PPP4C

Summary

PPP4C (protein phosphatase 4 catalytic subunit, HGNC:9319) is a protein-coding gene on chromosome 16p11.2, encoding Serine/threonine-protein phosphatase 4 catalytic subunit (P60510). Protein phosphatase that is involved in many processes such as microtubule organization at centrosomes, maturation of spliceosomal snRNPs, apoptosis, DNA repair, tumor necrosis factor (TNF)-alpha signaling, activation of c-Jun N-terminal kinase MAPK8, regulation of histone acety…. It is a common-essential gene (DepMap: required in 96.0% of cancer cell lines).

Enables protein serine/threonine phosphatase activity. Involved in regulation of double-strand break repair via homologous recombination. Located in several cellular components, including chromatin; cytosol; and nucleoplasm. Part of protein phosphatase 4 complex.

Source: NCBI Gene 5531 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 27 total — 2 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 96.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_002720

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9319
Approved symbol	PPP4C
Name	protein phosphatase 4 catalytic subunit
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	PP4, PPX
Ensembl gene	ENSG00000149923
Ensembl biotype	protein_coding
OMIM	602035
Entrez	5531

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 26 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay

ENST00000279387, ENST00000561610, ENST00000562222, ENST00000562664, ENST00000563200, ENST00000563597, ENST00000563732, ENST00000564966, ENST00000566749, ENST00000567040, ENST00000567642, ENST00000567828, ENST00000568810, ENST00000627746, ENST00000901308, ENST00000901309, ENST00000901310, ENST00000901311, ENST00000901312, ENST00000901313, ENST00000901314, ENST00000901315, ENST00000901316, ENST00000901317, ENST00000901318, ENST00000901319, ENST00000924271, ENST00000924272, ENST00000924273, ENST00000924274, ENST00000924275, ENST00000924276, ENST00000924277, ENST00000954848, ENST00000954849

RefSeq mRNA: 5 — MANE Select: NM_002720 NM_001303503, NM_001303504, NM_001303506, NM_001303507, NM_002720

CCDS: CCDS10669

Canonical transcript exons

ENST00000279387 — 9 exons

Exon	Start	End
ENSE00000992979	30084933	30085376
ENSE00000992987	30075994	30076094
ENSE00003487059	30084666	30084855
ENSE00003495865	30076315	30076475
ENSE00003582279	30081259	30081310
ENSE00003596603	30082746	30082847
ENSE00003606881	30082484	30082534
ENSE00003613996	30083655	30083781
ENSE00003615244	30083394	30083567

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.2766 / max 1204.8596, expressed in 1824 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153621	50.2766	1824

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.72	gold quality
monocyte	CL:0000576	97.70	gold quality
endometrium epithelium	UBERON:0004811	97.68	gold quality
granulocyte	CL:0000094	97.61	gold quality
stromal cell of endometrium	CL:0002255	97.50	gold quality
mucosa of transverse colon	UBERON:0004991	97.37	gold quality
mononuclear cell	CL:0000842	97.27	gold quality
leukocyte	CL:0000738	97.25	gold quality
esophagus mucosa	UBERON:0002469	96.82	gold quality
right testis	UBERON:0004534	96.73	gold quality
left testis	UBERON:0004533	96.67	gold quality
skin of abdomen	UBERON:0001416	96.12	gold quality
skin of leg	UBERON:0001511	96.05	gold quality
ganglionic eminence	UBERON:0004023	96.03	gold quality
left adrenal gland	UBERON:0001234	95.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.91	gold quality
right lobe of liver	UBERON:0001114	95.84	gold quality
left adrenal gland cortex	UBERON:0035825	95.84	gold quality
spleen	UBERON:0002106	95.82	gold quality
right adrenal gland	UBERON:0001233	95.81	gold quality
ventricular zone	UBERON:0003053	95.79	gold quality
right adrenal gland cortex	UBERON:0035827	95.77	gold quality
esophagus	UBERON:0001043	95.73	gold quality
transverse colon	UBERON:0001157	95.71	gold quality
body of stomach	UBERON:0001161	95.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.55	gold quality
embryo	UBERON:0000922	95.50	gold quality
upper lobe of left lung	UBERON:0008952	95.40	gold quality
left uterine tube	UBERON:0001303	95.20	gold quality
apex of heart	UBERON:0002098	95.07	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.67
E-MTAB-6142	no	195.66
E-MTAB-8060	no	125.02
E-CURD-88	no	3.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMAD5

miRNA regulators (miRDB)

42 targeting PPP4C, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 36)

• Protein phosphatase 4 interacts with the Survival of Motor Neurons complex and enhances the temporal localisation of snRNPs (PMID:12668731)
• protein phosphatase 4 has a role in NF-kappaB p65 Thr dephosphorylation (PMID:15073167)
• IRS-4 is subject to regulation by TNF-alpha, and PP4 mediates TNF-alpha-induced degradation of IRS-4 (PMID:15331607)
• PP4 is a positive regulator for HPK1 and the HPK1-JNK signaling pathway (PMID:15364934)
• Our work uncovers a unique regulatory mechanism of MT organization by PP4c through its targets Cdk1 and NDEL1 via regulation of katanin p60 distribution. (PMID:18347064)
• Analysis of the role of the serine/threonine protein phosphatase, protein phosphatase 4, in controlling the apoptosis of HEK 293 T cells, using the complementary techniques of gene over-expression and down regulation through RNA interference. (PMID:18424272)
• The results suggest that Ppp4c-R2-R3 complexes may co-ordinate centrosome maturation and cell migration via regulation of RhoGTPases. (PMID:18487071)
• A three-protein PP4 phosphatase complex in mammalian cells, containing PP4C, PP4R2, and PP4R3beta, specifically dephosphorylates ATR-mediated gamma-H2AX generated during DNA replication. (PMID:18614045)
• PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2.PP4R3, and alpha4, and the regulatory subunits of PP4c have evolved different modes of interaction with the catalytic subunit (PMID:18715871)
• An evolutionarily conserved gamma histone 2AX phosphatase active on both DNA-damaged and undamaged chromatin. (PMID:18758438)
• PP4 activity significantly affects the mutation rate in leukemic T-cells, indicating that PP4 dysfunction may be important in the development and progression of leukemia (PMID:19539371)
• PP4R2, a regulatory subunit of PP4, mediates the DNA damage-dependent association between RPA2 and the PP4C catalytic subunit. (PMID:20154705)
• The authors devised a novel proteomic strategy for systematic identification of proteins dephosphorylated by PP4C and identified KRAB-domain-associated protein 1 (KAP-1) as a substrate. (PMID:22491012)
• Overexpression of PP4C is associated with poor prognosis in patients with stage II pancreatic ductal adenocarcinoma. (PMID:22665577)
• PP4C and KAP1 are in the same epistasis group, and PP4 is involved in NHEJ-mediated DSB repair, possibly through regulating the phosphorylation status of KAP1. (PMID:22732494)
• PP4R1 and PP4c Cooperate to Catalyze IKK Dephosphorylation (PMID:23084358)
• Results show PP4C as a fostriecin-sensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis. (PMID:23671329)
• PP4c is a key regulator of cortical development that changes the orientation of progenitor division responsible for the transition between symmetric and asymmetric cell division. (PMID:23830831)
• Recombinant gamma-tubulin can be phosphorylated by Cdk1-cyclin B or Brsk1 and dephosphorylated by Ppp4c-R2-R3A in vitro. (PMID:23966160)
• Data indicate that the major phosphatase responsible for dephosphorylation of of BAF Ser-4 to be protein phosphatase 4 catalytic subunit. (PMID:24265311)
• PP4 and Wip1 are differentially required to counteract the p53-dependent cell cycle arrest in G1 and G2, by antagonizing early or late p53-mediated responses, respectively (PMID:24711418)
• Stathmin plays an essential role of in Merkel cell polyomavirus small tumor antigen-mediated microtubule destabilization and cell motility and this process is regulated by cellular phosphatase catalytic subunit of protein phosphatase 4. (PMID:25320307)
• These data suggested a potential role of PP4C in tumor progression. (PMID:25927939)
• mutual regulatory mechanisms exist between PP4 and SAF-A. Interactions between PP4 and SAF-A played a role in prometaphase/metaphase transition. (PMID:27041735)
• Data show that protein phosphatase 4 catalytic subunit (PP4C) knockdown decreases glioma cell proliferation. (PMID:27059736)
• Knockdown of Alpha4 preferentially impacts the expression of PP4c and PP6c compared to expression levels of PP2Ac. (PMID:27169767)
• PP4 regulates breast cancer cell survival and identifies a novel PP4c-PEA15 signalling axis in the control of breast cancer cell survival. (PMID:27317964)
• Sciatic nerve but not spinal injury induces calcium-dependent PP4 activity that is required for HDAC3 dephosphorylation. (PMID:31268609)
• PP4C facilitates lung cancer proliferation and inhibits apoptosis via activating MAPK/ERK pathway. (PMID:32139257)
• Comprehensive analysis of PPPCs family reveals the clinical significance of PPP1CA and PPP4C in breast cancer. (PMID:34964699)
• Loss of PP4 contributes to diesel exhaust particles-induced epithelial barrier integrity disruption and alarmins release. (PMID:36458827)
• SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex. (PMID:37309898)
• Protein Phosphatase 4 Is Required for Centrobin Function in DNA Damage Repair. (PMID:37759442)
• DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11. (PMID:37906628)
• AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner. (PMID:38424148)
• Comprehensive analysis of PPP4C’s impact on prognosis, immune microenvironment, and immunotherapy response in lung adenocarcinoma using single-cell sequencing and multi-omics. (PMID:39026674)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp4ca	ENSDARG00000070570
danio_rerio	ppp4cb	ENSDARG00000076439
mus_musculus	Ppp4c	ENSMUSG00000030697
rattus_norvegicus	Ppp4c	ENSRNOG00000019813
drosophila_melanogaster	Pp4-19C	FBGN0023177
caenorhabditis_elegans		WBGENE00004085
caenorhabditis_elegans		WBGENE00004086

Paralogs (12): PPP5C (ENSG00000011485), PPEF1 (ENSG00000086717), PPP2CB (ENSG00000104695), PPP3CB (ENSG00000107758), PPP2CA (ENSG00000113575), PPP6C (ENSG00000119414), PPP3CC (ENSG00000120910), PPP3CA (ENSG00000138814), PPEF2 (ENSG00000156194), PPP1CA (ENSG00000172531), PPP1CC (ENSG00000186298), PPP1CB (ENSG00000213639)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 4 catalytic subunit — P60510 (reviewed: P60510)

Alternative names: Protein phosphatase X

All UniProt accessions (7): P60510, A0A024R625, H3BPN5, H3BTA2, H3BV22, H3BVE3, I3L4X0

UniProt curated annotations — full annotation on UniProt →

Function. Protein phosphatase that is involved in many processes such as microtubule organization at centrosomes, maturation of spliceosomal snRNPs, apoptosis, DNA repair, tumor necrosis factor (TNF)-alpha signaling, activation of c-Jun N-terminal kinase MAPK8, regulation of histone acetylation, DNA damage checkpoint signaling, NF-kappa-B activation and cell migration. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3. The PPP4C-PPP4R2-PPP4R3A PP4 complex specifically dephosphorylates H2AX phosphorylated on Ser-140 (gamma-H2AX) generated during DNA replication and required for DNA double strand break repair. Dephosphorylates NDEL1 at CDK1 phosphorylation sites and negatively regulates CDK1 activity in interphase. In response to DNA damage, catalyzes RPA2 dephosphorylation, an essential step for DNA repair since it allows the efficient RPA2-mediated recruitment of RAD51 to chromatin.

Subunit / interactions. Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complexes PPP4C-PPP4R1, PPP4C-PPP4R2, PPP4C-PPP4R2-PPP4R3A, PPP4C-PPP4R2-PPP4R3B and PPP4C-PPP4R4. The PPP4C-PPP4R2 complex appears to be a tetramer composed of 2 molecules of PPP4C and 2 molecules of PPP4R2. Interacts with REL, NFKB1/p50 and RELA. Interacts with SMN1 and GEMIN4. Interacts with IRS4 (phosphorylated). Interacts with SMEK1/PPP4R3A; the interaction requires PP4R2. Interacts with HDAC3.

Subcellular location. Cytoplasm. Nucleus. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Methylation at the C-terminal Leu-307 is critical for interactions with regulatory subunits and functions in DNA repair.

Cofactor. Binds 2 manganese ions per subunit.

Similarity. Belongs to the PPP phosphatase family. PP-4 (PP-X) subfamily.

RefSeq proteins (5): NP_001290432, NP_001290433, NP_001290435, NP_001290436, NP_002711* (*=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
IPR047129	PPA2-like	Family

Pfam: PF00149

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 (19 total): mutagenesis site 7, binding site 7, modified residue 2, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60510-F1	94.87	0.92

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 (1): 115 (proton donor)

Ligand- & substrate-binding residues (7): 54; 56; 82; 82; 114; 164; 238

Post-translational modifications (2): 2, 307

Mutagenesis-validated functional residues (7):

Position	Phenotype
39	diminishes interaction with ppp4r4.
64	abolishes interaction with ppp4r4.
76	diminishes interaction with ppp4r4.
82	loss of activity.
107	diminishes interaction with ppp4r4.
277	abolishes interaction with ppp4r4; no effect on interaction with ppp4r1 and ppp4r2.
307	unable to dephosphorylate 53bp1 and kar1, loss of dsb repair activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 162 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_REGULATION_OF_DNA_REPAIR, GOCC_MICROTUBULE_ORGANIZING_CENTER, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, chr16p11, GOCC_CENTROSOME, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, MORF_PPP6C, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (3): double-strand break repair via homologous recombination (GO:0000724), regulation of double-strand break repair via homologous recombination (GO:0010569), regulation of double-strand break repair (GO:2000779)

GO Molecular Function (5): protein serine/threonine phosphatase activity (GO:0004722), metal ion binding (GO:0046872), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), protein phosphatase 4 complex (GO:0030289), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
double-strand break repair	2
recombinational repair	1
regulation of DNA recombination	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair	1
regulation of DNA repair	1
phosphoprotein phosphatase activity	1
cation binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
membrane	1
cell periphery	1
protein serine/threonine phosphatase complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

140 interactions, top by confidence:

A	B	Type	Score
PPP4R2	PPP4C	psi-mi:“MI:0914”(association)	0.950
PPP4C	IGBP1	psi-mi:“MI:0915”(physical association)	0.950
IGBP1	PPP4C	psi-mi:“MI:0915”(physical association)	0.950
PPP4R2	PPP4C	psi-mi:“MI:0915”(physical association)	0.950
PPP4C	PPP4R2	psi-mi:“MI:0915”(physical association)	0.950
IGBP1	PPP6C	psi-mi:“MI:0914”(association)	0.940
PPP4R1	PPP4C	psi-mi:“MI:0915”(physical association)	0.930
PPP4R3A	PPP4C	psi-mi:“MI:0914”(association)	0.920
PPP4C	PPP4R3A	psi-mi:“MI:0914”(association)	0.920
PPP4R3B	PPP4C	psi-mi:“MI:0914”(association)	0.890
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
PPP4C	PPP2R1A	psi-mi:“MI:0915”(physical association)	0.880
TIPRL	PPP4C	psi-mi:“MI:0914”(association)	0.850
PPP4C	TIPRL	psi-mi:“MI:0407”(direct interaction)	0.850
PPP4C	TIPRL	psi-mi:“MI:0915”(physical association)	0.850
PPP4R4	PPP4C	psi-mi:“MI:0915”(physical association)	0.830

BioGRID (368): PPP4C (Two-hybrid), PPP4C (Affinity Capture-MS), PPP4C (Co-fractionation), PPP4C (Co-fractionation), PPP4C (Proximity Label-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4C (Affinity Capture-MS)

ESM2 similar proteins: A0C1E4, A0CCD2, A0DJ90, A2XN40, A6H772, A8WGP3, A9JRC7, O04860, O04951, O76932, P11084, P11611, P20604, P23696, P23778, P32345, P36614, P48463, P48528, P48529, P48577, P48578, P49576, P60510, P62714, P62715, P62716, P63330, P63331, P67774, P67775, P67776, P67777, P97470, Q06009, Q07098, Q07099, Q07100, Q0P594, Q10BT5

Diamond homologs: A0C1E4, A0CCD2, A0CNL9, A0DJ90, A2X2G3, A2XN40, A2YEB4, A3C4N5, A6H772, A8WGP3, A8XE00, A9JRC7, G5EGK8, O00743, O04860, O04951, O74789, O76932, P0C5D7, P11084, P11493, P11611, P20604, P23594, P23595, P23635, P23636, P23696, P23778, P30366, P32345, P32598, P32838, P36614, P48463, P48480, P48483, P48528, P48529, P48577

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
PPP4C	up-regulates	BANF1	dephosphorylation
PPP4R3A	up-regulates	PPP4C	binding
PPP4C	“down-regulates activity”	HDAC3	dephosphorylation
PPP4C	“up-regulates activity”	RELA	dephosphorylation
PPP4C	“down-regulates activity”	NDEL1	dephosphorylation
PPP4C	“up-regulates activity”	ACACA	dephosphorylation
PPP4C	“down-regulates activity”	PLK1	dephosphorylation
PPP4C	“down-regulates activity”	CDK1	dephosphorylation
PPP4C	“down-regulates activity”	TRIM28	dephosphorylation
PPP4C	“up-regulates activity”	TP53BP1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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
mRNA Splicing - Minor Pathway	7	23.4×	1e-06
Cyclin A/B1/B2 associated events during G2/M transition	5	23.0×	9e-05
Negative regulation of MAPK pathway	5	19.8×	2e-04
mRNA Splicing	10	16.4×	8e-08
mRNA Polyadenylation	10	13.1×	4e-07
CHD1 and CHD2 subfamily	8	13.0×	1e-05
Processing of Capped Intron-Containing Pre-mRNA	10	12.3×	6e-07
mRNA Splicing - Major Pathway	13	10.6×	8e-08

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	8	56.1×	6e-10
mRNA splicing, via spliceosome	11	11.3×	1e-06
RNA splicing	9	8.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
145058	GRCh38/hg38 16p11.2(chr16:29634999-30185969)x1	Pathogenic
2506560	GRCh37/hg19 16p11.2(chr16:29495011-30206548)	Pathogenic

SpliceAI

1235 predictions. Top by Δscore:

Variant	Effect	Δscore
16:30076101:G:GG	donor_gain	1.0000
16:30076154:G:GT	donor_gain	1.0000
16:30076442:A:T	donor_gain	1.0000
16:30076473:CAGGT:C	donor_loss	1.0000
16:30076474:AGG:A	donor_loss	1.0000
16:30076475:GGT:G	donor_loss	1.0000
16:30076477:T:A	donor_loss	1.0000
16:30081311:G:GG	donor_gain	1.0000
16:30082533:GA:G	donor_gain	1.0000
16:30082535:G:GG	donor_gain	1.0000
16:30082743:CAGG:C	acceptor_loss	1.0000
16:30082744:AG:A	acceptor_gain	1.0000
16:30082745:GG:G	acceptor_gain	1.0000
16:30082745:GGTA:G	acceptor_gain	1.0000
16:30082745:GGTAG:G	acceptor_loss	1.0000
16:30082839:GCACT:G	donor_gain	1.0000
16:30083563:GCAAG:G	donor_gain	1.0000
16:30083564:CAAG:C	donor_gain	1.0000
16:30083564:CAAGG:C	donor_loss	1.0000
16:30083565:AAG:A	donor_gain	1.0000
16:30083566:AG:A	donor_gain	1.0000
16:30083567:GG:G	donor_gain	1.0000
16:30083568:G:GG	donor_gain	1.0000
16:30083568:GTAA:G	donor_loss	1.0000
16:30083640:T:TA	acceptor_gain	1.0000
16:30083651:GTA:G	acceptor_loss	1.0000
16:30083653:A:AG	acceptor_gain	1.0000
16:30083654:G:GG	acceptor_gain	1.0000
16:30083654:GA:G	acceptor_gain	1.0000
16:30083654:GAT:G	acceptor_gain	1.0000

AlphaMissense

2026 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:30081306:T:A	V49D	1.000
16:30082489:C:G	C52W	1.000
16:30082490:G:C	G53R	1.000
16:30082491:G:A	G53D	1.000
16:30082491:G:T	G53V	1.000
16:30082493:G:C	D54H	1.000
16:30082494:A:C	D54A	1.000
16:30082494:A:G	D54G	1.000
16:30082494:A:T	D54V	1.000
16:30082495:C:A	D54E	1.000
16:30082495:C:G	D54E	1.000
16:30082499:C:A	H56N	1.000
16:30082499:C:G	H56D	1.000
16:30082502:G:A	G57R	1.000
16:30082502:G:C	G57R	1.000
16:30082503:G:A	G57E	1.000
16:30082503:G:T	G57V	1.000
16:30082518:T:C	L62P	1.000
16:30082527:T:C	L65P	1.000
16:30082780:T:C	F79S	1.000
16:30082785:G:A	G81R	1.000
16:30082785:G:C	G81R	1.000
16:30082785:G:T	G81W	1.000
16:30082786:G:A	G81E	1.000
16:30082786:G:T	G81V	1.000
16:30082788:G:C	D82H	1.000
16:30082789:A:C	D82A	1.000
16:30082789:A:G	D82G	1.000
16:30082789:A:T	D82V	1.000
16:30082790:C:A	D82E	1.000

dbSNP variants (sampled 300 via entrez): RS1000377194 (16:30081430 C>T), RS1000482241 (16:30076491 C>T), RS1000492029 (16:30076058 A>G,T), RS1000753260 (16:30081630 C>T), RS1000940636 (16:30084236 A>G), RS1001318084 (16:30077991 C>G), RS1002046468 (16:30079694 C>T), RS1002172854 (16:30084863 G>A,C), RS1002734374 (16:30079414 T>C), RS1003098311 (16:30074311 C>G), RS1003376375 (16:30078127 A>G), RS1004322221 (16:30084011 C>A), RS1004563036 (16:30084381 G>A), RS1004666606 (16:30075123 T>C), RS1004790230 (16:30080990 G>C)

Disease associations

OMIM: gene MIM:602035 | disease phenotypes: MIM:602066

GenCC curated gene-disease

Mondo (1): infantile convulsions and choreoathetosis (MONDO:0011178)

Orphanet (1): Infantile convulsions and choreoathetosis (Orphanet:31709)

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002539_82	Schizophrenia	5.000000e-11
GCST004521_236	Autism spectrum disorder or schizophrenia	4.000000e-10
GCST006011_45	Mean corpuscular volume	2.000000e-08
GCST006803_23	Schizophrenia	6.000000e-13
GCST007293_15	Body fat distribution (arm fat ratio)	6.000000e-06
GCST007293_81	Body fat distribution (arm fat ratio)	4.000000e-08
GCST007324_29	Adventurousness	3.000000e-08
GCST007611_22	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	7.000000e-09
GCST007928_52	Medication use (diuretics)	4.000000e-13
GCST010703_269	Brain morphology (MOSTest)	4.000000e-13
GCST90002382_436	Eosinophil percentage of white cells	2.000000e-36

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0008579	risk-taking behaviour
EFO:0009928	Diuretic use measurement
EFO:0004346	neuroimaging measurement
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535522	Infantile convulsions and paroxysmal choreoathetosis, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465552 (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: 3 (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
CHEMBL17377	FOSTRIECIN	2	3

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.52	IC50	3	nM	FOSTRIECIN

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 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
[(1E,3R,4R,6R,7Z,9Z,11E)-3,6,13-trihydroxy-3-methyl-1-[(2R)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] dihydrogen phosphate	1973979: Inhibition of PP4 (unknown origin) phosphatase domain	ic50	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	2
Nickel	increases expression	2
Ozone	increases abundance, affects expression, affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases expression, increases abundance, affects cotreatment	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
hexabrominated diphenyl ether 153	decreases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Aspirin	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Catechin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	affects cotreatment, 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
CHEMBL5326481	Binding	Inhibition of PP4 (unknown origin) phosphatase domain	Dual function of protein phosphatase 5 (PPP5C): An emerging therapeutic target for drug discovery. — Eur J Med Chem

Clinical trials (associated diseases)

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