PPM1K

Summary

PPM1K (protein phosphatase, Mg2+/Mn2+ dependent 1K, HGNC:25415) is a protein-coding gene on chromosome 4q22.1, encoding Protein phosphatase Mn(2+)-dependent 1K (Q8N3J5). Serine/threonine-protein phosphatase component of macronutrients metabolism.

This gene encodes a member of the PPM family of Mn2+/Mg2+-dependent protein phosphatases. The encoded protein, essential for cell survival and development, is targeted to the mitochondria where it plays a key role in regulation of the mitochondrial permeability transition pore.

Source: NCBI Gene 152926 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maple syrup urine disease, mild variant (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 152 total — 2 pathogenic
• Phenotypes (HPO): 3
• MANE Select transcript: NM_152542

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25415
Approved symbol	PPM1K
Name	protein phosphatase, Mg2+/Mn2+ dependent 1K
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp761G058, PP2Ckappa, hPTMP, PP2Cm, BDP
Ensembl gene	ENSG00000163644
Ensembl biotype	protein_coding
OMIM	611065
Entrez	152926

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000295908, ENST00000505022, ENST00000506423, ENST00000508256, ENST00000509340, ENST00000510548, ENST00000511506, ENST00000513546, ENST00000514204, ENST00000608933, ENST00000882963, ENST00000882964, ENST00000882965, ENST00000951959, ENST00000951960, ENST00000951961, ENST00000951962

RefSeq mRNA: 1 — MANE Select: NM_152542 NM_152542

CCDS: CCDS3629

Canonical transcript exons

ENST00000608933 — 7 exons

Exon	Start	End
ENSE00002032702	88284406	88284561
ENSE00003611246	88268741	88268906
ENSE00003648348	88265001	88265135
ENSE00003703060	88268190	88268334
ENSE00003707109	88277143	88277243
ENSE00003708574	88257620	88262726
ENSE00003710874	88278144	88278642

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5455 / max 254.6478, expressed in 1532 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53085	5.6780	1266
53088	2.2496	484
53089	1.3760	359
53083	0.8028	326
53084	0.5278	231
53086	0.5009	239
53087	0.3661	191
53082	0.0443	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.82	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.37	gold quality
myocardium	UBERON:0002349	98.67	gold quality
heart right ventricle	UBERON:0002080	97.81	gold quality
oviduct epithelium	UBERON:0004804	97.54	gold quality
postcentral gyrus	UBERON:0002581	97.20	gold quality
parietal lobe	UBERON:0001872	96.90	gold quality
middle temporal gyrus	UBERON:0002771	96.87	gold quality
kidney epithelium	UBERON:0004819	96.79	gold quality
medial globus pallidus	UBERON:0002477	96.57	gold quality
globus pallidus	UBERON:0001875	96.23	gold quality
superior frontal gyrus	UBERON:0002661	96.13	gold quality
palpebral conjunctiva	UBERON:0001812	95.74	gold quality
substantia nigra pars compacta	UBERON:0001965	95.63	gold quality
pons	UBERON:0000988	95.51	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.48	gold quality
ileal mucosa	UBERON:0000331	95.45	gold quality
ventricular zone	UBERON:0003053	95.36	gold quality
endothelial cell	CL:0000115	95.29	gold quality
tibialis anterior	UBERON:0001385	95.29	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.23	gold quality
superficial temporal artery	UBERON:0001614	95.16	gold quality
cardiac ventricle	UBERON:0002082	95.14	gold quality
heart left ventricle	UBERON:0002084	95.04	gold quality
entorhinal cortex	UBERON:0002728	95.03	gold quality
superior vestibular nucleus	UBERON:0007227	95.02	gold quality
vena cava	UBERON:0004087	94.95	gold quality
germinal epithelium of ovary	UBERON:0001304	94.82	gold quality
adult organism	UBERON:0007023	94.72	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	14.99
E-CURD-122	yes	13.27
E-CURD-112	yes	12.00
E-ANND-3	yes	10.44
E-MTAB-6678	yes	4.47
E-MTAB-6386	no	390.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

242 targeting PPM1K, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
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-9-5P	100.00	72.28	2361
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 11)

• A novel member of human protein phosphatase 2C gene family named PP2Ckappa was isolated from a human fetal brain cDNA library. (PMID:16685424)
• The cloned phosphatase has a mitochondrial leader sequence and its amino acid sequence places it in the PP2C family like two known mitochondrial phosphatases. (PMID:17336929)
• The 2.4 A PP2Cm structure reveals a central beta-sandwich with two bound metal ions in the active-site cleft. (PMID:22291014)
• Overweight people with the C allele of the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 may benefit less in weight loss and improved insulin sensitivity than those without it on a energy-restricted high-fat diet. (PMID:23446828)
• miR-204 and miR-211 directly repress PPM1K expression via 3’UTR. (PMID:26592513)
• PPM1K rs1440581 may affect changes in glucose metabolism during weight loss, and this effect is dependent on dietary fat and carbohydrate intakes. (PMID:28768654)
• Branched chain amino acids related genetic variant rs1440581 was associated with an increased risk of incident T2 Diabetes in a Chinese population. This variant might modify effect of weight gain on development in Insulin resistance. (PMID:29855804)
• three Mg(2+) were located in the active site of the PPM1K N94K instead of two Mg(2+) in the PPM1K wild type (PMID:30451284)
• The role of PP5 and PP2C in cardiac health and disease. (PMID:33964402)
• Effects of PPM1K rs1440581 and rs7678928 on serum branched-chain amino acid levels and risk of cardiovascular disease. (PMID:34382495)
• PPM1K-regulated impaired catabolism of branched-chain amino acids orchestrates polycystic ovary syndrome. (PMID:36863088)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppm1kb	ENSDARG00000010655
danio_rerio	ppm1ka	ENSDARG00000076011
mus_musculus	Ppm1k	ENSMUSG00000037826
rattus_norvegicus	Ppm1k	ENSRNOG00000006893
drosophila_melanogaster	CG10376	FBGN0032702
caenorhabditis_elegans		WBGENE00001412

Paralogs (16): PPM1F (ENSG00000100034), TAB1 (ENSG00000100324), PPM1A (ENSG00000100614), PPM1H (ENSG00000111110), PPM1G (ENSG00000115241), ILKAP (ENSG00000132323), PPM1B (ENSG00000138032), PPM1J (ENSG00000155367), PPM1L (ENSG00000163590), PPM1M (ENSG00000164088), PDP1 (ENSG00000164951), PPM1D (ENSG00000170836), PDP2 (ENSG00000172840), PPM1E (ENSG00000175175), PP2D1 (ENSG00000183977), PPM1N (ENSG00000213889)

Protein

Protein identifiers

Protein phosphatase Mn(2+)-dependent 1K — Q8N3J5 (reviewed: Q8N3J5)

Alternative names: Branched-chain alpha-ketoacid dehydrogenase phosphatase, PP2C domain-containing protein phosphatase 1K, PP2C-like mitochondrial protein, PP2C-type mitochondrial phosphoprotein phosphatase, Protein phosphatase 2C family member, Protein phosphatase 2C isoform kappa, [3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase, mitochondrial

All UniProt accessions (6): A0A0A0MQZ4, Q8N3J5, V9GY69, V9GYI6, V9GYS8, V9GYZ5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein phosphatase component of macronutrients metabolism. Forms a functional kinase and phosphatase pair with BCKDK, serving as a metabolic regulatory node that coordinates branched-chain amino acids (BCAAs) with glucose and lipid metabolism via two distinct phosphoprotein targets: mitochondrial BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex and cytosolic ACLY, a lipogenic enzyme of Krebs cycle. At high levels of branched-chain ketoacids, dephosphorylates and activates mitochondrial BCKDH complex, a multisubunit complex consisting of three multimeric components each involved in different steps of BCAA catabolism: E1 composed of BCKDHA and BCKDHB, E2 core composed of DBT monomers, and E3 composed of DLD monomers. Tightly associates with the E2 component of BCKDH complex and dephosphorylates BCKDHA on Ser-337. Regulates the reversible phosphorylation of ACLY in response to changes in cellular carbohydrate abundance such as occurs during fasting to feeding metabolic transition. At fasting state, appears to dephosphorylate ACLY on Ser-455 and inactivate it. Refeeding stimulates MLXIPL/ChREBP transcription factor, leading to increased BCKDK to PPM1K expression ratio, phosphorylation and activation of ACLY that ultimately results in the generation of malonyl-CoA and oxaloacetate immediate substrates of de novo lipogenesis and gluconeogenesis, respectively. Recognizes phosphosites having SxS or RxxS motifs and strictly depends on Mn(2+) ions for the phosphatase activity. Regulates Ca(2+)-induced opening of mitochondrial transition pore and apoptotic cell death.

Subunit / interactions. Monomer. Interacts with E1 and E2 components of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex; this interaction requires colocalization in mitochondria. Interacts with BCKDHA but not with BCKDHB of the E1 component. Interacts with the 24-meric E2 core composed of DBT monomers with a 24:1 stoichiometry; the N-terminal region (residues 49-61) of PPM1K and C-terminal linker of the lipoyl domain of DBT (residues 145-160) are critical for this interaction, whereas the lipoyl prosthetic group is dispensable. Competes with BCKDK for binding to the E2 core; this interaction is modulated by branched-chain alpha-keto acids. At steady state, BCKDH holoenzyme preferentially binds BCKDK and BCKDHA is phosphorylated. In response to high levels of branched-chain alpha-keto acids, the inhibitory BCKDK is replaced by activating PPM1K leading to BCKDHA dephosphorylation and BCAA degradation.

Subcellular location. Mitochondrion matrix.

Disease relevance. Maple syrup urine disease, mild variant (MSUDMV) [MIM:615135] A mild form of maple syrup urine disease, a metabolic disorder due to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration. Clinical features include mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine. If untreated, maple syrup urine disease can lead to seizures, coma, and death. The disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still involve developmental delay and other medical problems if not treated. MSUDMV is characterized by increased plasma levels of branched-chain amino acids (BCAA) apparent at birth. Treatment with a low-protein diet free of BCAA can result in normal psychomotor development and lack of metabolic episodes. The gene represented in this entry is involved in disease pathogenesis.

Activity regulation. Up-regulated upon interaction with the 24-meric DBT/E2 core of the BCKDH complex. Inhibited by Mg(2+) and Ca(2+) ions likely by competing with Mn(2+) ions for binding to the same metal-binding sites.

Cofactor. Binds 2 Mn(2+) ions per subunit.

Pathway. Protein modification.

Similarity. Belongs to the PP2C family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N3J5-1	1	yes
Q8N3J5-2	2
Q8N3J5-3	3

RefSeq proteins (1): NP_689755* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000222	PP2C_BS	Binding_site
IPR001932	PPM-type_phosphatase-like_dom	Domain
IPR015655	PP2C	Family
IPR036457	PPM-type-like_dom_sf	Homologous_superfamily

Pfam: PF00481

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)
• EC 3.1.3.52 — [3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase (BRENDA: 4 organisms, 8 substrates, 44 inhibitors, 4 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
P-NITROPHENYL PHOSPHATE	3–200	11
RRAPTVA	0.058–1.954	4
4-NITROPHENYL PHOSPHATE	3.8–50.9	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3
PHOSPHORYLATED MYOSIN LIGHT CHAIN PEPTIDE	0.01–0.11	3
PHOSPHOSERINE-MYELIN BASIC PROTEIN	0.0004–0.022	3
DLDVPIPGRFDRRVSVAAE	0.0006–0.0138	2
DLDVPIPGRFDRRVY(P)VAAE	0.0025–0.023	2
PHOSPHORYLASE A	0.004–0.021	2
RRA(PT)VA	0.0536–0.308	2
80S-RIBOSOME	0.0027	1
AAAPTVA	0.206	1

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-seryl-[3-methyl-2-oxobutanoate dehydrogenase] + H2O = L-seryl-[3-methyl-2-oxobutanoate dehydrogenase] + phosphate (RHEA:77247)

UniProt features (59 total): strand 15, helix 9, mutagenesis site 7, turn 5, binding site 5, splice variant 4, sequence variant 4, sequence conflict 4, region of interest 2, transit peptide 1, chain 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2IQ1	X-RAY DIFFRACTION	2.25
4DA1	X-RAY DIFFRACTION	2.38
6AK7	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N3J5-F1	83.07	0.68

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 (5): 127; 127; 128; 298; 337

Post-translational modifications (1): 248

Mutagenesis-validated functional residues (7):

Position	Phenotype
104	decreases the affinity toward bckdha by 61-fold. decreases the catalytic efficiency toward bckdha down to 2%.
109	loss of serine/threonine phosphatase activity toward bckdha.
127	loss of serine/threonine phosphatase activity toward bckdha.
129	slightly decreases the catalytic efficiency toward bckdha. does not affect the interaction with dbt.
236	complete loss of serine/threonine phosphatase activity toward bckdha. does not affect the interaction with dbt.
298	loss of serine/threonine phosphatase activity toward bckdha. does not affect the interaction with dbt.
337	loss of serine/threonine phosphatase activity toward bckdha.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9912529	H139Hfs13* PPM1K causes a mild variant of MSUD

MSigDB gene sets: 244 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, ZHAN_MULTIPLE_MYELOMA_PR_DN, XU_GH1_AUTOCRINE_TARGETS_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_MITOCHONDRIAL_TRANSPORT, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, AFP1_Q6, chr4q22, GOBP_AMINO_ACID_CATABOLIC_PROCESS, GOBP_MEMBRANE_ORGANIZATION

GO Biological Process (4): branched-chain amino acid catabolic process (GO:0009083), regulation of mitochondrial membrane permeability involved in apoptotic process (GO:1902108), regulation of intracellular signal transduction (GO:1902531), protein dephosphorylation (GO:0006470)

GO Molecular Function (8): protein serine/threonine phosphatase activity (GO:0004722), manganese ion binding (GO:0030145), [3-methyl-2-oxobutanoate dehydrogenase (lipoamide)]-phosphatase activity (GO:0047385), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), cation binding (GO:0043169), metal ion binding (GO:0046872)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Maple Syrup Urine Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	2
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
apoptotic process	1
apoptotic mitochondrial changes	1
regulation of mitochondrial membrane permeability	1
regulation of signal transduction	1
intracellular signal transduction	1
dephosphorylation	1
protein modification process	1
transition metal ion binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
ion binding	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1889 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPM1K	BCKDK	O14874	789
PPM1K	BCKDHA	P12694	677
PPM1K	BCKDHB	P21953	624
PPM1K	BCAT2	O15382	621
PPM1K	PPTC7	Q8NI37	616
PPM1K	PPM1M	Q96MI6	576
PPM1K	PDP1	Q9P0J1	545
PPM1K	PPM1H	Q9ULR3	515
PPM1K	SLC25A44	Q96H78	483
PPM1K	PPM1J	Q5JR12	463
PPM1K	PDP2	Q9P2J9	457
PPM1K	DBT	P11182	453
PPM1K	NEK8	Q86SG6	452
PPM1K	CALM1	P02593	450
PPM1K	FAM110B	Q8TC76	438

IntAct

51 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
PPM1K	DBT	psi-mi:“MI:0914”(association)	0.790
PPM1K	BIRC2	psi-mi:“MI:0915”(physical association)	0.720
BIRC2	PPM1K	psi-mi:“MI:0915”(physical association)	0.720
XIAP	PPM1K	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	PPM1K	psi-mi:“MI:0915”(physical association)	0.560
UBXN11	PPM1K	psi-mi:“MI:0915”(physical association)	0.560
MAGEA11	PPM1K	psi-mi:“MI:0915”(physical association)	0.560
PPM1K	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
MYO15B	PPM1K	psi-mi:“MI:0915”(physical association)	0.560
ZNF410	PPM1K	psi-mi:“MI:0915”(physical association)	0.560
PPM1K	LDHA	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	PPM1K	psi-mi:“MI:0915”(physical association)	0.370
PPM1K	LMTK2	psi-mi:“MI:0915”(physical association)	0.370
PPM1K	AATK	psi-mi:“MI:0915”(physical association)	0.370
PPM1K	ERBB3	psi-mi:“MI:0915”(physical association)	0.370
PPM1K	PTK7	psi-mi:“MI:0915”(physical association)	0.370
MYB	PPM1K	psi-mi:“MI:0915”(physical association)	0.370
CHCHD1	RCN2	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
PPM1K	PMPCB	psi-mi:“MI:0914”(association)	0.350
PPM1K	BCKDK	psi-mi:“MI:0914”(association)	0.350
COQ9	ACOT7	psi-mi:“MI:0914”(association)	0.350

BioGRID (51): PPM1K (Two-hybrid), DBT (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), PPM1K (Two-hybrid), BIRC2 (Two-hybrid), PPM1K (Affinity Capture-MS), NME2 (Affinity Capture-MS), BCKDHB (Affinity Capture-MS), PPM1K (Affinity Capture-MS), DBT (Affinity Capture-MS), BCKDHA (Affinity Capture-MS), IDE (Affinity Capture-MS), PPM1K (Affinity Capture-MS), PMPCB (Affinity Capture-MS)

ESM2 similar proteins: A0A3L7I2I8, A3A8W2, A4IF63, A6K136, D2GXS7, D3ZQG6, F7H9X2, O60733, O62829, O62830, O75688, O88483, P20650, P35813, P35814, P35816, P42694, P49443, P93006, P97570, P97819, Q05AL2, Q15750, Q28DF4, Q2PC20, Q3UV70, Q5F361, Q5R522, Q5RA52, Q5SMK6, Q69QZ0, Q69VD9, Q6ING9, Q6NYU2, Q6ZHC8, Q7XJ53, Q7XUC5, Q84JD5, Q8AYC9, Q8BXN7

Diamond homologs: A0A7U2MSD6, A0BLX0, A0BQL0, A0CUB5, A0DSB3, A0DTY1, A3A8W2, A3A8W6, A3CCP9, A5PJZ2, A6K136, B8NLZ3, G0RT93, O04719, O62829, O62830, O75688, O81716, O88483, P20650, P34221, P35813, P35814, P35815, P35816, P36982, P36993, P39966, P49443, P49444, P49595, P49596, P49597, P49598, P93006, Q09172, Q09173, Q0DBU3, Q0IIF0, Q0JL75

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PPM1K	“up-regulates activity”	BCKDHA	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	91
Likely benign	40
Benign	10

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3236750	NM_152542.5(PPM1K):c.1A>G (p.Met1Val)	Pathogenic
4736875	NM_152542.5(PPM1K):c.586C>T (p.Arg196Ter)	Pathogenic

SpliceAI

1773 predictions. Top by Δscore:

Variant	Effect	Δscore
4:88264951:T:A	donor_gain	1.0000
4:88264956:T:A	donor_gain	1.0000
4:88264960:T:TA	donor_gain	1.0000
4:88268913:G:C	acceptor_gain	1.0000
4:88268913:G:GC	acceptor_gain	1.0000
4:88268916:T:C	acceptor_gain	1.0000
4:88268916:T:TC	acceptor_gain	1.0000
4:88268918:A:AC	acceptor_gain	1.0000
4:88268918:A:C	acceptor_gain	1.0000
4:88271057:T:TA	donor_gain	1.0000
4:88271058:C:A	donor_gain	1.0000
4:88277242:CCCTT:C	acceptor_gain	1.0000
4:88277243:CCTT:C	acceptor_gain	1.0000
4:88264925:A:C	donor_gain	0.9900
4:88268740:CCTTT:C	donor_gain	0.9900
4:88268904:TTG:T	acceptor_gain	0.9900
4:88268905:TG:T	acceptor_gain	0.9900
4:88268907:C:CC	acceptor_gain	0.9900
4:88268910:CAAG:C	acceptor_gain	0.9900
4:88268915:A:C	acceptor_gain	0.9900
4:88270296:A:AC	donor_gain	0.9900
4:88270297:A:C	donor_gain	0.9900
4:88277246:T:C	acceptor_gain	0.9900
4:88264914:TGCAA:T	donor_gain	0.9800
4:88264938:AATG:A	donor_gain	0.9800
4:88264941:G:A	donor_gain	0.9800
4:88265008:G:C	donor_gain	0.9800
4:88265136:C:CC	acceptor_gain	0.9800
4:88268735:TAGTA:T	donor_loss	0.9800
4:88268736:AGTAC:A	donor_loss	0.9800

AlphaMissense

2466 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:88262700:G:C	N338K	0.999
4:88262700:G:T	N338K	0.999
4:88262704:T:A	D337V	0.999
4:88262704:T:G	D337A	0.999
4:88265092:C:T	G299E	0.999
4:88265095:T:A	D298V	0.999
4:88265098:G:A	T297I	0.999
4:88268248:C:T	G265E	0.999
4:88268253:A:C	S263R	0.999
4:88268253:A:T	S263R	0.999
4:88268255:T:G	S263R	0.999
4:88268256:T:A	R262S	0.999
4:88268256:T:G	R262S	0.999
4:88268257:C:A	R262I	0.999
4:88268257:C:G	R262T	0.999
4:88268821:G:C	S209R	0.999
4:88268821:G:T	S209R	0.999
4:88268823:T:G	S209R	0.999
4:88268825:T:A	D208V	0.999
4:88268825:T:G	D208A	0.999
4:88268828:C:A	G207V	0.999
4:88268828:C:T	G207E	0.999
4:88268829:C:A	G207W	0.999
4:88268829:C:G	G207R	0.999
4:88268829:C:T	G207R	0.999
4:88268880:C:G	A190P	0.999
4:88268889:C:A	G187W	0.999
4:88278201:C:T	G128E	0.999
4:88278204:T:A	D127V	0.999
4:88278259:C:G	D109H	0.999

dbSNP variants (sampled 300 via entrez): RS1000128564 (4:88266403 G>A), RS1000199434 (4:88264590 G>A), RS10002084 (4:88261699 T>C), RS1000350878 (4:88273411 T>A,C), RS1000502887 (4:88264863 A>G,T), RS10007869 (4:88272176 C>T), RS1000881729 (4:88280894 A>T), RS1000921431 (4:88273170 A>G), RS1000969766 (4:88271823 G>A,T), RS1001043410 (4:88285669 TTAAAA>T), RS1001147563 (4:88277575 G>A), RS1001308640 (4:88274712 T>C), RS1001427658 (4:88284594 G>A), RS1001491312 (4:88282306 G>A), RS1001495236 (4:88273505 A>C)

Disease associations

OMIM: gene MIM:611065 | disease phenotypes: MIM:615135

GenCC curated gene-disease

Disease	Classification	Inheritance
maple syrup urine disease, mild variant	Moderate	Autosomal recessive
intermediate maple syrup urine disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
maple syrup urine disease, mild variant	Moderate	AR

Mondo (2): maple syrup urine disease, mild variant (MONDO:0014057), intermediate maple syrup urine disease (MONDO:0017052)

Orphanet (1): Maple syrup urine disease (Orphanet:511)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0010911	Hyperleucinemia
HP:0010913	Hyperisoleucinemia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000245_1	Conduct disorder (maternal expressed emotions interaction)	7.000000e-06
GCST001391_2	Metabolite levels	2.000000e-16
GCST001639_19	Metabolite levels	1.000000e-10
GCST002650_2	Coffee consumption (cups per day)	9.000000e-08
GCST006076_1	Branched-chain amino acid levels (Leucine)	4.000000e-25
GCST006077_1	Branched-chain amino acid levels (Isoleucine)	6.000000e-19
GCST006078_2	Branched-chain amino acid levels (Valine)	4.000000e-24
GCST009240_287	Serum metabolite levels (CMS)	2.000000e-17
GCST009242_374	Serum metabolite levels	4.000000e-13
GCST010512_5	Serum uric acid levels	9.000000e-15

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008342	parental emotion expression measurmement
EFO:0004725	metabolite measurement
EFO:0004723	coronary artery calcification
EFO:0004330	coffee consumption
EFO:0006782	cups of coffee per day measurement
EFO:0005134	amino acid measurement
EFO:0004761	uric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs149713212	PPM1K		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
Cyclosporine	increases expression	3
sodium arsenite	decreases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases methylation, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
geldanamycin	increases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(2-butoxyethyl) phosphate	affects expression	1
afimoxifene	decreases reaction, increases expression	1
butyraldehyde	increases expression	1
tibolone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
avobenzone	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
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TF46	HAP1 PPM1K (-) 1	Cancer cell line	Male
CVCL_TF47	HAP1 PPM1K (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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