PPM1K

protein-coding

protein phosphatase, Mg2+/Mn2+ dependent 1K, the group of Protein phosphatases, Mg2+/Mn2+ dependent

Gene summary

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. [provided by RefSeq, Sep 2012]

MANE transcript

NM_152542.5

Inheritance

ClinVar variants

P:2U:88B:36

Top phenotype

Maple syrup urine disease, mild variant

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr4:88,257,620-88,284,769

External References & Databases

Ensembl (ENSG00000163644)

Transcript & Mutation Effects

hg38 • Region Span ~27.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

maple syrup urine disease, mild variantMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014057

Submitter: PanelApp Australia

maple syrup urine disease, mild variantLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014057

Submitter: Ambry Genetics

maple syrup urine disease, mild variantMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014057

Submitter: ClinGen

*PPM1K* was first reported in relation to autosomal recessive maple syrup urine disease, mild variant in 2013 (Oyarzabal A, et al., 2013, PMID: 23086801). Three cases have been identified in three publications (PMIDs: 23242558, 36706222, 40047138) with homozygous putative loss of function variants (frameshift and start-loss) or missense. In addition to the three cases, evidence supporting this gene-disease relationship includes the experimental data of the role of *PPM1K* as the BCKD complex E1α phosphatase (PMID: 19411760), its interaction with additional MSUD genes *BCKDHA* and *DBT* (PMID: 19411760), its alteration of dephosphorylation in both patient and non-patient cells which could be rescued with WT expression (PMID: 23086801 and PMID: 19411760), a knockdown zebrafish model (PMID: 17374715) with limited relevant characterization, and a knockout mouse (PMID: 19411760 ) which recapitulated the characteristic elevation of branched chain amino acids seen in patients. In summary, there is moderate genetic evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally approved by the Aminoacidopathy GCEP on 09/25/2020. It was reevaluated on 10/25/2023. As a result of this reevaluation a second case was identified (PMID: 36706222) and increased the classification from Limited to Moderate (SOP Version 9). It was again reevaluated on 12/17/25 and a new case was identified (PMID: 40047138) however the classification remained Moderate.

maple syrup urine disease, mild variantLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014057

Submitter: Labcorp Genetics (formerly Invitae)

maple syrup urine disease, mild variantMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014057

Submitter: Ambry Genetics

intermediate maple syrup urine diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017052

Submitter: Orphanet

Clinical Genomic Database (CGD)

Maple syrup urine disease, mild variantAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: The condition can result in neurologic sequelae, and medical/dietary treatment (with low protein diet without branched-chain amino acids) can allow normal cognitive development

Refs: 23086801

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPM1K variants in ClinVar

4 Conditions Cataloged

Maple syrup urine disease, mild variantTotal: 108

not specifiedTotal: 48

not providedTotal: 12

PPM1K-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152542.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				28 clinvar	3 clinvar	31
missense			85 clinvar	4 clinvar	1 clinvar	90
nonsense	1 clinvar					1
start loss	1 clinvar					1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	0	88	32	4	126

Highest pathogenic variant AF is 0.000002736577

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152542.5	RefSeq	NP_689755.3	6	MANE Select
ENST00000608933.6	Ensembl	ENSP00000477341.1	6	MANE Select
ENST00000295908.11	Ensembl	ENSP00000295908.7	5	Standard
ENST00000295908.12	Ensembl	ENSP00000295908.7	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ppm1k	Danio rerio	Structure: endocardial ring Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

ppm1k

Danio rerio

Structure: endocardial ring

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Branched-chain amino acid catabolism
Metabolism of amino acids and derivatives
Metabolism

Biological Process

protein dephosphorylation
branched-chain amino acid catabolic process
positive regulation of pyruvate dehydrogenase activity

Molecular Function

protein serine/threonine phosphatase activity
magnesium-dependent protein serine/threonine phosphatase activity
protein binding
metal ion binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000608933
Coding exons: 6
Length: 27150
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.29	160	213	0.752	0.0000113	2462
Missense (PolyPhen)		43	66.494	0.64667		742
Synonymous	0.649	71	78.3	0.907	0.00000420	735
Loss of Function	1.40	8	13.6	0.589	6.57e-7	168

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000061	0.000058	rare
Ashkenazi Jewish	0.0015	0.0015	notable
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates the mitochondrial permeability transition pore and is essential for cellular survival and development. {ECO:0000269|PubMed:17374715}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:23086801}. Note=The gene represented in this entry is involved in disease pathogenesis.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.592
RVIS EVS: -0.16
RVIS percentile EVS: 42.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.450

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium