PPM1K

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

Basic information

Region (hg38): 4:88257619-88284769

Links

ENSG00000163644 ∙ NCBI:152926 ∙ OMIM:611065 ∙ HGNC:25415 ∙ Uniprot:Q8N3J5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intermediate maple syrup urine disease (Supportive), mode of inheritance: AR
• maple syrup urine disease, mild variant (Limited), mode of inheritance: AR
• maple syrup urine disease, mild variant (Limited), mode of inheritance: Unknown
• maple syrup urine disease, mild variant (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Maple syrup urine disease, mild variant	AR	Biochemical	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	Biochemical	23086801

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PPM1K gene.

• Maple syrup urine disease, mild variant (74 variants)
• Inborn genetic diseases (16 variants)
• not provided (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PPM1K gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				16	3	19
missense			52	2	2	56
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	1	2	5
non coding				5	2	7
Total	0	0	53	23	7

Variants in PPM1K

This is a list of pathogenic ClinVar variants found in the PPM1K region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-88262614-G-C		Maple syrup urine disease, mild variant	Uncertain significance (Apr 30, 2023)
4-88262618-C-A		Maple syrup urine disease, mild variant	Uncertain significance (Jun 10, 2022)
4-88262634-T-C		Maple syrup urine disease, mild variant	Likely benign (May 03, 2022)
4-88262639-A-T		Maple syrup urine disease, mild variant	Uncertain significance (Oct 07, 2020)
4-88262657-T-C		Maple syrup urine disease, mild variant • not specified	Uncertain significance (Oct 30, 2023)
4-88262659-T-C		Maple syrup urine disease, mild variant	Uncertain significance (Nov 24, 2023)
4-88262680-G-A		Maple syrup urine disease, mild variant	Uncertain significance (Aug 28, 2022)
4-88262733-G-C		Maple syrup urine disease, mild variant	Uncertain significance (Nov 12, 2018)
4-88262741-A-T		Maple syrup urine disease, mild variant	Uncertain significance (Aug 04, 2023)
4-88264992-C-G		Maple syrup urine disease, mild variant	Likely benign (Apr 24, 2021)
4-88264992-C-T			Likely benign (Jun 29, 2018)
4-88265010-C-T		Maple syrup urine disease, mild variant • PPM1K-related disorder	Benign (Jan 24, 2024)
4-88265013-C-T		PPM1K-related disorder	Likely benign (May 27, 2019)
4-88265014-G-A		Maple syrup urine disease, mild variant • not specified	Uncertain significance (Dec 02, 2023)
4-88265015-C-T		Maple syrup urine disease, mild variant	Uncertain significance (Mar 20, 2021)
4-88265017-T-C		Maple syrup urine disease, mild variant	Uncertain significance (Apr 05, 2019)
4-88265027-C-T		Maple syrup urine disease, mild variant	Benign (Jan 29, 2024)
4-88265028-G-A		Maple syrup urine disease, mild variant	Likely benign (Jul 15, 2022)
4-88265063-T-C		Maple syrup urine disease, mild variant	Uncertain significance (Sep 05, 2023)
4-88265071-C-G		Maple syrup urine disease, mild variant	Uncertain significance (Mar 29, 2024)
4-88265100-G-A		Maple syrup urine disease, mild variant	Likely benign (Jul 03, 2022)
4-88265130-A-C		Maple syrup urine disease, mild variant	Likely benign (Oct 13, 2023)
4-88265144-A-C		Maple syrup urine disease, mild variant	Uncertain significance (Oct 30, 2022)
4-88268176-A-G		Maple syrup urine disease, mild variant	Likely benign (Mar 04, 2022)
4-88268204-T-A		not specified	Uncertain significance (Apr 25, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PPM1K	protein_coding	protein_coding	ENST00000608933	6	27150

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000147	0.876	125714	0	34	125748	0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.29	160	213	0.752	0.0000113	2462
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000185	0.000184
Ashkenazi Jewish	0.00149	0.00149
East Asian	0.000109	0.000109
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.000107	0.000105
Middle Eastern	0.000109	0.000109
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Branched-chain amino acid catabolism;Metabolism of amino acids and derivatives;Metabolism (Consensus)

Recessive Scores

• pRec: 0.114

Intolerance Scores

• loftool: 0.592
• rvis_EVS: -0.16
• rvis_percentile_EVS: 42.06

Haploinsufficiency Scores

• pHI: 0.998
• hipred: N
• hipred_score: 0.444
• ghis: 0.507

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.450

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ppm1k
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: ppm1k
• Affected structure: endocardial ring
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: protein dephosphorylation;branched-chain amino acid catabolic process;positive regulation of pyruvate dehydrogenase activity
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: protein serine/threonine phosphatase activity;magnesium-dependent protein serine/threonine phosphatase activity;protein binding;metal ion binding