MTHFD2
protein-codingmethylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase
Gene summary
This gene encodes a nuclear-encoded mitochondrial bifunctional enzyme with methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The enzyme functions as a homodimer and is unique in its absolute requirement for magnesium and inorganic phosphate. Formation of the enzyme-magnesium complex allows binding of NAD. Alternative splicing results in two different transcripts, one protein-coding and the other not protein-coding. This gene has a pseudogene on chromosome 7. [provided by RefSeq, Mar 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MTHFD2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006636.4. 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 | 3 | 1 | 4 | |||
| missense | 49 | 2 | 51 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 55 | 3 | 0 | 58 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006627.2 | 8 | MANE Select | |
| Ensembl | ENSP00000377617.2 | 8 | MANE Select | |
| RefSeq | NP_001397121.1 | 6 | Standard | |
| Ensembl | ENSP00000386542.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- One carbon pool by folate - Homo sapiens (human)
- Folate malabsorption, hereditary
- Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)
- Methotrexate Action Pathway
- Folate Metabolism
Biological Process
- tetrahydrofolate interconversion
- tetrahydrofolate metabolic process
- folic acid metabolic process
- oxidation-reduction process
Molecular Function
- magnesium ion binding
- methenyltetrahydrofolate cyclohydrolase activity
- methylenetetrahydrofolate dehydrogenase (NAD+) activity
- methylenetetrahydrofolate dehydrogenase (NADP+) activity
- phosphate ion binding
Cellular Component
- extracellular space
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394053
- Coding exons
- 8
- Length
- 19004
- Individuals with no LoFs
- 124831
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 124851
- p
- 0.0000801
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.481 | 172 | 191 | 0.902 | 0.00000921 | 2250 |
| Missense (PolyPhen) | 57 | 72.089 | 0.79069 | 946 | ||
| Synonymous | -0.384 | 75 | 70.9 | 1.06 | 0.00000359 | 719 |
| Loss of Function | 2.14 | 7 | 16.3 | 0.429 | 9.42e-7 | 182 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| Latino/Admixed American | 0.00018 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency. {ECO:0000269|PubMed:16100107}.;
Recessive Scores
- pRec
- 0.255
Intolerance Scores
- LoFtool
- 0.447
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 36.86
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.979
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |