PPP3R1

Summary

PPP3R1 (protein phosphatase 3 regulatory subunit B, alpha, HGNC:9317) is a protein-coding gene on chromosome 2p14, encoding Calcineurin subunit B type 1 (P63098). Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase.

Enables phosphatase binding activity and protein domain specific binding activity. Involved in calcineurin-NFAT signaling cascade and positive regulation of transcription by RNA polymerase II. Part of calcineurin complex. Implicated in Alzheimer’s disease and dilated cardiomyopathy.

Source: NCBI Gene 5534 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss 58 (Limited, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 15 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000945

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9317
Approved symbol	PPP3R1
Name	protein phosphatase 3 regulatory subunit B, alpha
Location	2p14
Locus type	gene with protein product
Status	Approved
Aliases	CALNB1, CNB, CNB1
Ensembl gene	ENSG00000221823
Ensembl biotype	protein_coding
OMIM	601302
Entrez	5534

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000234310, ENST00000409377, ENST00000409752

RefSeq mRNA: 1 — MANE Select: NM_000945 NM_000945

CCDS: CCDS46310

Canonical transcript exons

ENST00000234310 — 6 exons

Exon	Start	End
ENSE00001191356	68252125	68252532
ENSE00001191364	68178857	68181010
ENSE00003601764	68217092	68217131
ENSE00003702498	68187255	68187314
ENSE00003707678	68186468	68186652
ENSE00003710215	68188514	68188690

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 97.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 91.9297 / max 1416.7447, expressed in 1826 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28859	84.2436	1826
28860	3.4530	1357
28863	2.5634	939
28861	1.2800	624
28862	0.3897	174

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	97.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.08	gold quality
nucleus accumbens	UBERON:0001882	96.90	gold quality
calcaneal tendon	UBERON:0003701	96.84	gold quality
right frontal lobe	UBERON:0002810	96.54	gold quality
monocyte	CL:0000576	96.31	gold quality
caudate nucleus	UBERON:0001873	96.29	gold quality
prefrontal cortex	UBERON:0000451	96.18	gold quality
putamen	UBERON:0001874	96.03	gold quality
cerebellar hemisphere	UBERON:0002245	95.82	gold quality
cerebellar cortex	UBERON:0002129	95.81	gold quality
mononuclear cell	CL:0000842	95.58	gold quality
leukocyte	CL:0000738	95.51	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.51	gold quality
amygdala	UBERON:0001876	95.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.81	gold quality
cingulate cortex	UBERON:0003027	94.70	gold quality
anterior cingulate cortex	UBERON:0009835	94.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.40	gold quality
colonic epithelium	UBERON:0000397	94.30	gold quality
ganglionic eminence	UBERON:0004023	94.15	gold quality
stromal cell of endometrium	CL:0002255	94.12	gold quality
cerebellum	UBERON:0002037	93.88	gold quality
islet of Langerhans	UBERON:0000006	93.72	gold quality
pons	UBERON:0000988	93.12	gold quality
muscle of leg	UBERON:0001383	92.97	gold quality
gastrocnemius	UBERON:0001388	92.65	gold quality
neocortex	UBERON:0001950	92.41	gold quality
telencephalon	UBERON:0001893	92.40	gold quality
frontal cortex	UBERON:0001870	92.06	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.67
E-MTAB-7316	no	590.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

336 targeting PPP3R1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
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-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-181A-5P	99.99	72.96	2995

Literature-anchored findings (GeneRIF, showing 29)

• these data imply novel functions of calcineurin and NF-kappaB for successful IS maturation. (PMID:17038582)
• Endothelin 1 (ET-1) activates calcineurin and causes nuclear translocation of NFATc1, implicating the pathway in the ET-1-mediated stimulation of osteoblasts. (PMID:17237284)
• IGF-1/PPP3R1 gene polymorphisms influence muscle phenotypic responses to strength training in both black and white older men and women. (PMID:17761791)
• Data show that the calcineurin pathway is activated in hypertrophic myocardium as demonstrated by increased calcineurin activity and expression of calcineurin A-beta and B, and GATA-4, and a shift of cytoplasmic NFAT-3 into the nucleus. (PMID:18034994)
• analysis of the secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin binding (PMID:18296442)
• No significant differences in calcineurin b expression was observed between patients with schizophrenia and normal controls (PMID:18343007)
• Overexpression of calcineurin B subunit enhances the oncogenic potential of HEK293 cells (PMID:18422742)
• Study found that although calcineurin/NFAT signalling pathway has an important, non-redundant role in the regulation of lymphocyte developmental checkpoints, it is not essential for the development of blood myeloid lineages. (PMID:18818667)
• CNB gene 5I/5D polymorphism is associated with the risk of left ventricular hypertrophy and physical performance of athletes. (PMID:18825932)
• A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants. (PMID:19285944)
• Data suggest an association between polymorphisms in PPP3CA, PPP3R1 and PPP3R2 and baseline levels or trainability of endurance phenotype traits. (PMID:20107831)
• CNB binds to proteasome subunit alpha type 7 (PSMA7) and inhibits the transactivation activity of hypoxia-inducible factor-1alpha (HIF-1alpha) via the proteasome pathway. (PMID:21256111)
• Findings demonstrate that CaN functions as a critical signaling molecule during Th cell activation, regulating Bcl-10 phosphorylation and NF-kappaB activation. (PMID:21674474)
• immunostimulatory protein and acts as a vaccine adjuvant inducing protective cellular and humoral responses against pneumococcal infection (PMID:21722668)
• CnB M118K fails to enhance the activities of NF-AT and p53 induced by CnA in HeLa-s cells. (PMID:21910968)
• These findings reveal a novel signaling pathway (CnB-CD11b-NF-kappaB-TRAIL) regulating TRAIL expression and may help to understand the roles of the calcineurin B subunit in the regulation of innate immunity. (PMID:22197822)
• Pancreatic beta cells lacking Cnb1 fail to express genes revealed to be direct NFAT targets required for replication, insulin storage, and secretion. (PMID:22814600)
• Further evidence that specific variations in MAPT (rs3785883) and PPP3R1 (rs1868402) are associated with accelerated progression of Alzheimer’s disease (PMID:23727081)
• Expression level of PPP3R1 and GATA4, and NFATC4 genes for transcription factors did not differ in studied subgroups of patients. (PMID:23888774)
• Data (including data from micro-dissected trophoblasts and trophoblastic BeWo cell line) suggest that microRNA-512-3p participates in placental function by targeting PPP3R1, encoding a regulatory subunit of calcineurin B. (PMID:24246042)
• CnB is a novel host-derived immunostimulatory factor, having a role as an agonist in monocytes, and specificity in TLR4 signaling through TRAF3 and TRAF6, in response to various agonists. (PMID:26471241)
• we report that exogenous CnB is taken up by cells in a time- and concentration-dependent manner via clathrin-dependent receptor-mediated internalization. Our findings further confirm that uptake is mediated by the TLR4/MD2 complex together with the co-receptor CD14 (PMID:27090571)
• The mRNA expressions of PPP3CB and MEF2C were significantly up-regulated, and CAMK1 and PPP3R1 were significantly down-regulated in mitral regurgitation(MR) patients compared to normal subjects. Moreover, MR patients had significantly increased mRNA levels of PPP3CB, MEF2C and PLCE1 compared to aortic valve disease patients (PMID:27907007)
• The CnB 5I/5D variation was found to be significantly associated with CAD. The 5-base pair deletion results in increased serum calcineurin levels. (PMID:28827117)
• expression of PPP3R1 decreased respectively in psoriatic lesions and HaCaT cells. (PMID:29181737)
• iTRAQ results show that let-7e is associated with the expression of anti-viral proteins. What’s more, calcineurin subunit B type 1, an anti-tumor factor, is upregulated by let-7e after LPS stimulation (PMID:29505169)
• A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58. (PMID:32337552)
• The CnB1 p.D102A variant is linked to dilated cardiomyopathy via impaired Calcineurin activity. (PMID:32882262)
• PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca[2+] Influx. (PMID:36901851)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp3r1a	ENSDARG00000092659
mus_musculus	Ppp3r1	ENSMUSG00000033953
rattus_norvegicus		ENSRNOG00000065686
drosophila_melanogaster	CanB	FBGN0010014
drosophila_melanogaster	CanB2	FBGN0015614
caenorhabditis_elegans		WBGENE00000554

Paralogs (8): TESC (ENSG00000088992), CIB2 (ENSG00000136425), CIB3 (ENSG00000141977), CIB4 (ENSG00000157884), CHP2 (ENSG00000166869), CIB1 (ENSG00000185043), CHP1 (ENSG00000187446), PPP3R2 (ENSG00000188386)

Protein

Protein identifiers

Calcineurin subunit B type 1 — P63098 (reviewed: P63098)

Alternative names: Protein phosphatase 2B regulatory subunit 1, Protein phosphatase 3 regulatory subunit B alpha isoform 1

All UniProt accessions (3): D3YTA9, P63098, F6U1T9

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.

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). Interacts with catalytic subunit PPP3CA/calcineurin A. Interacts with catalytic subunit PPP3CB/calcineurin A. Interacts with CIB1 (via C-terminal region); the interaction increases upon cardiomyocyte hypertrophy. Interacts with RCAN1. Interacts with SPATA33 (via PQIIIT motif).

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Sarcolemma.

Miscellaneous. This protein has four functional calcium-binding sites. Although African swine fever virus infects pigs and not humans, human PPP3R1 and PPP3CA have been used for the crystallization. PPP3CA and PPP3R1 interact 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.

Similarity. Belongs to the calcineurin regulatory subunit family.

RefSeq proteins (1): NP_000936* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site

Pfam: PF13499

UniProt features (50 total): binding site 20, helix 13, strand 6, domain 4, site 2, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
4F0Z	X-RAY DIFFRACTION	1.7
6NUC	X-RAY DIFFRACTION	1.9
6NUF	X-RAY DIFFRACTION	1.9
3LL8	X-RAY DIFFRACTION	2
9NXE	X-RAY DIFFRACTION	2.09
1AUI	X-RAY DIFFRACTION	2.1
9NXN	X-RAY DIFFRACTION	2.1
4OR9	X-RAY DIFFRACTION	2.23
2P6B	X-RAY DIFFRACTION	2.3
6NUU	X-RAY DIFFRACTION	2.3
7U0T	X-RAY DIFFRACTION	2.45
5SVE	X-RAY DIFFRACTION	2.6
4ORC	X-RAY DIFFRACTION	2.7
4ORA	X-RAY DIFFRACTION	2.75
1M63	X-RAY DIFFRACTION	2.8
1MF8	X-RAY DIFFRACTION	3.1
9NXF	X-RAY DIFFRACTION	3.13
9CHU	ELECTRON MICROSCOPY	3.49
9B9G	ELECTRON MICROSCOPY	3.5
9CHX	ELECTRON MICROSCOPY	3.5
9CHV	ELECTRON MICROSCOPY	3.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63098-F1	91.48	0.81

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): 118 (interaction with pxvp motif in substrates of the catalytic subunit); 122 (interaction with pxvp motif in substrates of the catalytic subunit)

Ligand- & substrate-binding residues (20): 37; 42; 63; 65; 67; 69; 74; 100; 102; 104; 106; 111 …

Post-translational modifications (2): 106, 2

Function

Pathways and Gene Ontology

Reactome pathways

25 pathways

ID	Pathway
R-HSA-111447	Activation of BAD and translocation to mitochondria
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
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-111885	Opioid Signalling
R-HSA-114452	Activation of BH3-only proteins
R-HSA-1168372	Downstream signaling events of B Cell Receptor (BCR)
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-195721	Signaling by WNT
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling
R-HSA-372790	Signaling by GPCR
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-388396	GPCR downstream signalling
R-HSA-418594	G alpha (i) signalling events
R-HSA-5357801	Programmed Cell Death
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5621481	C-type lectin receptors (CLRs)
R-HSA-983705	Signaling by the B Cell Receptor (BCR)

MSigDB gene sets: 411 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, KEGG_MAPK_SIGNALING_PATHWAY, chr2p14, GOBP_LUNG_CELL_DIFFERENTIATION, GOBP_GLIAL_CELL_DEVELOPMENT, IVANOVA_HEMATOPOIESIS_MATURE_CELL, PID_NFAT_3PATHWAY

GO Biological Process (16): branching involved in blood vessel morphogenesis (GO:0001569), epithelial to mesenchymal transition (GO:0001837), protein import into nucleus (GO:0006606), heart development (GO:0007507), myelination in peripheral nervous system (GO:0022011), calcineurin-NFAT signaling cascade (GO:0033173), positive regulation of transcription by RNA polymerase II (GO:0045944), lung epithelial cell differentiation (GO:0060487), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886), regulation of synaptic vesicle cycle (GO:0098693), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), postsynaptic modulation of chemical synaptic transmission (GO:0099170), positive regulation of calcium ion import across plasma membrane (GO:1905665), negative regulation of calcium ion import across plasma membrane (GO:1905949), Schwann cell development (GO:0014044), protein localization to nucleus (GO:0034504)

GO Molecular Function (9): calcium-dependent protein serine/threonine phosphatase activity (GO:0004723), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), calcium-dependent protein serine/threonine phosphatase regulator activity (GO:0008597), phosphatase binding (GO:0019902), protein domain specific binding (GO:0019904), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): nucleoplasm (GO:0005654), cytosol (GO:0005829), calcineurin complex (GO:0005955), protein serine/threonine phosphatase complex (GO:0008287), sarcolemma (GO:0042383), Schaffer collateral - CA1 synapse (GO:0098685), hippocampal mossy fiber to CA3 synapse (GO:0098686), parallel fiber to Purkinje cell synapse (GO:0098688), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Immune System	2
Signal Transduction	2
Activation of BH3-only proteins	1
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
Programmed Cell Death	1
Apoptosis	1
G alpha (i) signalling events	1
Intrinsic Pathway for Apoptosis	1
Signaling by the B Cell Receptor (BCR)	1
Innate Immune System	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
synapse	3
calcium ion import across plasma membrane	2
regulation of calcium ion import across plasma membrane	2
protein binding	2
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
mesenchymal cell differentiation	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
animal organ development	1
circulatory system development	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
calcineurin-mediated signaling	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
epithelial cell differentiation	1
lung epithelium development	1
lung cell differentiation	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
positive regulation of calcineurin-mediated signaling	1
regulation of vesicle-mediated transport	1
synaptic vesicle cycle	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
modulation of chemical synaptic transmission	1
postsynapse	1
positive regulation of calcium ion import	1
positive regulation of calcium ion transmembrane transport	1
negative regulation of calcium ion import	1
negative regulation of calcium ion transmembrane transport	1
Schwann cell differentiation	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

151 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
PPP3CA	PPP3R1	psi-mi:“MI:0915”(physical association)	0.830
PPP3CA	PPP3R1	psi-mi:“MI:0914”(association)	0.830
PPP3R1	PPP3CA	psi-mi:“MI:0915”(physical association)	0.830
PPP3CA	PPP3R1	psi-mi:“MI:0915”(physical association)	0.820
PPP3CA	PPP3R1	psi-mi:“MI:0407”(direct interaction)	0.820
PPP3CC	PPP3R1	psi-mi:“MI:0915”(physical association)	0.800
GSK3A	AXIN1	psi-mi:“MI:0914”(association)	0.800
AKAP5	PRKAR2A	psi-mi:“MI:0915”(physical association)	0.760
RCAN1	PPP3CB	psi-mi:“MI:0914”(association)	0.660
CRTC2	PPP3CC	psi-mi:“MI:0914”(association)	0.640
ESS2	ACADS	psi-mi:“MI:0914”(association)	0.640
KLRG2	GLRX3	psi-mi:“MI:0914”(association)	0.640

BioGRID (115): PPP3R1 (Two-hybrid), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Two-hybrid), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS)

ESM2 similar proteins: G5EDN6, O73761, P0CM54, P0CM55, P21457, P22728, P25296, P28470, P29104, P34057, P35243, P35332, P42322, P43080, P43081, P46065, P48451, P61022, P61023, P62760, P62761, P62762, P62763, P62764, P63098, P63099, P63100, P79880, P87072, Q24214, Q2TBI5, Q4R5F7, Q54MF3, Q55G87, Q5R6S5, Q5R7F0, Q5RD22, Q63810, Q63811, Q6BWS8

Diamond homologs: A0PJX0, B1A8Z2, C7A276, C7A278, G5EDN6, O75838, P28470, P63098, P63099, P63100, Q0IQB6, Q0P523, Q17QE5, Q2TBI5, Q3HRN8, Q3HRN9, Q568Z7, Q63810, Q63811, Q6CGE6, Q6PC72, Q7XC27, Q96LZ3, Q96Q77, Q99828, Q9D9N5, Q9LTB8, Q9R010, Q9W2Q5, Q9Z0F4, Q9Z309, O81223, O81445, P06707, P06708, P0CM54, P0CM55, P25296, P29290, P29291

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PPP3R1	“form complex”	Calcineurin	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 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
DARPP-32 events	6	38.6×	2e-06
FCERI mediated Ca+2 mobilization	5	24.1×	2e-04
Opioid Signalling	5	17.9×	8e-04
Integration of energy metabolism	5	11.9×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
calcineurin-NFAT signaling cascade	7	54.6×	1e-08
skeletal muscle fiber development	5	25.2×	2e-04
response to calcium ion	5	14.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1534 predictions. Top by Δscore:

Variant	Effect	Δscore
2:68186462:ACTT:A	donor_loss	1.0000
2:68186464:TTACA:T	donor_loss	1.0000
2:68186465:T:TG	donor_loss	1.0000
2:68186465:TACAG:T	donor_loss	1.0000
2:68186466:A:AC	donor_gain	1.0000
2:68186466:A:AT	donor_loss	1.0000
2:68186466:AC:A	donor_loss	1.0000
2:68186466:ACAG:A	donor_gain	1.0000
2:68186467:C:A	donor_loss	1.0000
2:68186467:C:CA	donor_gain	1.0000
2:68186467:CA:C	donor_gain	1.0000
2:68186467:CAG:C	donor_gain	1.0000
2:68186467:CAGC:C	donor_gain	1.0000
2:68186467:CAGCA:C	donor_gain	1.0000
2:68186648:AGCAA:A	acceptor_gain	1.0000
2:68186649:GCAA:G	acceptor_gain	1.0000
2:68186650:CAA:C	acceptor_gain	1.0000
2:68186650:CAAC:C	acceptor_gain	1.0000
2:68186651:AA:A	acceptor_gain	1.0000
2:68186651:AACTA:A	acceptor_loss	1.0000
2:68186652:AC:A	acceptor_loss	1.0000
2:68186652:ACTAA:A	acceptor_loss	1.0000
2:68186653:C:CC	acceptor_gain	1.0000
2:68186653:C:T	acceptor_loss	1.0000
2:68187249:ACTT:A	donor_loss	1.0000
2:68187250:CTTA:C	donor_loss	1.0000
2:68187251:TTAC:T	donor_loss	1.0000
2:68187251:TTACA:T	donor_loss	1.0000
2:68187252:TACAC:T	donor_loss	1.0000
2:68187253:A:AC	donor_gain	1.0000

AlphaMissense

1155 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:68186645:G:C	F96L	1.000
2:68186645:G:T	F96L	1.000
2:68186647:A:G	F96L	1.000
2:68186474:G:C	F153L	0.999
2:68186474:G:T	F153L	0.999
2:68186476:A:G	F153L	0.999
2:68186515:C:G	A140P	0.999
2:68186547:A:G	L129S	0.999
2:68186598:A:G	L112P	0.999
2:68186613:A:C	I107S	0.999
2:68186613:A:T	I107N	0.999
2:68186635:C:G	D100H	0.999
2:68186646:A:G	F96S	0.999
2:68186649:G:T	A95D	0.999
2:68187290:A:G	F82S	0.999
2:68187303:C:G	G78R	0.999
2:68187310:G:C	F75L	0.999
2:68187310:G:T	F75L	0.999
2:68187311:A:G	F75S	0.999
2:68187312:A:G	F75L	0.999
2:68188578:A:C	N52K	0.999
2:68188578:A:T	N52K	0.999
2:68188621:A:G	L38S	0.999
2:68188645:A:G	L30P	0.999
2:68188653:A:C	F27L	0.999
2:68188653:A:T	F27L	0.999
2:68188654:A:G	F27S	0.999
2:68188655:A:G	F27L	0.999
2:68186475:A:G	F153S	0.998
2:68186490:A:T	I148K	0.998

dbSNP variants (sampled 300 via entrez): RS1000039131 (2:68219085 A>G), RS1000067912 (2:68210324 T>C), RS1000104324 (2:68191306 A>G), RS1000206961 (2:68215422 T>C), RS1000225340 (2:68186117 T>A,C), RS1000246290 (2:68200084 C>G,T), RS1000284612 (2:68237699 C>T), RS1000340353 (2:68221856 C>A,G), RS1000414863 (2:68232191 A>G,T), RS1000425124 (2:68250742 T>G), RS1000437531 (2:68195211 T>A), RS1000491209 (2:68194845 T>C), RS1000520891 (2:68189559 A>G), RS1000591171 (2:68239436 A>T), RS1000653026 (2:68200947 G>A)

Disease associations

OMIM: gene MIM:601302 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 58	Limited	Autosomal dominant

Mondo (2): neurodevelopmental disorder (MONDO:0700092), autosomal dominant nonsyndromic hearing loss 58 (MONDO:0014293)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002647_77	Height	8.000000e-10
GCST005316_330	Intelligence (MTAG)	1.000000e-09
GCST006269_807	General cognitive ability	8.000000e-09
GCST007201_2	Schizophrenia	6.000000e-06
GCST008648_9	Urinary potassium excretion	6.000000e-09
GCST012229_32	Hip index	5.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0009283	potassium measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2082 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 168,247 (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
CHEMBL160	CYCLOSPORINE	4	168,247

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1868402	PPP3R1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	3
Valproic Acid	decreases expression, increases methylation	3
Cadmium	increases abundance, increases expression, decreases reaction	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, affects expression, increases abundance	1
sodium arsenite	increases expression	1
beta-methylcholine	affects expression	1
bafilomycin A	affects cotreatment, increases lipidation, increases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Bortezomib	decreases expression	1
Amiodarone	increases expression	1
Atrazine	increases expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Estradiol	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4828865	Binding	Inhibition of CNB (unknown origin) using p-NPP as substrate preincubated for 10 mins followed by substrate addition by spectrophotometry analysis	Efophylins A and B, Two C2-Asymmetric Macrodiolide Immunosuppressants from Streptomyces malaysiensis. — J Nat Prod

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0LL	Ubigene HeLa PPP3R1 KO	Cancer cell line	Female
CVCL_TG20	HAP1 PPP3R1 (-) 1	Cancer cell line	Male
CVCL_TG21	HAP1 PPP3R1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice