PPP2R5C

Summary

PPP2R5C (protein phosphatase 2 regulatory subunit B’gamma, HGNC:9311) is a protein-coding gene on chromosome 14q32.31, encoding Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (Q13362). The B regulatory subunit might modulate substrate selectivity and catalytic activity, and might also direct the localization of the catalytic enzyme to a particular subcellular compartment.

The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a gamma isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 5527 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Houge-Janssens syndrome 4 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 156 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 116
• MANE Select transcript: NM_001352913

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9311
Approved symbol	PPP2R5C
Name	protein phosphatase 2 regulatory subunit B’gamma
Location	14q32.31
Locus type	gene with protein product
Status	Approved
Aliases	B56G, PR61G, B56gamma
Ensembl gene	ENSG00000078304
Ensembl biotype	protein_coding
OMIM	601645
Entrez	5527

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 20 protein_coding, 9 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000328724, ENST00000334743, ENST00000350249, ENST00000422945, ENST00000445439, ENST00000553554, ENST00000553730, ENST00000553842, ENST00000553890, ENST00000554137, ENST00000554147, ENST00000554442, ENST00000554504, ENST00000555237, ENST00000556068, ENST00000556086, ENST00000556218, ENST00000556260, ENST00000556307, ENST00000556373, ENST00000556493, ENST00000556570, ENST00000556805, ENST00000556946, ENST00000557071, ENST00000557095, ENST00000557534, ENST00000557621, ENST00000557714, ENST00000557716, ENST00000561006, ENST00000607042, ENST00000694906, ENST00000956808, ENST00000956809, ENST00000956810

RefSeq mRNA: 10 — MANE Select: NM_001352913 NM_001161725, NM_001161726, NM_001352912, NM_001352913, NM_001352914, NM_001352915, NM_001352916, NM_002719, NM_178586, NM_178587

CCDS: CCDS45163, CCDS53911, CCDS53912, CCDS91934, CCDS9964, CCDS9965

Canonical transcript exons

ENST00000694906 — 16 exons

Exon	Start	End
ENSE00000660390	101906402	101906529
ENSE00001780490	101912401	101912473
ENSE00002434531	101761709	101761920
ENSE00002518618	101925141	101927977
ENSE00003467498	101883432	101883562
ENSE00003471933	101883257	101883349
ENSE00003488330	101894507	101894560
ENSE00003492130	101909589	101909690
ENSE00003496572	101762905	101762970
ENSE00003519176	101901719	101901889
ENSE00003540237	101856686	101856885
ENSE00003579419	101890237	101890296
ENSE00003605417	101917831	101917947
ENSE00003610252	101882161	101882271
ENSE00003664156	101893000	101893108
ENSE00003691249	101786018	101786183

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.3506 / max 824.5619, expressed in 1820 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141602	15.2033	1755
141600	11.7678	1782
141594	8.6268	1650
141595	7.5742	1029
141601	2.9065	1304
141615	1.4586	110
141619	1.1987	157
141620	1.0904	128
141621	1.0563	98
141596	0.9666	451

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.15	gold quality
endothelial cell	CL:0000115	98.89	gold quality
colonic epithelium	UBERON:0000397	98.87	gold quality
granulocyte	CL:0000094	98.39	gold quality
calcaneal tendon	UBERON:0003701	97.78	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.67	gold quality
tonsil	UBERON:0002372	97.55	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.47	gold quality
rectum	UBERON:0001052	97.39	gold quality
ventricular zone	UBERON:0003053	97.37	gold quality
amygdala	UBERON:0001876	97.28	gold quality
tibia	UBERON:0000979	97.27	gold quality
blood	UBERON:0000178	97.24	gold quality
vermiform appendix	UBERON:0001154	97.18	gold quality
right lung	UBERON:0002167	97.16	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.12	gold quality
leukocyte	CL:0000738	97.10	gold quality
bone marrow cell	CL:0002092	97.08	gold quality
male germ cell	CL:0000015	97.05	gold quality
visceral pleura	UBERON:0002401	97.03	gold quality
monocyte	CL:0000576	97.01	gold quality
heart left ventricle	UBERON:0002084	97.01	gold quality
Ammon’s horn	UBERON:0001954	96.97	gold quality
mononuclear cell	CL:0000842	96.96	gold quality
cardiac ventricle	UBERON:0002082	96.92	gold quality
nucleus accumbens	UBERON:0001882	96.85	gold quality
gall bladder	UBERON:0002110	96.84	gold quality
ganglionic eminence	UBERON:0004023	96.84	gold quality
caudate nucleus	UBERON:0001873	96.82	gold quality
lymph node	UBERON:0000029	96.79	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	1060.59
E-HCAD-4	yes	115.09
E-MTAB-8142	yes	89.37
E-CURD-46	yes	42.78
E-CURD-122	yes	39.62
E-CURD-88	yes	34.85
E-GEOD-135922	yes	33.82
E-MTAB-8410	yes	24.64
E-HCAD-9	yes	18.93
E-MTAB-6911	no	356.25
E-MTAB-10553	no	11.18
E-CURD-112	no	3.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KAT5, KAT7, NRL

miRNA regulators (miRDB)

97 targeting PPP2R5C, 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-8485	100.00	77.57	4731
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-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-3941	99.86	70.54	2735
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-577	99.78	69.13	2479

Literature-anchored findings (GeneRIF, showing 26)

• B56gamma1 alters the dynamic assembly/disassembly process of nuclear speckles in heart cells. (PMID:15778281)
• Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A (PMID:16524888)
• B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. (PMID:17245430)
• PP2A-B56gamma1 phosphatase complexes have a role in cardiac local signaling (PMID:17663574)
• show an important link between ATM activity and the tumor-suppressive function of B56gamma-protein phosphatase 2A (PMID:17967874)
• the dynamic nuclear distribution of the B56gamma3 regulatory subunit controls nuclear PP2A activity, which regulates cell cycle controllers, such as p27, to restrain cell cycle progression, and may be responsible for the tumor suppressor function of PP2A (PMID:20448040)
• a mechanistic basis for the p53-dependent and -independent functions of B56gamma-PP2A (PMID:20473327)
• ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56gamma3, B56gamma2 and B56delta, after DNA damage. (PMID:21460856)
• Overexpression of PPP2R5C in T-cell malignancy as well as in myeloid leukemia cells might relate to its proliferation and differentiation. (PMID:21548944)
• structural insight into the PP2A holoenzyme assembly and emphasizes the importance of HEAT repeat 1 in B56gamma-PP2A tumor-suppressive function (PMID:22315229)
• Results show that mutations lost B56gamma tumor-suppressive activity by two distinct mechanisms: one is by disrupting interactions with the PP2A AC core and the other with B56gamma-PP2A substrates (p53 and unknown proteins). (PMID:23723076)
• PPP2R5C-siRNA treatment altered gene expression profiles in malignant T cells (PMID:23941244)
• Data indicate that the regulatory PP2A subunit B56gamma mediates suppression of NF-kappaB resulting in increased NF-kappaB target gene expression in T cells. (PMID:24719332)
• KIF4A and PP2A-B56G and -B56E create a spatially restricted negative feedback loop counteracting Aurora B in anaphase. (PMID:25512391)
• Differential expression of the transcripts PPP2R5C connects ubiquitin-proteasome system with infection-inflammation in preterm births and preterm premature rupture of membranes. (PMID:25884766)
• propose that the mechanism for proliferation inhibition and increased apoptosis of K562 cells following PPP2R5C suppression may be related to the alteration of expression profiles of BRAF, AKT2, AKT3, NFKB2 and STAT3 genes (PMID:25888193)
• Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth (PMID:25972378)
• our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state. (PMID:26440364)
• PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more) of lung adenocarcinoma. (PMID:26986830)
• Kelch-like protein 42 is a profibrotic ubiquitin E3 ligase involved in systemic sclerosis. (PMID:32071084)
• A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment. (PMID:32195664)
• Structural basis of host protein hijacking in human T-cell leukemia virus integration. (PMID:32561747)
• Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56gamma. (PMID:33028863)
• [The Relationship between PPP2R5C and Molt-4 Cell Viability, HSP90-GR Signal in Childhood Acute T Lymphocytic Leukemia]. (PMID:35123608)
• A functional interaction between liprin-alpha1 and B56gamma regulatory subunit of protein phosphatase 2A supports tumor cell motility. (PMID:36171301)
• Combined detection of SDC2/ADHFE1/PPP2R5C methylation in stool DNA for colorectal cancer screening. (PMID:37270460)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ppp2r5c	ENSMUSG00000017843
rattus_norvegicus	Ppp2r5c	ENSRNOG00000004973
drosophila_melanogaster	wrd	FBGN0042693
caenorhabditis_elegans		WBGENE00007554
caenorhabditis_elegans		WBGENE00012348

Paralogs (4): PPP2R5A (ENSG00000066027), PPP2R5B (ENSG00000068971), PPP2R5D (ENSG00000112640), PPP2R5E (ENSG00000154001)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform — Q13362 (reviewed: Q13362)

Alternative names: PP2A B subunit isoform B’-gamma, PP2A B subunit isoform B56-gamma, PP2A B subunit isoform PR61-gamma, PP2A B subunit isoform R5-gamma, Renal carcinoma antigen NY-REN-29

All UniProt accessions (17): Q13362, A0A8Q3WKR3, G3V292, G3V2U3, G3V5T2, H0YJ12, H0YJ35, H0YJ49, H0YJU0, H0YJZ3, H0YK25, H0YK26, H0YN58, H0YN84, H0YNJ3, H0YNR8, Q96B13

UniProt curated annotations — full annotation on UniProt →

Function. The B regulatory subunit might modulate substrate selectivity and catalytic activity, and might also direct the localization of the catalytic enzyme to a particular subcellular compartment. The PP2A-PPP2R5C holoenzyme may specifically dephosphorylate and activate TP53 and play a role in DNA damage-induced inhibition of cell proliferation. PP2A-PPP2R5C may also regulate the ERK signaling pathway through ERK dephosphorylation.

Subunit / interactions. PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B’’/PR72/PR130/PR59 and R5/B’/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with PPP2CA and PPP2R1A; the interaction is direct. Interacts with SGO1; the interaction is direct. Isoform 1 and isoform 2 interact with TP53 (phosphorylated at Ser-15 by ATM); increased upon DNA damage it drives PP2A-mediated dephosphorylation of TP53 at Thr-55. Interacts with IER3 and/or ERK kinases; regulates ERK dephosphorylation. Interacts with CIP2A; this interaction stabilizes CIP2A.

Subcellular location. Nucleus. Chromosome. Centromere.

Tissue specificity. Highest levels in heart, skeletal muscle and brain. Lower levels in pancreas, kidney, lung and placenta. Very low levels in liver.

Post-translational modifications. Isoform Gamma-3 is phosphorylated on serine residues. Isoform Gamma-1 phosphorylation by ERK2 is IER3-dependent and inhibits ERK dephosphorylation by PP2A-PPP2R5C.

Disease relevance. Houge-Janssens syndrome 4 (HJS4) [MIM:621185] An autosomal dominant neurodevelopmental disorder characterized by stable developmental delay, intellectual disability of variable degrees, poor or absent speech, generalized hypotonia, seizures, behavioral features, and abnormal coordination. Most affected individuals have a large head circumference or macrocephaly. Disease onset is in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated upon DNA damage.

Similarity. Belongs to the phosphatase 2A regulatory subunit B56 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q13362-1	Gamma-3	yes
Q13362-2	Gamma-1
Q13362-3	Gamma-2
Q13362-4	4
Q13362-5	5

RefSeq proteins (10): NP_001155197, NP_001155198, NP_001339841, NP_001339842, NP_001339843, NP_001339844, NP_001339845, NP_002710, NP_848701, NP_848702 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002554	PP2A_B56	Family
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily

Pfam: PF01603

UniProt features (65 total): helix 27, sequence variant 20, turn 5, splice variant 4, strand 3, sequence conflict 2, chain 1, region of interest 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
5JJA	X-RAY DIFFRACTION	2.35
6VRO	X-RAY DIFFRACTION	2.45
2JAK	X-RAY DIFFRACTION	2.6
3FGA	X-RAY DIFFRACTION	2.7
5K6S	X-RAY DIFFRACTION	2.79
5SWF	X-RAY DIFFRACTION	2.82
5SW9	X-RAY DIFFRACTION	2.85
9GNJ	X-RAY DIFFRACTION	2.85
7OUF	ELECTRON MICROSCOPY	3
7OUG	ELECTRON MICROSCOPY	3.1
6OYL	X-RAY DIFFRACTION	3.15
6TOQ	X-RAY DIFFRACTION	3.16
9MF5	ELECTRON MICROSCOPY	3.2
2NPP	X-RAY DIFFRACTION	3.3
7PEL	ELECTRON MICROSCOPY	3.34
7SOY	ELECTRON MICROSCOPY	3.4
9MIP	ELECTRON MICROSCOPY	3.4
2IAE	X-RAY DIFFRACTION	3.5
7OUH	ELECTRON MICROSCOPY	3.5
2NYM	X-RAY DIFFRACTION	3.6
6VOY	ELECTRON MICROSCOPY	3.7
2NYL	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13362-F1	85.15	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

62 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-196299	Beta-catenin phosphorylation cascade
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-389356	Co-stimulation by CD28
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-432142	Platelet sensitization by LDL
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5339716	Signaling by GSK3beta mutants
R-HSA-5358747	CTNNB1 S33 mutants aren’t phosphorylated
R-HSA-5358749	CTNNB1 S37 mutants aren’t phosphorylated
R-HSA-5358751	CTNNB1 S45 mutants aren’t phosphorylated
R-HSA-5358752	CTNNB1 T41 mutants aren’t phosphorylated
R-HSA-5467337	APC truncation mutants have impaired AXIN binding
R-HSA-5467340	AXIN missense mutants destabilize the destruction complex
R-HSA-5467348	Truncations of AMER1 destabilize the destruction complex
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-5673000	RAF activation
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-6804757	Regulation of TP53 Degradation
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-109582	Hemostasis
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1280218	Adaptive Immune System
R-HSA-141424	Amplification of signal from the kinetochores
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 338 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, AAGCCAT_MIR135A_MIR135B, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HNF1_Q6, CAGCTG_AP4_Q5, REACTOME_CO_STIMULATION_BY_CD28, MODULE_503, PUJANA_CHEK2_PCC_NETWORK, MAHAJAN_RESPONSE_TO_IL1A_DN, TCF4_Q5, MODULE_195

GO Biological Process (12): signal transduction (GO:0007165), negative regulation of cell population proliferation (GO:0008285), DNA damage response, signal transduction by p53 class mediator (GO:0030330), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), meiotic sister chromatid cohesion (GO:0051177), negative regulation of cell cycle process (GO:0010948), protein processing (GO:0016485), intracellular signal transduction (GO:0035556), meiotic sister chromatid cohesion, centromeric (GO:0051754), nuclear chromosome segregation (GO:0098813), regulation of mitotic cell cycle phase transition (GO:1901990)

GO Molecular Function (4): protein phosphatase regulator activity (GO:0019888), protein phosphatase activator activity (GO:0072542), protein binding (GO:0005515), peptidase activity (GO:0008233)

GO Cellular Component (10): protein phosphatase type 2A complex (GO:0000159), chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), cytosol (GO:0005829), chromosome (GO:0005694), cytoplasm (GO:0005737), membrane (GO:0016020), catalytic complex (GO:1902494)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by CTNNB1 phospho-site mutants	4
Regulation of T cell activation by CD28 family	2
RAF/MAP kinase cascade	2
Amplification of signal from the kinetochores	1
Signaling by WNT	1
Degradation of beta-catenin by the destruction complex	1
Mitotic Anaphase	1
Mitotic Prometaphase	1
Platelet homeostasis	1
TCF dependent signaling in response to WNT	1
Signaling by WNT in cancer	1
Signaling by APC mutants	1
Signaling by AXIN mutants	1
Signaling by AMER1 mutants	1
RHO GTPase Effectors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
phosphoprotein phosphatase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
sister chromatid cohesion	1
regulation of cell cycle process	1
cell cycle process	1
negative regulation of cell cycle	1
proteolysis	1
protein maturation	1
signal transduction	1
meiotic sister chromatid cohesion	1
centromeric sister chromatid cohesion	1
chromosome segregation	1
regulation of mitotic cell cycle	1
mitotic cell cycle phase transition	1
regulation of cell cycle phase transition	1
phosphatase regulator activity	1
protein phosphatase binding	1
phosphatase activator activity	1
protein phosphatase regulator activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
protein serine/threonine phosphatase complex	1

Protein interactions and networks

STRING

1380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP2R5C	PPP2R1A	P30153	955
PPP2R5C	PPP2CA	P05323	941
PPP2R5C	PPP2R1B	P30154	924
PPP2R5C	PPP2R2A	P50409	894
PPP2R5C	PPP2R3A	Q06190	848
PPP2R5C	PPP2R2D	Q66LE6	723
PPP2R5C	PPP2R2C	Q9Y2T4	722
PPP2R5C	STRN	O43815	707
PPP2R5C	PTPA	Q15257	705
PPP2R5C	PPP2R5B	Q15173	700
PPP2R5C	PPP2R5D	Q14738	674
PPP2R5C	SGO1	Q5FBB7	644
PPP2R5C	PPP2R3B	Q9Y5P8	633
PPP2R5C	CDCA2	Q69YH5	608
PPP2R5C	MINK1	Q8N4C8	600

IntAct

93 interactions, top by confidence:

A	B	Type	Score
PPP2CA	PPP2R1A	psi-mi:“MI:0915”(physical association)	0.990
PPP2R1A	PPP2CA	psi-mi:“MI:0915”(physical association)	0.990
PPP2R5C	PPP2R1A	psi-mi:“MI:0914”(association)	0.940
PPP2R5C	PPP2R1A	psi-mi:“MI:0915”(physical association)	0.940
PPP2R1A	PPP2R5C	psi-mi:“MI:0915”(physical association)	0.940
PPP2R5C	PPP2CA	psi-mi:“MI:0915”(physical association)	0.930
PPP2CA	PPP2R5C	psi-mi:“MI:0915”(physical association)	0.930
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
PPP2CA	STRN	psi-mi:“MI:0914”(association)	0.840
PPP2CB	STRN	psi-mi:“MI:0914”(association)	0.790
PRR14	PPP2R1A	psi-mi:“MI:0914”(association)	0.790
PPP2CB	CEP43	psi-mi:“MI:0914”(association)	0.730
PPP2R5C	TP53	psi-mi:“MI:2364”(proximity)	0.650
PPP2R5C	TP53	psi-mi:“MI:0914”(association)	0.650
PPP2R5C	TP53	psi-mi:“MI:0915”(physical association)	0.650
PPP2R1B	PPP2R5C	psi-mi:“MI:0915”(physical association)	0.590
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
Ppp2r1a	FECH	psi-mi:“MI:0915”(physical association)	0.560
MDM2	PPP2R5C	psi-mi:“MI:0915”(physical association)	0.560
RAF1	PPP2R5C	psi-mi:“MI:0203”(dephosphorylation reaction)	0.540

BioGRID (155): PPP2R5C (Reconstituted Complex), PPP2R5C (Affinity Capture-Western), PPP2R5C (Affinity Capture-MS), PPP2R5C (Affinity Capture-MS), PPP2R5C (Affinity Capture-MS), API5 (Co-fractionation), LSM6 (Co-fractionation), LSM7 (Co-fractionation), PPP2R1A (Co-fractionation), PPP2R1B (Co-fractionation), PPP2R2A (Co-fractionation), PPP2R5C (Co-fractionation), PPP2R5C (Co-fractionation), PPP2R5C (Co-fractionation), PPP2R5C (Co-fractionation)

ESM2 similar proteins: A2VE70, A4FV68, E0CZ22, O04375, O04376, O35638, O43156, P50851, Q08AM6, Q0V9L1, Q13362, Q15172, Q15173, Q16537, Q28647, Q28651, Q5ZIW5, Q60996, Q61151, Q66L58, Q68F38, Q68F70, Q6DCF2, Q6I621, Q6PD03, Q6PD28, Q80TR8, Q80W83, Q80W92, Q80WQ2, Q8C0Y0, Q8CIM8, Q8JGR7, Q8K2Z4, Q8LF36, Q8N3U4, Q8RW96, Q8WVM7, Q91V83, Q96HW7

Diamond homologs: A4FV68, O04375, O04376, O18178, P38903, P78759, Q10428, Q13362, Q14738, Q15172, Q15173, Q16537, Q28647, Q28651, Q28653, Q28654, Q54VB6, Q60996, Q61151, Q6I621, Q6PD03, Q6PD28, Q80W83, Q8LF36, Q8RW96, Q93YV6, Q9LU89, Q9LVE2, Q9SV41, Q9ZQY6

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
CHEK2	up-regulates	PPP2R5C	phosphorylation
IER3	down-regulates	PPP2R5C	binding
MAPK1	down-regulates	PPP2R5C	phosphorylation
MAPK3	down-regulates	PPP2R5C	phosphorylation
PPP2R5C	down-regulates	MAPK1	binding
PPP2R5C	down-regulates	MAPK3	binding
PPP2R5C	down-regulates	RPS6KB1	binding
PPP2R5C	up-regulates	ATF1	dephosphorylation
PPP2R5C	“up-regulates quantity by stabilization”	TP53	dephosphorylation
PPP2R5C	“up-regulates activity”	PPP2CA	binding
PPP2R5C	down-regulates	Gbeta	binding
PPP2R5C	down-regulates	ERK1/2	binding
Gbeta	down-regulates	PPP2R5C	phosphorylation
ERK1/2	down-regulates	PPP2R5C	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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
Spry regulation of FGF signaling	6	68.0×	3e-08
Signaling by GSK3beta mutants	5	60.4×	5e-07
CTNNB1 S33 mutants aren’t phosphorylated	5	60.4×	5e-07
CTNNB1 S37 mutants aren’t phosphorylated	5	60.4×	5e-07
CTNNB1 S45 mutants aren’t phosphorylated	5	60.4×	5e-07
CTNNB1 T41 mutants aren’t phosphorylated	5	60.4×	5e-07
Stabilization of p53	5	60.4×	5e-07
RAF activation	10	53.3×	1e-12

GO biological processes:

GO term	Partners	Fold	FDR
protein dephosphorylation	7	22.2×	2e-05
MAPK cascade	7	15.3×	2e-04
protein stabilization	8	7.6×	1e-03
cell division	10	6.6×	4e-04
negative regulation of apoptotic process	9	4.5×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	69
Likely benign	34
Benign	14

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
217454	NM_001352913.2(PPP2R5C):c.540_542del (p.Thr181del)	Pathogenic
3899885	F55L	Pathogenic
3899886	E122K	Pathogenic
3899887	A130del	Pathogenic
3899888	H133P	Pathogenic
3899889	H133L	Pathogenic
1076998	NM_001352913.2(PPP2R5C):c.694C>T (p.Arg232Trp)	Likely pathogenic
1098393	NM_001352913.2(PPP2R5C):c.563A>G (p.His188Arg)	Likely pathogenic
4076587	NM_001352913.2(PPP2R5C):c.310T>C (p.Cys104Arg)	Likely pathogenic
4535086	NM_001352913.2(PPP2R5C):c.566T>C (p.Leu189Pro)	Likely pathogenic

SpliceAI

3430 predictions. Top by Δscore:

Variant	Effect	Δscore
14:101810034:GAG:G	donor_gain	1.0000
14:101810035:AG:A	donor_gain	1.0000
14:101810035:AGG:A	donor_loss	1.0000
14:101810036:GG:G	donor_gain	1.0000
14:101810036:GGTA:G	donor_loss	1.0000
14:101810037:G:GG	donor_gain	1.0000
14:101829444:G:T	donor_gain	1.0000
14:101856676:T:TA	acceptor_gain	1.0000
14:101856681:TTCA:T	acceptor_loss	1.0000
14:101856682:TCA:T	acceptor_loss	1.0000
14:101856683:CAGAT:C	acceptor_loss	1.0000
14:101856684:A:AG	acceptor_gain	1.0000
14:101856684:AGAT:A	acceptor_gain	1.0000
14:101856685:G:GG	acceptor_gain	1.0000
14:101856685:GA:G	acceptor_gain	1.0000
14:101856685:GAT:G	acceptor_gain	1.0000
14:101856685:GATG:G	acceptor_gain	1.0000
14:101856685:GATGT:G	acceptor_gain	1.0000
14:101856790:G:GT	donor_gain	1.0000
14:101856882:TATG:T	donor_gain	1.0000
14:101856884:TGGTA:T	donor_loss	1.0000
14:101856885:GGTA:G	donor_loss	1.0000
14:101856886:G:GA	donor_loss	1.0000
14:101856886:G:GG	donor_gain	1.0000
14:101856887:T:TC	donor_loss	1.0000
14:101883256:GCTT:G	acceptor_gain	1.0000
14:101891817:C:G	donor_gain	1.0000
14:101892998:A:AG	acceptor_gain	1.0000
14:101892999:G:GA	acceptor_gain	1.0000
14:101892999:GT:G	acceptor_gain	1.0000

AlphaMissense

3859 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:101856789:G:C	K66N	1.000
14:101856789:G:T	K66N	1.000
14:101856798:A:C	K69N	1.000
14:101856798:A:T	K69N	1.000
14:101882218:T:C	F118L	1.000
14:101882219:T:C	F118S	1.000
14:101882220:T:A	F118L	1.000
14:101882220:T:G	F118L	1.000
14:101882222:A:G	D119G	1.000
14:101882233:G:C	D123H	1.000
14:101882240:C:A	P125Q	1.000
14:101882257:T:A	W131R	1.000
14:101882257:T:C	W131R	1.000
14:101882259:G:C	W131C	1.000
14:101882259:G:T	W131C	1.000
14:101882267:T:C	L134P	1.000
14:101883433:T:C	L167P	1.000
14:101883456:G:C	D175H	1.000
14:101883463:G:C	R177P	1.000
14:101883469:G:C	R179T	1.000
14:101883469:G:T	R179I	1.000
14:101883470:A:C	R179S	1.000
14:101883470:A:T	R179S	1.000
14:101883478:T:C	L182P	1.000
14:101883480:A:G	K183E	1.000
14:101883481:A:T	K183I	1.000
14:101883482:A:C	K183N	1.000
14:101883482:A:T	K183N	1.000
14:101883490:T:C	L186P	1.000
14:101883492:C:A	H187N	1.000

dbSNP variants (sampled 300 via entrez): RS1000007215 (14:101814116 A>G), RS1000020103 (14:101853261 TA>T,TAA), RS1000051801 (14:101876422 T>C), RS1000069936 (14:101786414 A>G), RS1000072601 (14:101813595 A>C,G), RS1000113200 (14:101789352 C>T), RS1000136019 (14:101863849 G>T), RS1000164315 (14:101781648 G>T), RS1000166938 (14:101788912 T>C), RS1000183906 (14:101908326 A>T), RS1000236958 (14:101881423 G>C), RS1000238857 (14:101781458 C>T), RS1000249688 (14:101876755 A>G), RS1000273260 (14:101915368 C>T), RS1000301939 (14:101824055 T>C)

Disease associations

OMIM: gene MIM:601645 | disease phenotypes: MIM:621185, MIM:615637

GenCC curated gene-disease

Disease	Classification	Inheritance
Houge-Janssens syndrome 4	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (6): Houge-Janssens syndrome 4 (MONDO:0978293), prostate cancer (MONDO:0008315), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), macrocephaly-developmental delay syndrome (MONDO:0014289), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (3): Familial prostate cancer (Orphanet:1331), Macrocephaly-developmental delay syndrome (Orphanet:397612), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

116 total (30 of 116 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000132	Menorrhagia
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000589	Coloboma
HP:0000639	Nystagmus
HP:0000666	Horizontal nystagmus
HP:0000711	Restlessness
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000740_2	Autism	3.000000e-06
GCST005025_41	Anti-saccade response	8.000000e-06
GCST009391_2049	Metabolite levels	8.000000e-06
GCST010676_8	Leukoderma in response to rhododendrol	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006874	antisaccade response measurement
EFO:0010508	malate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects expression, increases abundance, affects cotreatment, increases methylation	3
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	decreases expression, affects methylation	3
methylmercuric chloride	decreases expression, increases expression	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Valproic Acid	decreases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	decreases phosphorylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
alpha phellandrene	increases expression	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
coenzyme Q10	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	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
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants, Occupational	affects expression	1
Amiodarone	increases expression	1
Atrazine	increases expression	1
Camptothecin	increases response to substance, increases expression, increases reaction	1

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3EK	Abcam HEK293T PPP2R5C KO	Transformed cell line	Female
CVCL_D9P6	Ubigene HEK293 PPP2R5C KO	Transformed cell line	Female
CVCL_E1FJ	Abcam A-431 PPP2R5C KO	Cancer cell line	Female
CVCL_TG09	HAP1 PPP2R5C (-) 1	Cancer cell line	Male
CVCL_TG10	HAP1 PPP2R5C (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

504 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,
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery