PPP3CA

protein phosphatase 3 catalytic subunit alpha, the group of MicroRNA protein coding host genes|Protein phosphatase catalytic subunits

Basic information

Region (hg38): 4:101023409-101348278

Previous symbols: [ "CALN", "CALNA" ]

Links

ENSG00000138814 ∙ NCBI:5530 ∙ OMIM:114105 ∙ HGNC:9314 ∙ Uniprot:Q08209 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• epileptic encephalopathy, infantile or early childhood, 1 (Moderate), mode of inheritance: AD
• arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (Limited), mode of inheritance: AD
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (Supportive), mode of inheritance: AD
• epileptic encephalopathy, infantile or early childhood, 1 (Strong), mode of inheritance: AD
• arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 91; Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Musculoskeletal; Neurologic	28942967; 29432562

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PPP3CA gene.

• Epileptic encephalopathy, infantile or early childhood, 1 (9 variants)
• not provided (8 variants)
• Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (2 variants)
• Intellectual disability;Seizure (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PPP3CA gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	109	4	115
missense	7	6	133	5		151
nonsense		1				1
start loss						0
frameshift	8	5		1		14
inframe indel			6			6
splice donor/acceptor (+/-2bp)	1	2				3
splice region			17	20	1	38
non coding			8	61	26	95
Total	16	14	149	176	30

Variants in PPP3CA

This is a list of pathogenic ClinVar variants found in the PPP3CA region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-101025791-T-C			Benign (May 15, 2021)
4-101025820-CA-C			Benign (May 14, 2021)
4-101025820-CAA-C			Benign (May 14, 2021)
4-101025820-CAAA-C			Benign (May 14, 2021)
4-101025857-G-A		PPP3CA-related disorder	Benign (Jun 20, 2019)
4-101025858-G-T			Benign (Aug 01, 2024)
4-101025868-C-T			Likely benign (Dec 13, 2023)
4-101025871-A-C			Uncertain significance (Nov 08, 2022)
4-101025872-A-C			Uncertain significance (Jul 10, 2023)
4-101025875-TTGC-T			Uncertain significance (Dec 14, 2022)
4-101025880-G-A			Likely benign (May 15, 2023)
4-101025887-C-T		Developmental disorder	Likely benign (Mar 04, 2021)
4-101025890-C-CCATTGCTGT			Uncertain significance (Mar 11, 2022)
4-101025892-A-G			Likely benign (Jan 09, 2023)
4-101025893-T-C		Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development;Epileptic encephalopathy, infantile or early childhood, 1	Uncertain significance (Oct 29, 2023)
4-101025893-T-TTGCTGTCC		Autism spectrum disorder	Likely benign (Nov 19, 2020)
4-101025901-C-T			Likely benign (Jan 02, 2024)
4-101025902-G-A			Uncertain significance (Dec 13, 2021)
4-101025903-T-A			Uncertain significance (Apr 10, 2022)
4-101025904-G-A			Uncertain significance (May 02, 2023)
4-101025906-C-T			Uncertain significance (Nov 15, 2022)
4-101025907-G-A			Likely benign (Dec 18, 2023)
4-101025918-A-G		Epileptic encephalopathy, infantile or early childhood, 1	Uncertain significance (-)
4-101025922-G-A			Likely benign (Oct 22, 2023)
4-101025932-T-TTGA			Uncertain significance (Oct 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PPP3CA	protein_coding	protein_coding	ENST00000394854	14	324870

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000121	120544	0	4	120548	0.0000166

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.63	112	284	0.394	0.0000147	3436
Missense in Polyphen		16	104.04	0.15379		1251
Synonymous	0.0834	101	102	0.990	0.00000523	961
Loss of Function	4.91	1	30.1	0.0333	0.00000167	363

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000143	0.000143
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:15671020, PubMed:18838687, PubMed:19154138, PubMed:23468591). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (PubMed:17498738, PubMed:17502104, PubMed:23468591, PubMed:27974827, PubMed:22343722). In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (PubMed:15671020). In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (PubMed:18838687). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation (PubMed:26248042). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138). {ECO:0000250|UniProtKB:P48452, ECO:0000269|PubMed:15671020, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:17502104, ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:23468591, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:28942967}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Oxytocin signaling pathway - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Axon guidance - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Renin secretion - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Tacrolimus/Cyclosporine Pathway, Pharmacodynamics;Physiological and Pathological Hypertrophy of the Heart;Energy Metabolism;MicroRNAs in cardiomyocyte hypertrophy;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Alzheimers Disease;Spinal Cord Injury;Amyotrophic lateral sclerosis (ALS);T-Cell Receptor and Co-stimulatory Signaling;Cardiac Hypertrophic Response;Serotonin and anxiety;Initiation of transcription and translation elongation at the HIV-1 LTR;G Protein Signaling Pathways;MAPK Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Mitochondrial Gene Expression;Serotonin and anxiety-related events;Wnt Signaling Pathway;Signaling by GPCR;Signaling by WNT;Signal Transduction;regulation of pgc-1a;regulation of ck1/cdk5 by type 1 glutamate receptors;nitric oxide signaling pathway;endocytotic role of ndk phosphins and dynamin;role of mef2d in t-cell apoptosis;effects of calcineurin in keratinocyte differentiation;nfat and hypertrophy of the heart ;signaling pathway from g-protein families;t cell receptor signaling pathway;bcr signaling pathway;Calcineurin activates NFAT;Signaling by the B Cell Receptor (BCR);CLEC7A (Dectin-1) induces NFAT activation;CLEC7A (Dectin-1) signaling;C-type lectin receptors (CLRs);FCERI mediated Ca+2 mobilization;Fc epsilon receptor (FCERI) signaling;Innate Immune System;Immune System;Adaptive Immune System;Downstream signaling events of B Cell Receptor (BCR);DARPP-32 events;Ca2+ pathway;Beta-catenin independent WNT signaling;fmlp induced chemokine gene expression in hmc-1 cells;BCR signaling pathway;C-MYB transcription factor network;Opioid Signalling;G alpha (i) signalling events;GPCR downstream signalling;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.303

Intolerance Scores

• loftool: 0.0811
• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.15

Haploinsufficiency Scores

• pHI: 0.915
• hipred: Y
• hipred_score: 0.825
• ghis: 0.634

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Ppp3ca
• Phenotype: renal/urinary system phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;response to amphetamine;protein dephosphorylation;protein import into nucleus;calcium ion transport;Wnt signaling pathway, calcium modulating pathway;brain development;transition between fast and slow fiber;cardiac muscle hypertrophy in response to stress;dephosphorylation;positive regulation of cell migration;calcineurin-NFAT signaling cascade;multicellular organismal response to stress;negative regulation of chromatin binding;cellular response to drug;Fc-epsilon receptor signaling pathway;T cell activation;skeletal muscle tissue regeneration;positive regulation of cell adhesion;positive regulation of endocytosis;positive regulation of transcription by RNA polymerase II;negative regulation of insulin secretion;skeletal muscle fiber development;negative regulation of dendrite morphogenesis;positive regulation of DNA-binding transcription factor activity;response to calcium ion;excitatory postsynaptic potential;positive regulation of calcineurin-NFAT signaling cascade;cellular response to glucose stimulus;calcineurin-mediated signaling;postsynaptic modulation of chemical synaptic transmission;positive regulation of cardiac muscle hypertrophy in response to stress;negative regulation of production of miRNAs involved in gene silencing by miRNA;positive regulation of connective tissue replacement
• Cellular component: nucleoplasm;cytoplasm;mitochondrion;cytosol;calcineurin complex;cytoplasmic side of plasma membrane;Z disc;slit diaphragm;sarcolemma;dendritic spine;Schaffer collateral - CA1 synapse;glutamatergic synapse
• Molecular function: protein serine/threonine phosphatase activity;calcium ion binding;protein binding;calmodulin binding;drug binding;cyclosporin A binding;enzyme binding;calmodulin-dependent protein phosphatase activity;protein heterodimerization activity;protein dimerization activity