PPA1

Summary

PPA1 (inorganic pyrophosphatase 1, HGNC:9226) is a protein-coding gene on chromosome 10q22.1, encoding Inorganic pyrophosphatase (Q15181). It is a common-essential gene (DepMap: required in 90.6% of cancer cell lines).

The protein encoded by this gene is a member of the inorganic pyrophosphatase (PPase) family. PPases catalyze the hydrolysis of pyrophosphate to inorganic phosphate, which is important for the phosphate metabolism of cells. Studies of a similar protein in bovine suggested a cytoplasmic localization of this enzyme.

Source: NCBI Gene 5464 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 55 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 90.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_021129

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9226
Approved symbol	PPA1
Name	inorganic pyrophosphatase 1
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	SID6-8061, Ppase, IOPPP, PP1
Ensembl gene	ENSG00000180817
Ensembl biotype	protein_coding
OMIM	179030
Entrez	5464

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000373230, ENST00000373232, ENST00000460755, ENST00000495346, ENST00000610026, ENST00000625364, ENST00000851537, ENST00000851538, ENST00000851539, ENST00000915851, ENST00000915852, ENST00000915853, ENST00000963482

RefSeq mRNA: 1 — MANE Select: NM_021129 NM_021129

CCDS: CCDS7299

Canonical transcript exons

ENST00000373232 — 11 exons

Exon	Start	End
ENSE00001261955	70204873	70204915
ENSE00001261965	70206264	70206333
ENSE00001261972	70209205	70209290
ENSE00001261978	70209558	70209685
ENSE00001261983	70213463	70213589
ENSE00001261985	70214500	70214586
ENSE00001261994	70217812	70217931
ENSE00001262004	70218764	70218817
ENSE00001459828	70202835	70203186
ENSE00001459830	70233264	70233429
ENSE00003579518	70230341	70230399

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 145.5988 / max 1085.4831, expressed in 1823 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109829	97.3166	1820
109830	39.7058	1796
109828	8.5763	1676

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.47	gold quality
cerebellar vermis	UBERON:0004720	99.47	gold quality
substantia nigra pars compacta	UBERON:0001965	99.39	gold quality
ventricular zone	UBERON:0003053	99.35	gold quality
germinal epithelium of ovary	UBERON:0001304	99.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.33	gold quality
palpebral conjunctiva	UBERON:0001812	99.32	gold quality
ganglionic eminence	UBERON:0004023	99.30	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.30	gold quality
type B pancreatic cell	CL:0000169	99.29	gold quality
esophagus squamous epithelium	UBERON:0006920	99.29	gold quality
epithelium of esophagus	UBERON:0001976	99.17	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.16	gold quality
colonic mucosa	UBERON:0000317	99.15	gold quality
cortical plate	UBERON:0005343	99.15	gold quality
squamous epithelium	UBERON:0006914	99.14	gold quality
jejunal mucosa	UBERON:0000399	99.13	gold quality
superior vestibular nucleus	UBERON:0007227	99.13	gold quality
middle temporal gyrus	UBERON:0002771	99.11	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.11	gold quality
pigmented layer of retina	UBERON:0001782	99.10	gold quality
pericardium	UBERON:0002407	99.10	gold quality
tibia	UBERON:0000979	99.09	gold quality
cervix epithelium	UBERON:0004801	99.07	gold quality
cervix squamous epithelium	UBERON:0006922	99.07	gold quality
islet of Langerhans	UBERON:0000006	99.05	gold quality
tongue squamous epithelium	UBERON:0006919	99.04	gold quality
mammalian vulva	UBERON:0000997	99.03	gold quality
postcentral gyrus	UBERON:0002581	99.02	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.02	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	4492.45
E-HCAD-4	yes	88.42
E-HCAD-8	yes	53.47
E-MTAB-10287	yes	47.49
E-GEOD-137537	yes	38.18
E-CURD-46	yes	31.26
E-HCAD-6	yes	27.70
E-CURD-122	yes	26.58
E-HCAD-10	yes	19.60
E-MTAB-10042	yes	14.56
E-CURD-88	yes	13.40
E-MTAB-8271	yes	8.88
E-HCAD-9	yes	8.42
E-MTAB-9801	yes	7.63
E-MTAB-6678	yes	7.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, FOXO1, GATA4, MYB

miRNA regulators (miRDB)

26 targeting PPA1, 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-5692A	100.00	74.40	6850
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-101-5P	96.84	65.66	649
HSA-MIR-617	96.79	65.96	738

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 32)

• Neither human hexokinase-1 nor human inorganic pyrophosphatase expression segregated concordantly with human cytoplasmic glutamic-oxaloacetic transaminase expression. (PMID:17494625)
• Data are consistent with the postsynaptic gephyrin scaffold acting as a platform for protein phosphatase 1 (PP1), which regulates gephyrin cluster size by dephosphorylation of gephyrin- or cytoskeleton-associated proteins. (PMID:20206270)
• IRBIT opposes the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities (PMID:21317537)
• PP1gamma is the major histone H3 phosphatase acting on the mitotically phosphorylated residues H3T3ph, H3S10ph, H3T11ph, and H3S28ph. (PMID:21514157)
• Pyrophosphatase overexpression is associated with invasion, metastasis and recurrence in gastric cancer (PMID:22797819)
• Results identify PP1 as a novel regulator of Cl(-)-HCO3(-) anion exchangers activity which, in concert with CFTR, coordinates events at both apical and basolateral membranes, crucial for efficient HCO3(-) secretion from Calu-3 cells. (PMID:23215877)
• PPP1R42 regulation of PP1 function in centrosome separation. (PMID:23718219)
• The human PP1 interaction with the measles V protein is mediated by a conserved PP1-binding motif in the C-terminal region of the V protein. (PMID:25011105)
• Measles virus binding to DC-SIGN leads to inhibition of PP1 phosphatase activity and hence inhibition of RIG-I and Mda5 dephosphorylation. (PMID:25011106)
• findings indicate that brain PP-1I associates with and is regulated by the associated protein kinases C-TAK1 and PFTK1 (PMID:25028520)
• PP-1 and Akt have roles in AR-v7 protein expression and activities when AR is functionally blocked (PMID:26378044)
• PPA1 may serve as a potential biomarker of poor prognosis in patients with gastric cancer (PMID:26722435)
• The Newcastle disease virus-induced translation shutoff at late infection times was attributed to sustaining phosphorylation of eIF2a, which is mediated by continual activation of PKR and degradation of PP1. (PMID:26869028)
• Proteomic profiling identifies the inorganic pyrophosphatase (PPA1) protein as a potential biomarker of metastasis in laryngeal squamous cell carcinoma. (PMID:26948660)
• Thus, the Ska complex, specifically the Ska1 C-terminal domain, recruits PP1 to kinetochores to oppose spindle checkpoint signaling kinases and promote anaphase onset. (PMID:26981768)
• enhanced NEK2 expression in hepatocellular carcinoma (HCC) promotes HCC progression and drug resistance by promoting PP1/Akt and Wnt pathway activation, which may represent a new therapeutic target for HCC. (PMID:27509921)
• Results show that PPA1 expression is significantly higher in many tumors, especially those of lung and ovarian origin, which suggests that PPA1 plays an important role in carcinogenesis and in the development of some tumors. (PMID:27666431)
• PPA1 serves as a potential prognostic biomarker for patients with Ovarian serous carcinoma. (PMID:28202851)
• The p37 controls cortical NuMA levels via the phosphatase PP1 and its regulatory subunit Repo-Man, but it acts independently of Galphai, the kinase Aurora A, and the phosphatase PP2A. (PMID:29222185)
• Study identified phosphorylation of RV[S/T]F motifs in known and previously unidentified PP1 regulatory proteins as a cell cycle-dependent event and shows that Aurora B was the primary kinase responsible for this phosphorylation event during mitosis. (PMID:29764992)
• PP1-NIPP1 expression resulted in the build up of RNA-DNA hybrids (R-loops), enhanced chromatin compaction and a diminished repair of DNA double-strand breaks. (PMID:29898919)
• PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore. (PMID:31433993)
• CDK1-counteracting phosphatases PP1 and PP2A-B55, together with Aurora and Polo kinases, contribute to the temporal regulation and order of events in the different stages of mitotic exit from anaphase to cytokinesis. (Review) (PMID:31494926)
• PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20. (PMID:32755477)
• The PP1 regulator PPP1R2 coordinately regulates AURKA and PP1 to control centrosome phosphorylation and maintain central spindle architecture. (PMID:33238888)
• Mutation of SPINOPHILIN (PPP1R9B) found in human tumors promotes the tumorigenic and stemness properties of cells. (PMID:33537097)
• Crystallographic and modeling study of the human inorganic pyrophosphatase 1: A potential anti-cancer drug target. (PMID:33583053)
• PP1, PKA and DARPP-32 in breast cancer: A retrospective assessment of protein and mRNA expression. (PMID:33991172)
• Basolateral protein Scribble binds phosphatase PP1 to establish a signaling network maintaining apicobasal polarity. (PMID:34634305)
• Inorganic pyrophosphatase 1 activates the phosphatidylinositol 3-kinase/Akt signaling to promote tumorigenicity and stemness properties in colorectal cancer. (PMID:37141926)
• PHI-1, an Endogenous Inhibitor Protein for Protein Phosphatase-1 and a Pan-Cancer Marker, Regulates Raf-1 Proteostasis. (PMID:38136612)
• Structural and biochemical characterization of active sites mutant in human inorganic pyrophosphatase. (PMID:38428647)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppa1b	ENSDARG00000030441
danio_rerio	ppa1a	ENSDARG00000099933
mus_musculus	Ppa1	ENSMUSG00000020089
rattus_norvegicus	Ppa1	ENSRNOG00000063854
drosophila_melanogaster	Nurf-38	FBGN0016687
caenorhabditis_elegans		WBGENE00008149

Paralogs (1): PPA2 (ENSG00000138777)

Protein

Protein identifiers

Inorganic pyrophosphatase — Q15181 (reviewed: Q15181)

Alternative names: Pyrophosphate phospho-hydrolase

All UniProt accessions (3): Q15181, Q5SQT6, V9HWB5

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed ubiquitously.

Similarity. Belongs to the PPase family.

RefSeq proteins (1): NP_066952* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008162	Pyrophosphatase	Family
IPR036649	Pyrophosphatase_sf	Homologous_superfamily

Pfam: PF00719

Enzyme classification (BRENDA):

• EC 3.6.1.1 — inorganic diphosphatase (BRENDA: 104 organisms, 246 substrates, 220 inhibitors, 192 Km, 105 kcat entries)

Substrate kinetics (BRENDA)

25 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DIPHOSPHATE	—	121
MG-DIPHOSPHATE	0.0004–4.2	18
ATP	0.064–4.13	5
MG2+	1.65–4.9	4
TRIPHOSPHATE	0.0167–1.37	4
4-NITROPHENYL PHOSPHATE	69.7	1
ADP	4.43	1
CA-DIPHOSPHATE	0.19	1
CDP	3.12	1
CO-DIPHOSPHATE	0.29	1
CTP	3.61	1
GDP	3.56	1
GTP	3.63	1
GUANOSINE 5’-TETRAPHOSPHATE	0.1554	1
IDP	3.47	1

Catalyzed reactions (Rhea), 1 shown:

• diphosphate + H2O = 2 phosphate + H(+) (RHEA:24576)

UniProt features (48 total): strand 15, sequence conflict 12, helix 7, binding site 4, modified residue 4, turn 3, initiator methionine 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8J7Q	X-RAY DIFFRACTION	1.69
7BTN	X-RAY DIFFRACTION	2.38
6C45	X-RAY DIFFRACTION	2.39
7CMO	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15181-F1	96.22	0.96

Functional residue map

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

Ligand- & substrate-binding residues (4): 116; 121; 121; 153

Post-translational modifications (4): 2, 57, 228, 250

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-71737	Pyrophosphate hydrolysis
R-HSA-1430728	Metabolism
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 261 (showing top): XU_GH1_AUTOCRINE_TARGETS_UP, MODULE_151, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, KYNG_DNA_DAMAGE_DN, KYNG_DNA_DAMAGE_BY_4NQO, TGACCTY_ERR1_Q2, MODULE_331, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, FOSTER_TOLERANT_MACROPHAGE_UP, RAHMAN_TP53_TARGETS_PHOSPHORYLATED, DODD_NASOPHARYNGEAL_CARCINOMA_UP, NADLER_OBESITY_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP, ZAMORA_NOS2_TARGETS_UP, MARTIN_INTERACT_WITH_HDAC

GO Biological Process (1): phosphate-containing compound metabolic process (GO:0006796)

GO Molecular Function (5): magnesium ion binding (GO:0000287), inorganic diphosphate phosphatase activity (GO:0004427), pyrophosphatase activity (GO:0016462), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
tRNA Aminoacylation	1
Metabolism	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
metabolic process	1
metal ion binding	1
pyrophosphatase activity	1
hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

3788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPA1	MPRIP	Q6WCQ1	842
PPA1	PRKG1	P14619	740
PPA1	GPI	P06744	670
PPA1	ATP12A	P54707	630
PPA1	ATP4A	P20648	629
PPA1	TPI1	P00938	578
PPA1	SHMT2	P34897	558
PPA1	AARS1	P49588	549
PPA1	MARS1	P56192	545
PPA1	TP53	P04637	538
PPA1	PRUNE1	Q86TP1	532
PPA1	UGP2	Q16851	532
PPA1	TOP2A	P11388	531
PPA1	YARS1	P54577	530
PPA1	ALDH18A1	P54886	519

IntAct

79 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
MED20	POLR2A	psi-mi:“MI:2364”(proximity)	0.480
LMTK3	GPI	psi-mi:“MI:0914”(association)	0.420
LTK	PIK3R2	psi-mi:“MI:0914”(association)	0.420
PPA1	RPL14	psi-mi:“MI:0915”(physical association)	0.400
PPA1		psi-mi:“MI:0915”(physical association)	0.370
ERBB2	PPA1	psi-mi:“MI:0915”(physical association)	0.370
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
LCA5	IFT56	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
DLD	IRS4	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
MAPK13	DDX3X	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (233): C11orf54 (Co-fractionation), DDAH2 (Co-fractionation), DUT (Co-fractionation), ITPA (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PPA1 (Co-fractionation), PRDX2 (Co-fractionation), STIP1 (Co-fractionation)

ESM2 similar proteins: B0B8Z8, B0BAM7, O13505, O34955, O77460, O84777, P00817, P13998, P19117, P28239, P37980, P44529, P47593, P50308, P51064, P56153, P57190, P58733, P65750, P65751, P75250, P83777, Q15181, Q3KKS0, Q4R543, Q54PV8, Q5B912, Q5R8T6, Q68WE9, Q6BWA5, Q6C1T4, Q6FRB7, Q6MVH7, Q757J8, Q821T4, Q8D274, Q8EVW9, Q8EZ21, Q8KA31, Q8SR69

Diamond homologs: O13505, O77392, O77460, P00817, P13998, P19117, P28239, P37980, P83777, P87118, Q15181, Q18680, Q4R543, Q54PV8, Q5B912, Q5R8T6, Q6BWA5, Q6C1T4, Q6FRB7, Q6MVH7, Q757J8, Q8SR69, Q91VM9, Q93Y52, Q9C0T9, Q9D819, Q9H2U2, Q9LXC9, P75250, P77992, P80562, Q8DHR2, Q8EVW9, Q8TVE2, Q93V56, Q9KCG7, Q821T4, Q9LFF9, A2X8Q3, O23979

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1715 predictions. Top by Δscore:

Variant	Effect	Δscore
10:70203183:TCCA:T	acceptor_gain	1.0000
10:70203184:CCA:C	acceptor_gain	1.0000
10:70203184:CCAC:C	acceptor_gain	1.0000
10:70203185:CA:C	acceptor_gain	1.0000
10:70203185:CAC:C	acceptor_gain	1.0000
10:70203187:C:CC	acceptor_gain	1.0000
10:70203194:C:CT	acceptor_gain	1.0000
10:70204868:CTTA:C	donor_loss	1.0000
10:70204870:TA:T	donor_loss	1.0000
10:70204871:A:AC	donor_gain	1.0000
10:70204871:A:T	donor_loss	1.0000
10:70204872:C:CC	donor_gain	1.0000
10:70204872:CCGT:C	donor_gain	1.0000
10:70204911:GGTAA:G	acceptor_gain	1.0000
10:70204914:AA:A	acceptor_gain	1.0000
10:70204914:AACTA:A	acceptor_loss	1.0000
10:70204916:C:CC	acceptor_gain	1.0000
10:70204916:CTAA:C	acceptor_loss	1.0000
10:70206193:T:TA	donor_gain	1.0000
10:70206262:A:AC	donor_gain	1.0000
10:70206263:C:CC	donor_gain	1.0000
10:70206263:CAG:C	donor_gain	1.0000
10:70206330:CATG:C	acceptor_gain	1.0000
10:70209552:TATTA:T	donor_loss	1.0000
10:70209554:TTA:T	donor_loss	1.0000
10:70209555:TACCT:T	donor_loss	1.0000
10:70209556:ACC:A	donor_loss	1.0000
10:70209557:C:G	donor_loss	1.0000
10:70209562:T:C	donor_gain	1.0000
10:70209681:GATAT:G	acceptor_gain	1.0000

AlphaMissense

1951 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:70217830:G:C	N93K	1.000
10:70217830:G:T	N93K	1.000
10:70209615:C:A	K194N	0.999
10:70209615:C:G	K194N	0.999
10:70209632:A:G	W189R	0.999
10:70209632:A:T	W189R	0.999
10:70213509:T:A	K155N	0.999
10:70213509:T:G	K155N	0.999
10:70213510:T:A	K155I	0.999
10:70213514:A:G	W154R	0.999
10:70213514:A:T	W154R	0.999
10:70213515:G:C	D153E	0.999
10:70213515:G:T	D153E	0.999
10:70213516:T:A	D153V	0.999
10:70213516:T:C	D153G	0.999
10:70213516:T:G	D153A	0.999
10:70213517:C:G	D153H	0.999
10:70214521:A:C	D121E	0.999
10:70214521:A:T	D121E	0.999
10:70214522:T:A	D121V	0.999
10:70214537:T:A	D116V	0.999
10:70214537:T:G	D116A	0.999
10:70217825:C:T	G95D	0.999
10:70217835:A:G	W92R	0.999
10:70217835:A:T	W92R	0.999
10:70217844:C:G	G89R	0.999
10:70217844:C:T	G89R	0.999
10:70218770:T:A	K57N	0.999
10:70218770:T:G	K57N	0.999
10:70213531:T:A	D148V	0.998

dbSNP variants (sampled 300 via entrez): RS1000041882 (10:70229618 A>G), RS1000103873 (10:70225582 G>A,T), RS1000136142 (10:70229821 C>T), RS1000315676 (10:70232388 G>A), RS1000386020 (10:70235379 G>A), RS1000485739 (10:70212931 T>C), RS1000576194 (10:70209443 A>G), RS1000637050 (10:70203402 A>G), RS1000651314 (10:70220367 C>T), RS1001093107 (10:70207142 A>C,G), RS1001312665 (10:70204707 C>A,T), RS1001313550 (10:70216999 C>A), RS1001362968 (10:70204967 C>T), RS1001389647 (10:70233538 C>A,G,T), RS1001461616 (10:70220011 T>A)

Disease associations

OMIM: gene MIM:179030 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067227 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.88	Kd	1313	nM	CHEMBL5653589
5.88	ED50	1313	nM	CHEMBL5653589
5.07	Kd	8443	nM	CHEMBL3752910
5.07	ED50	8443	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149039: Binding affinity to human PPA1 incubated for 45 mins by Kinobead based pull down assay	kd	1.3130	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149039: Binding affinity to human PPA1 incubated for 45 mins by Kinobead based pull down assay	kd	8.4434	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Valproic Acid	affects cotreatment, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression	2
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, increases expression	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	increases reaction, affects binding	1
sodium phosphate	increases hydrolysis	1
bufalin	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	increases expression	1
microcystin RR	decreases expression, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
azoxystrobin	increases expression	1
chloropicrin	affects expression	1
enniatins	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Capecitabine	increases response to substance	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benztropine	increases expression, 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
CHEMBL5652081	Binding	Binding affinity to human PPA1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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