ME2
protein-codingmalic enzyme 2
Gene summary
This gene encodes a mitochondrial NAD-dependent malic enzyme, a homotetrameric protein, that catalyzes the oxidative decarboxylation of malate to pyruvate. It had previously been weakly linked to a syndrome known as Friedreich ataxia that has since been shown to be the result of mutation in a completely different gene. Certain single-nucleotide polymorphism haplotypes of this gene have been shown to increase the risk for idiopathic generalized epilepsy. Alternatively spliced transcript variants encoding different isoforms found for this gene. [provided by RefSeq, Dec 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~75.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0007661
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019243
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0005027
Submitter: ClinGen
*ME2* was first reported in relation to autosomal recessive epilepsy in 2005 (Greenberg et al., PMID: 15532013). A homozygous haplotype containing rs608781 (ClinVar ID: 1676763) was associated with susceptibility to adolescent-onset idiopathic generalized epilepsy via family-based and case-control evidence. Evidence refuting this gene-disease relationship is population frequency data from gnomAD v4.1.1 that indicates this variant is too common to cause epilepsy, with a filtering allele frequency of 0.92. Additionally, no significant association was found between *ME2* and epilepsy in a GWAS meta-analysis of over 29,000 cases and 52,000 controls (International League Against Epilepsy Consortium on Complex Epilepsies 2023, PMID: 37653029). Of note, this gene has also been implicated in neurodevelopmental disorders and autism. These assertions will be assessed separately. In summary, the evidence supporting the relationship between *ME2* and epilepsy has been refuted and no valid evidence remains to support the claim. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date May 19, 2026 (SOP Version 12).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ME2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002396.5. 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 | 1 | 3 | 1 | 5 | ||
| missense | 73 | 2 | 75 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 1 | 77 | 5 | 1 | 84 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002387.1 | 15 | MANE Select | |
| Ensembl | ENSP00000321070.5 | 15 | MANE Select | |
| RefSeq | NP_001161807.1 | 13 | Standard | |
| Ensembl | ENSP00000372384.2 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyruvate metabolism - Homo sapiens (human)
- Pyruvate Dehydrogenase Complex Deficiency
- Primary hyperoxaluria II, PH2
- Pyruvate kinase deficiency
- Leigh Syndrome
Biological Process
- pyruvate metabolic process
- tricarboxylic acid cycle
- malate metabolic process
- electron transport chain
- regulation of NADP metabolic process
Molecular Function
- malic enzyme activity
- malate dehydrogenase (decarboxylating) (NAD+) activity
- malate dehydrogenase (decarboxylating) (NADP+) activity
- oxaloacetate decarboxylase activity
- electron transfer activity
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000321341
- Coding exons
- 15
- Length
- 69273
- Individuals with no LoFs
- 125642
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 101
- Defined
- 125743
- p
- 0.000402
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.969 | 265 | 313 | 0.846 | 0.0000157 | 3790 |
| Missense (PolyPhen) | 120 | 143.2 | 0.83796 | 1783 | ||
| Synonymous | 0.640 | 98 | 106 | 0.921 | 0.00000512 | 1117 |
| Loss of Function | 1.26 | 27 | 35.0 | 0.771 | 0.00000219 | 392 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00027 | 0.00026 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00057 | 0.00054 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00060 | 0.00059 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
Recessive Scores
- pRec
- 0.148
Intolerance Scores
- LoFtool
- 0.974
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.59
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.741
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |