PPP6C

Summary

PPP6C (protein phosphatase 6 catalytic subunit, HGNC:9323) is a protein-coding gene on chromosome 9q33.3, encoding Serine/threonine-protein phosphatase 6 catalytic subunit (O00743). Catalytic subunit of protein phosphatase 6 (PP6). It is a selective cancer dependency (DepMap: 49.3% of cell lines).

This gene encodes the catalytic subunit of protein phosphatase, a component of a signaling pathway regulating cell cycle progression. Splice variants encoding different protein isoforms exist. The pseudogene of this gene is located on chromosome X.

Source: NCBI Gene 5537 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 41 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 49.3% of screened cell lines
• MANE Select transcript: NM_002721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9323
Approved symbol	PPP6C
Name	protein phosphatase 6 catalytic subunit
Location	9q33.3
Locus type	gene with protein product
Status	Approved
Aliases	PP6
Ensembl gene	ENSG00000119414
Ensembl biotype	protein_coding
OMIM	612725
Entrez	5537

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000373547, ENST00000415905, ENST00000451402, ENST00000456642, ENST00000889868, ENST00000919409, ENST00000919410

RefSeq mRNA: 3 — MANE Select: NM_002721 NM_001123355, NM_001123369, NM_002721

CCDS: CCDS48018, CCDS48019, CCDS6861

Canonical transcript exons

ENST00000373547 — 7 exons

Exon	Start	End
ENSE00000806631	125160841	125160906
ENSE00000806632	125158241	125158382
ENSE00001694091	125153533	125153742
ENSE00001836546	125189644	125189803
ENSE00001869249	125146573	125149921
ENSE00003526355	125153906	125153985
ENSE00003641745	125171085	125171180

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.5233 / max 288.0773, expressed in 1809 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102467	21.2887	1808
102465	1.4441	737
102466	0.7719	453
102468	0.7374	457
102469	0.2812	137

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.04	gold quality
sperm	CL:0000019	98.75	gold quality
secondary oocyte	CL:0000655	98.37	gold quality
male germ cell	CL:0000015	98.20	gold quality
cervix squamous epithelium	UBERON:0006922	98.00	gold quality
gingival epithelium	UBERON:0001949	97.96	gold quality
parotid gland	UBERON:0001831	97.91	gold quality
gingiva	UBERON:0001828	97.76	gold quality
buccal mucosa cell	CL:0002336	97.72	gold quality
tongue squamous epithelium	UBERON:0006919	97.20	gold quality
squamous epithelium	UBERON:0006914	96.89	gold quality
palpebral conjunctiva	UBERON:0001812	96.85	gold quality
amniotic fluid	UBERON:0000173	96.65	gold quality
oviduct epithelium	UBERON:0004804	96.58	gold quality
deltoid	UBERON:0001476	96.29	gold quality
epithelium of nasopharynx	UBERON:0001951	96.28	gold quality
tibialis anterior	UBERON:0001385	96.26	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.18	gold quality
mammalian vulva	UBERON:0000997	96.10	gold quality
epithelium of esophagus	UBERON:0001976	96.10	gold quality
upper leg skin	UBERON:0004262	96.10	gold quality
biceps brachii	UBERON:0001507	96.09	gold quality
esophagus squamous epithelium	UBERON:0006920	96.08	gold quality
oral cavity	UBERON:0000167	95.99	gold quality
hair follicle	UBERON:0002073	95.94	gold quality
colonic mucosa	UBERON:0000317	95.89	gold quality
vastus lateralis	UBERON:0001379	95.87	gold quality
cranial nerve II	UBERON:0000941	95.81	gold quality
quadriceps femoris	UBERON:0001377	95.80	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	483.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 49.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 31)

• Protein phosphatase 6 subunit with conserved Sit4-associated protein domain targets IkappaBepsilon (PMID:16769727)
• PP6 regulates cell cycle progression in human cells at least in part through control of cyclin D1 and the function of PP6 is distinct from its homolog Sit4 in yeast. (PMID:17568194)
• Our data demonstrate that protein phosphatase-6 associates with and activates DNA-PK in response to ionizing radiation. (PMID:19198648)
• results illustrate that the human PP6-associated proteins are capable of providing distinct rapamycin-sensitive and Sit4-dependent Sap functions in the heterologous context of the yeast cell (PMID:19621075)
• our results seem to discard the role of the previously described polymorphisms in SERPINE2, PPP6C and PBX3 in celiac disease susceptibility. (PMID:19626039)
• A novel function of DNA-PKcs is to recruit PP6 to sites of DNA damage and that PP6 contributes to the dephosphorylation of gamma-H2AX, the dissolution of ionizing radiation-induced foci, and release from the G(2)/M checkpoint in vivo. (PMID:20065038)
• Results demonstrate a role for PP6 as the T-loop phosphatase regulating Aurora A activity bound to its activator TPX2 during mitotic spindle formation. (PMID:21187329)
• PP6 is required for non-homologous end joining repair; its expression may harbor a protective role during the development of breast cancer tissues. (PMID:21451261)
• miR-373 can regulate cell cycle progression by targeting PPP6C transcripts and promotes the growth activity of HCC cells in vitro. The downregulation of PPP6C by miR-373 may explain why the expression of miR-373 can promote HCC cell proliferation. (PMID:21481188)
• Findings support the view that formation of micronuclei rather than chromosome instability alone explains how loss of PPP6C, and more generally mitotic spindle and centrosome defects, can act as drivers for genome instability in melanoma. (PMID:23729733)
• Results show that Sit4p and its mammalian orthologue, PP6, regulate traffic from the ER to the Golgi complex which is consistent with its role in coat recycling. (PMID:23864707)
• PP6c associates with E-cadherin in adherens junctions and is required to oppose casein kinase-1 to maintain cell surface localization of E-cadherin. (PMID:24063632)
• PP2A holoenzyme and PP6 were found stably associated with U1 snRNP; findings indicate that these phosphatases regulate splicing catalysis involving U1 snRNP and suggest an important evolutionary conserved role of PP2A family phosphatases in pre-mRNA splicing (PMID:24064353)
• PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors. (PMID:24336958)
• These results suggest that human PP6 interacts with and positively regulates the activity of the influenza A virus RNA-dependent RNA polymerase. (PMID:25187537)
• PP6 is involved in a diverse set of biological pathways. (PMID:25999147)
• Protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. (PMID:26138368)
• Data show 408 phosphopeptides on 272 proteins that increased and 298 phosphopeptides on 220 proteins that decreased in phosphorylation upon catalytic subunit of rotein phosphatase 6 (PP6c) depletion in mitotic cells. (PMID:26462736)
• findings suggest that BRCA1 is a novel modulator of PP6 signalling via its interaction with ANKRD28. (PMID:27026398)
• Knockdown of Alpha4 preferentially impacts the expression of PP4c and PP6c compared to expression levels of PP2Ac. (PMID:27169767)
• findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate antiviral immunity. (PMID:29053956)
• PP6 rapidly interacts with ASK3 in an osmolality-dependent manner, and it inactivates ASK3 to induce RVI and, thereby, cell survival under hyperosmotic stress. (PMID:29539411)
• Data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit. Thus, a mechanism for the previously puzzling observation of the Plk1-dependent regulation of Aurora A has been identified. (PMID:29764989)
• Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response. (PMID:32474700)
• PPP6C Negatively Regulates STING-Dependent Innate Immune Responses. (PMID:32753499)
• PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. (PMID:33789117)
• Protein phosphatase 6 promotes neurite outgrowth by promoting mTORC2 activity in N2a cells. (PMID:34314486)
• MiR-20a-5p functions as a potent tumor suppressor by targeting PPP6C in acute myeloid leukemia. (PMID:34587164)
• PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote TNFalpha-mediated cell death. (PMID:36071040)
• M6A-induced transcription factor IRF5 contributes to the progression of cervical cancer by upregulating PPP6C. (PMID:38745265)
• The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis. (PMID:38807188)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp6c	ENSDARG00000002949
mus_musculus	Ppp6c	ENSMUSG00000026753
rattus_norvegicus	Ppp6c	ENSRNOG00000015145
drosophila_melanogaster	PpV	FBGN0003139
caenorhabditis_elegans		WBGENE00007922

Paralogs (12): PPP5C (ENSG00000011485), PPEF1 (ENSG00000086717), PPP2CB (ENSG00000104695), PPP3CB (ENSG00000107758), PPP2CA (ENSG00000113575), PPP3CC (ENSG00000120910), PPP3CA (ENSG00000138814), PPP4C (ENSG00000149923), PPEF2 (ENSG00000156194), PPP1CA (ENSG00000172531), PPP1CC (ENSG00000186298), PPP1CB (ENSG00000213639)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 6 catalytic subunit — O00743 (reviewed: O00743)

All UniProt accessions (3): O00743, A0A024R861, Q5T1S7

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of protein phosphatase 6 (PP6). PP6 is a component of a signaling pathway regulating cell cycle progression in response to IL2 receptor stimulation. N-terminal domain restricts G1 to S phase progression in cancer cells, in part through control of cyclin D1. During mitosis, regulates spindle positioning. Down-regulates MAP3K7 kinase activation of the IL1 signaling pathway by dephosphorylation of MAP3K7. Also participates in the innate immune defense against viruses by desphosphorylating RIGI, an essential step that triggers RIGI-mediated signaling activation. Also regulates innate immunity by acting as a negative regulator of the cGAS-STING pathway: mediates dephosphorylation and inactivation of CGAS and STING1. CGAS dephosphorylation at ‘Ser-435’ impairs its ability to bind GTP, thereby inactivating it.

Subunit / interactions. Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with subunits PPP6R1, PPP6R2 and PPP6R3. Interacts with subunit ANKRD28. Interacts with IGBP1. Interacts with MAP3K7. Interacts with NFKBIE. Interacts with TRIM14 and WRNIP1; these interactions positively regulate the RIG-I signaling pathway.

Subcellular location. Mitochondrion. Cytoplasm.

Tissue specificity. Ubiquitously expressed in all tissues tested with highest expression levels in testis, heart, kidney, brain, stomach, liver and skeletal muscle and lowest in placenta, lung colon and spleen.

Cofactor. Binds 2 manganese ions per subunit.

Induction. Regulated by IL2/interleukin-2 in peripheral blood T cells.

Similarity. Belongs to the PPP phosphatase family. PP-6 (PP-V) subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
O00743-1	1	yes
O00743-2	2
O00743-3	3

RefSeq proteins (3): NP_001116827, NP_001116841, NP_002712* (*=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 (18 total): binding site 7, sequence variant 3, chain 2, splice variant 2, initiator methionine 1, modified residue 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00743-F1	95.80	0.94

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): 114 (proton donor)

Ligand- & substrate-binding residues (7): 237; 53; 55; 81; 81; 113; 163

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-171319	Telomere Extension By Telomerase
R-HSA-204005	COPII-mediated vesicle transport

MSigDB gene sets: 273 (showing top): MORF_MBD4, MORF_RAB5A, LU_IL4_SIGNALING, GOBP_VESICLE_LOCALIZATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_VESICLE_ORGANIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_VESICLE_TARGETING, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, MORF_SKP1A, GOBP_REGULATION_OF_IMMUNE_RESPONSE

GO Biological Process (7): G1/S transition of mitotic cell cycle (GO:0000082), protein dephosphorylation (GO:0006470), innate immune response (GO:0045087), COPII vesicle coat assembly (GO:0048208), negative regulation of cGAS/STING signaling pathway (GO:0160049), immune system process (GO:0002376), cGAS/STING signaling pathway (GO:0140896)

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 (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Extension of Telomeres	1
ER to Golgi Anterograde Transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
dephosphorylation	1
protein modification process	1
immune response	1
defense response to symbiont	1
vesicle coat assembly	1
protein-containing complex assembly	1
COPII-coated vesicle budding	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
cGAS/STING signaling pathway	1
biological_process	1
cytoplasmic pattern recognition receptor signaling pathway	1
phosphoprotein phosphatase activity	1
cation binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

4102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP6C	PPP6R1	Q9UPN7	992
PPP6C	PPP6R3	Q5H9R7	971
PPP6C	PPP6R2	O75170	954
PPP6C	NFKBIE	O00221	901
PPP6C	TIPRL	O75663	879
PPP6C	TRIM14	Q14142	846
PPP6C	ANKRD52	Q8NB46	838
PPP6C	IGBP1	P78318	816
PPP6C	EIF2AK4	Q9P2K8	798
PPP6C	ANKRD28	O15084	744
PPP6C	SF3B1	O75533	732
PPP6C	ANKRD44	Q8N8A2	688
PPP6C	PPP2R1A	P30153	688
PPP6C	WHR1	P49842	679
PPP6C	PPP4R2	Q9NY27	646

IntAct

166 interactions, top by confidence:

A	B	Type	Score
IGBP1	PPP6C	psi-mi:“MI:0914”(association)	0.940
PPP6C	IGBP1	psi-mi:“MI:0915”(physical association)	0.940
IGBP1	PPP6C	psi-mi:“MI:0915”(physical association)	0.940
PPP6C	PPP6R1	psi-mi:“MI:0915”(physical association)	0.920
PPP6R1	PPP6C	psi-mi:“MI:0914”(association)	0.920
PPP6C	ANKRD28	psi-mi:“MI:0914”(association)	0.870
PPP6C	PPP6R2	psi-mi:“MI:0915”(physical association)	0.870
PPP6C	ANKRD28	psi-mi:“MI:0915”(physical association)	0.870
ANKRD28	PPP6C	psi-mi:“MI:0914”(association)	0.870
PPP6R2	PPP6C	psi-mi:“MI:0914”(association)	0.870
PPP6R3	PPP6C	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (394): PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS), CSNK1D (Affinity Capture-Western), PPP6C (Affinity Capture-MS), PPP6C (Co-fractionation), PPP6C (Affinity Capture-MS), PPP6C (Proximity Label-MS), PPP6C (Proximity Label-MS), PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS), PPP6C (Affinity Capture-MS)

ESM2 similar proteins: A0C1E4, A0CCD2, A0DJ90, A6H772, A8WGP3, A9JRC7, O00743, O04951, O76932, P11084, P20604, P23778, P32345, P36614, P48528, P48529, P48578, P49576, P60510, P63330, P63331, P67774, P67775, P67776, P67777, P97470, Q06009, Q07099, Q07100, Q10298, Q27884, Q54RD6, Q59KY8, Q5BJ92, Q5R6K8, Q64620, Q6BFF6, Q6CNT6, Q6FM81, Q6IP91

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

9 interactions.

A	Effect	B	Mechanism
PPP6C	down-regulates	MAP3K7	dephosphorylation
PPP6C	“down-regulates activity”	MAP3K7	dephosphorylation
PPP6C	“up-regulates activity”	AGO2	dephosphorylation
PPP6C	“down-regulates activity”	CGAS	dephosphorylation
PPP6C	“up-regulates activity”	PRKDC	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 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
TP53 Regulates Metabolic Genes	5	9.1×	6e-03
KEAP1-NFE2L2 pathway	5	8.5×	8e-03
Signaling by Interleukins	7	6.3×	5e-03
Ub-specific processing proteases	7	5.2×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	16.3×	4e-03
MAPK cascade	7	12.1×	1e-03
negative regulation of apoptotic process	14	5.5×	3e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — BCC, MEL, SKCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1274 predictions. Top by Δscore:

Variant	Effect	Δscore
9:125149918:CAAA:C	acceptor_gain	1.0000
9:125153739:TTAA:T	acceptor_gain	1.0000
9:125153740:TAA:T	acceptor_gain	1.0000
9:125153743:C:CC	acceptor_gain	1.0000
9:125153901:CTTAC:C	donor_loss	1.0000
9:125153902:TTAC:T	donor_loss	1.0000
9:125153904:A:AC	donor_gain	1.0000
9:125153905:C:CA	donor_gain	1.0000
9:125153905:CA:C	donor_gain	1.0000
9:125153905:CAG:C	donor_gain	1.0000
9:125153981:CTCAT:C	acceptor_gain	1.0000
9:125153982:TCAT:T	acceptor_gain	1.0000
9:125153983:CAT:C	acceptor_gain	1.0000
9:125153983:CATC:C	acceptor_gain	1.0000
9:125153984:AT:A	acceptor_gain	1.0000
9:125153985:TC:T	acceptor_loss	1.0000
9:125153986:C:CA	acceptor_loss	1.0000
9:125153986:C:CC	acceptor_gain	1.0000
9:125153988:G:C	acceptor_gain	1.0000
9:125153988:G:GC	acceptor_gain	1.0000
9:125158379:CACC:C	acceptor_gain	1.0000
9:125160902:TAAAA:T	acceptor_gain	1.0000
9:125160907:C:CC	acceptor_gain	1.0000
9:125171079:TTTTA:T	donor_loss	1.0000
9:125171080:TTTA:T	donor_loss	1.0000
9:125171081:TTA:T	donor_loss	1.0000
9:125171082:TACC:T	donor_loss	1.0000
9:125171083:ACCTG:A	donor_loss	1.0000
9:125171084:CC:C	donor_loss	1.0000
9:125171176:AGCCG:A	acceptor_gain	1.0000

AlphaMissense

1989 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:125149679:G:C	F304L	1.000
9:125149679:G:T	F304L	1.000
9:125149681:A:G	F304L	1.000
9:125149785:G:A	A269V	1.000
9:125149785:G:T	A269D	1.000
9:125149790:A:C	N267K	1.000
9:125149790:A:T	N267K	1.000
9:125149805:G:C	C262W	1.000
9:125149809:T:C	Y261C	1.000
9:125149810:A:G	Y261H	1.000
9:125149815:G:T	P259H	1.000
9:125149818:G:T	A258D	1.000
9:125149821:G:A	S257F	1.000
9:125149823:C:A	W256C	1.000
9:125149823:C:G	W256C	1.000
9:125149825:A:G	W256R	1.000
9:125149825:A:T	W256R	1.000
9:125149863:C:A	G243V	1.000
9:125149863:C:T	G243D	1.000
9:125149864:C:A	G243C	1.000
9:125149864:C:G	G243R	1.000
9:125149875:A:G	L239P	1.000
9:125149875:A:T	L239Q	1.000
9:125149877:T:A	Q238H	1.000
9:125149877:T:G	Q238H	1.000
9:125149880:A:C	H237Q	1.000
9:125149880:A:T	H237Q	1.000
9:125149881:T:A	H237L	1.000
9:125149881:T:C	H237R	1.000
9:125149882:G:C	H237D	1.000

dbSNP variants (sampled 300 via entrez): RS1000061399 (9:125189086 A>T), RS1000065971 (9:125161844 T>C), RS1000108773 (9:125149765 C>T), RS1000183448 (9:125170480 A>C), RS1000214591 (9:125172772 A>C), RS1000218735 (9:125155920 A>C), RS1000259100 (9:125177504 C>G,T), RS1000333897 (9:125177760 A>T), RS1000415360 (9:125168224 T>C), RS1000416380 (9:125148470 G>T), RS1000436635 (9:125149476 G>A), RS1000592305 (9:125184169 C>T), RS1000648706 (9:125178398 G>A), RS1000673682 (9:125156230 T>C), RS1000701109 (9:125178576 C>A)

Disease associations

OMIM: gene MIM:612725 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007096_148	Pulse pressure	1.000000e-13
GCST007097_156	Pulse pressure	1.000000e-06
GCST007099_254	Systolic blood pressure	5.000000e-07
GCST007267_338	Systolic blood pressure	7.000000e-10
GCST010002_280	Refractive error	1.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105731 (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: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5268133
8.00	IC50	10	nM	CALYCULIN A
6.79	Kd	163	nM	CHEMBL5653589
6.79	ED50	163	nM	CHEMBL5653589
6.46	IC50	350	nM	MOLIBRESIB

PubChem BioAssay actives

4 with measured affinity, of 13 total; 4 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
(2R)-3-[(2S,6R,11R)-2-[(E,2S)-4-[(2S,2’R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5’-oxolane]-2’-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid	1924793: Inhibition of PP6 (unknown origin)	ic50	0.0010	uM
[(2R,3R,5R,7R,8S,9S)-2-[(1S,3S,4S,5R,6R,7E,9E,11E,13Z)-14-cyano-3,5-dihydroxy-1-methoxy-4,6,8,9,13-pentamethyltetradeca-7,9,11,13-tetraenyl]-9-[(E)-3-[2-[(2S)-4-[[(2S,3S,4S)-4-(dimethylamino)-2,3-dihydroxy-5-methoxypentanoyl]amino]butan-2-yl]-1,3-oxazol-4-yl]prop-2-enyl]-7-hydroxy-4,4,8-trimethyl-1,10-dioxaspiro[4.5]decan-3-yl] dihydrogen phosphate	1924807: Inhibition of PP6 (unknown origin) using [3H]-phosphohistone as substrate by liquid scintillation counting analysis	ic50	0.0100	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149057: Binding affinity to human PPP6C incubated for 45 mins by Kinobead based pull down assay	kd	0.1630	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179070: Inhibition of PPP6C (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.3500	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, decreases expression	2
bisphenol A	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
chloropicrin	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Methapyrilene	increases methylation	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	increases abundance, decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012574	Binding	Binding affinity to serine/threonine-protein phosphatase 6 catalytic subunit in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Clinical trials (associated diseases)

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