methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Summary

methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (MONDO:0009615) is a disease caused by MCEE (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MCEE (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 100

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency
Mondo ID	MONDO:0009615
MeSH	C565386
OMIM	251120
Orphanet	308425
SNOMED CT	765137006
UMLS	C1855100
MedGen	344419
GARD	0017390
Is cancer (heuristic)	no

Also known as: MCEE deficiency · methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency · methylmalonic acidemia due to methylmalonyl-CoA racemase deficiency · methylmalonic aciduria due to methylmalonyl-CoA epimerase deficiency · methylmalonic aciduria due to methylmalonyl-CoA racemase deficiency

Data availability: 100 ClinVar variants · 3 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 › methylmalonic acidemia › methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Related subtypes (6): methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, methylmalonic acidemia due to transcobalamin receptor defect, combined malonic and methylmalonic acidemia, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, isolated methylmalonic aciduria cblD type

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

100 retrieved; paginated sample, class counts are floors:

50 likely benign, 26 uncertain significance, 7 pathogenic, 6 conflicting classifications of pathogenicity, 5 likely pathogenic, 4 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424629	NC_000002.11:g.(?71004499)(74779761_?)del	C2orf78	Pathogenic	criteria provided, single submitter
2343	NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)	MCEE	Pathogenic	criteria provided, multiple submitters, no conflicts
2830026	NM_032601.4(MCEE):c.19dup (p.Ala7fs)	MCEE	Pathogenic	criteria provided, single submitter
2992461	NM_032601.4(MCEE):c.49dup (p.Ser17fs)	MCEE	Pathogenic	criteria provided, single submitter
3645072	NM_032601.4(MCEE):c.208_209insCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAATATTCTGG (p.Gly70delinsAlaGlyArgGlyGlySerArgLeuTer)	MCEE	Pathogenic	criteria provided, single submitter
3645773	NM_032601.4(MCEE):c.102_105dup (p.Asp36fs)	MCEE	Pathogenic	criteria provided, single submitter
833393	NC_000002.12:g.(?71109950)(71130239_?)del	MCEE	Pathogenic	criteria provided, single submitter
2443797	NM_032601.4(MCEE):c.379-644A>G	MCEE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735271	NM_032601.4(MCEE):c.375_378+4del	MCEE	Likely pathogenic	criteria provided, single submitter
2771364	NM_032601.4(MCEE):c.40+1G>T	MCEE	Likely pathogenic	criteria provided, single submitter
3247278	NC_000002.11:g.(?71351316)(71351693_?)dup	MCEE	Likely pathogenic	criteria provided, single submitter
3586905	NM_032601.4(MCEE):c.40+1G>A	MCEE	Likely pathogenic	criteria provided, single submitter
195391	NM_032601.4(MCEE):c.102C>G (p.Pro34=)	MCEE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203810	NM_032601.4(MCEE):c.427C>T (p.Arg143Cys)	MCEE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203812	NM_032601.4(MCEE):c.178A>C (p.Lys60Gln)	MCEE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336938	NM_032601.4(MCEE):c.312T>G (p.Arg104=)	MCEE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897202	NM_032601.4(MCEE):c.164T>C (p.Val55Ala)	MCEE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898375	NM_032601.4(MCEE):c.66C>T (p.Pro22=)	MCEE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003508	NM_032601.4(MCEE):c.3G>A (p.Met1Ile)	MCEE	Uncertain significance	criteria provided, single submitter
1007045	NM_032601.4(MCEE):c.226_227delinsAT (p.Ala76Met)	MCEE	Uncertain significance	criteria provided, single submitter
1025357	NM_032601.4(MCEE):c.41-9A>G	MCEE	Uncertain significance	criteria provided, single submitter
1045912	NM_032601.4(MCEE):c.376G>A (p.Glu126Lys)	MCEE	Uncertain significance	criteria provided, single submitter
1064290	NM_032601.4(MCEE):c.345C>A (p.Asn115Lys)	MCEE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368012	NM_032601.4(MCEE):c.140G>A (p.Arg47Gln)	MCEE	Uncertain significance	criteria provided, single submitter
1385948	NM_032601.4(MCEE):c.166C>T (p.Pro56Ser)	MCEE	Uncertain significance	criteria provided, single submitter
1412587	NC_000002.11:g.(?71337100)(71357349_?)dup	MCEE	Uncertain significance	criteria provided, single submitter
1444714	NM_032601.4(MCEE):c.140G>T (p.Arg47Leu)	MCEE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1513623	NM_032601.4(MCEE):c.466A>G (p.Lys156Glu)	MCEE	Uncertain significance	criteria provided, single submitter
1721139	NM_032601.4(MCEE):c.425T>A (p.Ile142Asn)	MCEE	Uncertain significance	criteria provided, single submitter
2081936	NM_032601.4(MCEE):c.38T>C (p.Val13Ala)	MCEE	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
MCEE	Definitive	Autosomal recessive	methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCEE	Orphanet:308425	Methylmalonic acidemia due to methylmalonyl-CoA epimerase 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
MCEE	HGNC:16732	ENSG00000124370	Q96PE7	Methylmalonyl-CoA epimerase, mitochondrial	gencc,clinvar
C2orf78	HGNC:34349	ENSG00000187833	A6NCI8	Uncharacterized protein C2orf78	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCEE	Methylmalonyl-CoA epimerase, mitochondrial	Methylmalonyl-CoA epimerase involved in propionyl-CoA metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCEE	Enzyme (other)	yes	5.1.99.1	MeMalonyl-CoA_epimerase, Glyas_Bleomycin-R_OHBP_Dase, VOC_core
C2orf78	Other/Unknown	no		DUF4629, C2orf78-like

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)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
left ventricle myocardium	1
right lobe of liver	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCEE	249	ubiquitous	marker	body of pancreas, right lobe of liver, left ventricle myocardium
C2orf78	7		marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCEE	2,320
C2orf78	133

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCEE	Q96PE7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C2orf78	A6NCI8	42.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Propionyl-CoA catabolism	1	2284.0×	0.002	MCEE
Mitochondrial Fatty Acid Beta-Oxidation	1	380.7×	0.007	MCEE
Fatty acid metabolism	1	131.3×	0.013	MCEE
Metabolism of lipids	1	31.6×	0.040	MCEE
Metabolism	1	11.6×	0.086	MCEE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-methylmalonyl-CoA metabolic process	1	16852.0×	1e-04	MCEE
short-chain fatty acid catabolic process	1	5617.3×	2e-04	MCEE

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MCEE	0	0
C2orf78	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MCEE	5.1.99.1	methylmalonyl-CoA epimerase

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	1	MCEE
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C2orf78

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)
MCEE	0	—
C2orf78	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.