Maple syrup urine disease, mild variant

Summary

Maple syrup urine disease, mild variant (MONDO:0014057) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 111

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maple syrup urine disease, mild variant
Mondo ID	MONDO:0014057
OMIM	615135
DOID	DOID:0061205
UMLS	C3554575
MedGen	767489
GARD	0018388
Is cancer (heuristic)	no

Also known as: maple syrup urine disease, mild variant · MSUDMV

Data availability: 111 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › maple syrup urine disease › maple syrup urine disease, mild variant

Related subtypes (8): pyruvate dehydrogenase E3 deficiency, classic maple syrup urine disease, intermediate maple syrup urine disease, intermittent maple syrup urine disease, thiamine-responsive maple syrup urine disease, maple syrup urine disease type 1A, maple syrup urine disease type 1B, maple syrup urine disease type 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

111 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 34 likely benign, 10 benign, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3236750	NM_152542.5(PPM1K):c.1A>G (p.Met1Val)	PPM1K	Pathogenic	no assertion criteria provided
4736875	NM_152542.5(PPM1K):c.586C>T (p.Arg196Ter)	PPM1K	Pathogenic	criteria provided, single submitter
1479838	NM_152542.5(PPM1K):c.527G>A (p.Arg176His)	PPM1K	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2446422	NM_005881.4(BCKDK):c.486C>A (p.His162Gln)	BCKDK	Uncertain significance	criteria provided, single submitter
1000474	NM_152542.5(PPM1K):c.974C>T (p.Ala325Val)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001639	NM_152542.5(PPM1K):c.208C>T (p.Arg70Cys)	PPM1K	Uncertain significance	criteria provided, single submitter
1038220	NM_152542.5(PPM1K):c.587G>A (p.Arg196Gln)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1046955	NM_152542.5(PPM1K):c.77G>A (p.Arg26His)	PPM1K	Uncertain significance	criteria provided, single submitter
1051463	NM_152542.5(PPM1K):c.47A>C (p.Gln16Pro)	PPM1K	Uncertain significance	criteria provided, single submitter
1058047	NM_152542.5(PPM1K):c.1075T>A (p.Phe359Ile)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372229	NM_152542.5(PPM1K):c.601C>G (p.Leu201Val)	PPM1K	Uncertain significance	criteria provided, single submitter
1380419	NM_152542.5(PPM1K):c.730G>A (p.Val244Ile)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1387128	NM_152542.5(PPM1K):c.1057A>G (p.Lys353Glu)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1400482	NM_152542.5(PPM1K):c.145C>T (p.Arg49Trp)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1406700	NM_152542.5(PPM1K):c.110C>T (p.Thr37Met)	PPM1K	Uncertain significance	criteria provided, single submitter
1427573	NM_152542.5(PPM1K):c.554C>A (p.Thr185Asn)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1430991	NM_152542.5(PPM1K):c.526C>G (p.Arg176Gly)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1464285	NM_152542.5(PPM1K):c.48G>T (p.Gln16His)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1469206	NM_152542.5(PPM1K):c.973G>A (p.Ala325Thr)	PPM1K	Uncertain significance	criteria provided, single submitter
1470917	NM_152542.5(PPM1K):c.595A>G (p.Ile199Val)	PPM1K	Uncertain significance	criteria provided, single submitter
1498675	NM_152542.5(PPM1K):c.670A>G (p.Ile224Val)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
1513815	NM_152542.5(PPM1K):c.1055A>G (p.Tyr352Cys)	PPM1K	Uncertain significance	criteria provided, single submitter
1524153	NM_152542.5(PPM1K):c.118A>C (p.Ser40Arg)	PPM1K	Uncertain significance	criteria provided, single submitter
1974989	NM_152542.5(PPM1K):c.1096G>T (p.Ala366Ser)	PPM1K	Uncertain significance	criteria provided, single submitter
1982883	NM_152542.5(PPM1K):c.188A>G (p.Asn63Ser)	PPM1K	Uncertain significance	criteria provided, single submitter
2046368	NM_152542.5(PPM1K):c.292G>A (p.Ala98Thr)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
2099392	NM_152542.5(PPM1K):c.647A>G (p.Lys216Arg)	PPM1K	Uncertain significance	criteria provided, single submitter
2111001	NM_152542.5(PPM1K):c.542C>T (p.Ala181Val)	PPM1K	Uncertain significance	criteria provided, single submitter
2141511	NM_152542.5(PPM1K):c.308A>G (p.Lys103Arg)	PPM1K	Uncertain significance	criteria provided, multiple submitters, no conflicts
2153548	NM_152542.5(PPM1K):c.760G>A (p.Val254Ile)	PPM1K	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PPM1K	Moderate	Autosomal recessive	maple syrup urine disease, mild variant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPM1K	Orphanet:268162	Intermediate maple syrup urine disease
BCKDK	Orphanet:308410	Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PPM1K	HGNC:25415	ENSG00000163644	Q8N3J5	Protein phosphatase Mn(2+)-dependent 1K	gencc,clinvar
BCKDK	HGNC:16902	ENSG00000103507	O14874	Branched-chain alpha-ketoacid dehydrogenase kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPM1K	Protein phosphatase Mn(2+)-dependent 1K	Serine/threonine-protein phosphatase component of macronutrients metabolism.
BCKDK	Branched-chain alpha-ketoacid dehydrogenase kinase	Serine/threonine-protein kinase component of macronutrients metabolism.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	42.0×	0.047
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPM1K	Phosphatase	yes	3.1.3.16	PP2C_BS, PPM-type_phosphatase-like_dom, PP2C
BCKDK	Kinase	yes		HATPase_dom, Sig_transdc_His_kin-like_C, His_kinase_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
apex of heart	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPM1K	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
BCKDK	257	ubiquitous	marker	apex of heart, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCKDK	3,756
PPM1K	1,991

Intra-cohort edges

A	B	Sources
BCKDK	PPM1K	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCKDK	O14874	5
PPM1K	Q8N3J5	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Branched-chain amino acid catabolism	2	475.8×	3e-05	PPM1K, BCKDK
Branched-chain ketoacid dehydrogenase kinase deficiency	1	1142.0×	0.002	BCKDK
H139Hfs13* PPM1K causes a mild variant of MSUD	1	1142.0×	0.002	PPM1K
Diseases of branched-chain amino acid catabolism	1	951.7×	0.002	BCKDK
Diseases of metabolism	1	40.2×	0.039	BCKDK
Metabolism of amino acids and derivatives	1	33.8×	0.039	BCKDK
Disease	1	6.5×	0.165	BCKDK
Metabolism	1	5.8×	0.165	BCKDK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
branched-chain amino acid catabolic process	2	1053.2×	9e-06	PPM1K, BCKDK
L-valine catabolic process	1	1685.2×	0.001	BCKDK
L-isoleucine catabolic process	1	1404.3×	0.001	BCKDK
amino acid catabolic process	1	1404.3×	0.001	BCKDK
regulation of pyruvate decarboxylation to acetyl-CoA	1	1404.3×	0.001	BCKDK
regulation of mitochondrial membrane permeability involved in apoptotic process	1	1404.3×	0.001	PPM1K
L-leucine catabolic process	1	1203.7×	0.001	BCKDK
lipid biosynthetic process	1	495.6×	0.003	BCKDK
regulation of intracellular signal transduction	1	443.5×	0.003	PPM1K
regulation of glucose metabolic process	1	280.9×	0.004	BCKDK
spermatogenesis	1	17.6×	0.056	BCKDK

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPM1K	0	0
BCKDK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BCKDK	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPM1K	3.1.3.16, 3.1.3.52	protein-serine/threonine phosphatase, [3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	PPM1K, BCKDK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PPM1K	0	—
BCKDK	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.