cells measured after 45 min of irradiation with 740 nm light by luciferase reporter gene assay	ic50	0.0490	uM
5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[4-[[4-[[2-[[(2R,5S,8S,11S,14S,17S,23S,26S,29S,32S)-17-ethyl-14-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-4,7,10,13,19,22,28,32-octamethyl-5,8,23,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-11,26-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]methoxy]acetyl]amino]phenyl]diazenyl]phenyl]pentanamide	497678: Inhibition of calcineurin-mediated NFAT activation in human Jurkat cells measured after 45 min of irradiation with 740 nm light by luciferase reporter gene assay	ic50	0.0890	uM
2-[[(2R,5S,8S,11S,14S,17S,23S,26S,29S,32S)-17-ethyl-14-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-4,7,10,13,19,22,28,32-octamethyl-5,8,23,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-11,26-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]methoxy]-N-[4-[[4-[[2-[[(2R,5S,8S,11S,14S,17S,23S,26S,29S,32S)-17-ethyl-14-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-4,7,10,13,19,22,28,32-octamethyl-5,8,23,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-11,26-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]methoxy]acetyl]amino]phenyl]diazenyl]phenyl]acetamide	497678: Inhibition of calcineurin-mediated NFAT activation in human Jurkat cells measured after 45 min of irradiation with 740 nm light by luciferase reporter gene assay	ic50	0.1400	uM
cyclosporine	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	0.1830	uM
methylsulfanylmethyl (E,5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhex-2-enoate	45449: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay (morn)	ic50	0.3480	uM
ethyl (E,5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhex-2-enoate	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	0.3630	uM
methyl (E,5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhex-2-enoate	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	0.5810	uM
2-fluoroethyl (E,5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhex-2-enoate	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	0.6360	uM
methoxymethyl (E,5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhex-2-enoate	45449: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay (morn)	ic50	0.7420	uM
ethyl (5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhexanoate	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	0.8400	uM
methyl (5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhexanoate	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	0.8900	uM
2-fluoroethyl (5R,6R)-6-[(2S,5R,11S,14S,17R,20R,23S,26S,29S,32R)-5-ethyl-1,7,10,16,20,23,25,28,31-nonamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-6-hydroxy-5-methylhexanoate	45446: Compound was evaluated for its inhibitory activity in a calcineurin inhibition assay	ic50	1.5390	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	5
Fluorouracil	increases expression, affects response to substance, affects cotreatment	4
Valproic Acid	increases expression, affects expression, decreases methylation	3
Cadmium Chloride	decreases expression, increases expression	3
bisphenol F	affects cotreatment, decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2
Irinotecan	affects cotreatment, increases expression, decreases expression, affects response to substance	2
Acetaminophen	increases expression	2
Air Pollutants	increases abundance, increases oxidation, affects expression, affects cotreatment	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Quercetin	affects binding, decreases activity, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases methylation	2
Thapsigargin	decreases activity, decreases response to substance, decreases phosphorylation, increases reaction, increases cleavage (+1 more)	2
aristolochic acid I	decreases expression	1
tylophorine	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	increases expression	1
1,2,3-trichloropropane	increases activity, increases cleavage	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
cypermethrin	decreases activity, decreases response to substance	1
sodium arsenite	affects methylation	1
4-hydroxy-2-nonenal	decreases expression	1
dan-shen root extract	decreases reaction, increases expression	1
chlorendic acid	increases activity, increases cleavage	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1

ChEMBL screening assays

24 unique, capped per target: 24 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1220314	Binding	Inhibition of calcineurin-mediated NFAT activation in human Jurkat cells by luciferase reporter gene assay	Augmented photoswitching modulates immune signaling. — Nat Chem Biol

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2BZ	Abcam HeLa PPP3CA KO	Cancer cell line	Female
CVCL_D9P8	Ubigene HEK293 PPP3CA KO	Transformed cell line	Female
CVCL_E0LJ	Ubigene HeLa PPP3CA KO	Cancer cell line	Female
CVCL_TG14	HAP1 PPP3CA (-) 1	Cancer cell line	Male
CVCL_TG15	HAP1 PPP3CA (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder