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Aliases for MTHFD2 Gene

Aliases for MTHFD2 Gene

  • Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2, Methenyltetrahydrofolate Cyclohydrolase 2 3 5
  • NMDMC 3 4
  • Bifunctional Methylenetetrahydrofolate Dehydrogenase/Cyclohydrolase, Mitochondrial 3
  • NAD-Dependent Methylene Tetrahydrofolate Dehydrogenase Cyclohydrolase 3

External Ids for MTHFD2 Gene

Previous GeneCards Identifiers for MTHFD2 Gene

  • GC02P074563
  • GC02P074638
  • GC02P074383
  • GC02P074400
  • GC02P074337
  • GC02P074095
  • GC02P074425
  • GC02P074161

Summaries for MTHFD2 Gene

Entrez Gene Summary for MTHFD2 Gene

  • 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]

GeneCards Summary for MTHFD2 Gene

MTHFD2 (Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2, Methenyltetrahydrofolate Cyclohydrolase) is a Protein Coding gene. Among its related pathways are Metabolism and Folate Metabolism. Gene Ontology (GO) annotations related to this gene include magnesium ion binding and formate-tetrahydrofolate ligase activity. An important paralog of this gene is MTHFD2L.

UniProtKB/Swiss-Prot for MTHFD2 Gene

  • Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.

Gene Wiki entry for MTHFD2 Gene

Additional gene information for MTHFD2 Gene

No data available for CIViC summary , Tocris Summary , PharmGKB "VIP" Summary , fRNAdb sequence ontologies and piRNA Summary for MTHFD2 Gene

Genomics for MTHFD2 Gene

GeneHancer (GH) Regulatory Elements for MTHFD2 Gene

Promoters and enhancers for MTHFD2 Gene
GeneHancer (GH) Identifier GH Type GH
GH Sources Gene Association Score Total Score TSS distance (kb) Number of Genes Away Size (kb) Transcription Factor
Binding Sites
Gene Targets
GH02J074196 Promoter/Enhancer 2.1 EPDnew Ensembl ENCODE 650.7 +0.2 185 3.9 CLOCK FEZF1 DMAP1 IRF4 YY1 SLC30A9 ZNF213 E2F8 ZNF143 SP3 ENSG00000279070 MTHFD2 PCGF1 ENSG00000273245 INO80B DUSP11 ALMS1 HTRA2 WBP1 AUP1
GH02J074528 Promoter/Enhancer 2.1 EPDnew Ensembl ENCODE 12 +331.8 331763 4.4 DMAP1 IRF4 YY1 SLC30A9 E2F8 ZNF143 SP3 NFYC GLIS1 NBN AUP1 HTRA2 LBX2 TTC31 CCDC142 PCGF1 DUSP11 MOB1A MOGS MTHFD2
GH02J074471 Promoter/Enhancer 2.1 EPDnew Ensembl ENCODE 12 +273.9 273887 2.5 ZFP64 DMAP1 YY1 SLC30A9 ZNF213 E2F8 ZNF143 SP3 NFYC MEF2D MRPL53 LBX2 MTHFD2 WBP1 INO80B HTRA2 DGUOK-AS1 MOGS CCDC142
GH02J074480 Promoter/Enhancer 2.1 EPDnew Ensembl ENCODE 12 +283.9 283858 3 PKNOX1 SMAD1 MLX ARNT ARID4B SIN3A DMAP1 ZNF2 YY1 SLC30A9 TTC31 CCDC142 LBX2 AUP1 MOGS ENSG00000273245 PCGF1 DUSP11 MTHFD2 MOB1A
GH02J074177 Promoter/Enhancer 2 EPDnew Ensembl ENCODE 11.9 -20.0 -20046 2.3 HDGF PKNOX1 ARID4B SIN3A DMAP1 IRF4 YY1 POLR2B ZNF766 ZNF207 MOB1A DUSP11 BOLA3-AS1 ENSG00000273245 AUP1 TTC31 DGUOK-AS1 ENSG00000217702 INO80B MOGS
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around MTHFD2 on UCSC Golden Path with GeneCards custom track

Top Transcription factor binding sites by QIAGEN in the MTHFD2 gene promoter:
  • NF-YB
  • NF-YA
  • NF-Y
  • CP1A
  • CBF-B
  • CBF-A
  • CBF(2)
  • C/EBPbeta
  • YY1
  • p53

Genomic Locations for MTHFD2 Gene

Genomic Locations for MTHFD2 Gene
19,004 bases
Plus strand
19,004 bases
Plus strand

Genomic View for MTHFD2 Gene

Genes around MTHFD2 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
MTHFD2 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for MTHFD2 Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for MTHFD2 Gene

Proteins for MTHFD2 Gene

  • Protein details for MTHFD2 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Recommended name:
    Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
    Protein Accession:
    Secondary Accessions:
    • Q53G90
    • Q53GV5
    • Q53S36
    • Q7Z650

    Protein attributes for MTHFD2 Gene

    350 amino acids
    Molecular mass:
    37895 Da
    Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
    Quaternary structure:
    • Homodimer.
    • This NAD-dependent bifunctional enzyme has very different kinetic properties than the larger NADP-dependent trifunctional enzyme and is unique in that it requires formation of an enzyme-magnesium complex to allow binding of NAD.
    • Sequence=AAX93061.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAD96546.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAD96761.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=CAA34431.1; Type=Erroneous initiation; Evidence={ECO:0000305};

    Three dimensional structures from OCA and Proteopedia for MTHFD2 Gene

    Alternative splice isoforms for MTHFD2 Gene


neXtProt entry for MTHFD2 Gene

Post-translational modifications for MTHFD2 Gene

  • Modification sites at PhosphoSitePlus
  • Modification sites at neXtProt

Other Protein References for MTHFD2 Gene

No data available for DME Specific Peptides for MTHFD2 Gene

Domains & Families for MTHFD2 Gene

Gene Families for MTHFD2 Gene

Human Protein Atlas (HPA):
  • Enzymes
  • Predicted intracellular proteins
  • Predicted secreted proteins

Graphical View of Domain Structure for InterPro Entry



  • Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
  • Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
genes like me logo Genes that share domains with MTHFD2: view

Function for MTHFD2 Gene

Molecular function for MTHFD2 Gene

UniProtKB/Swiss-Prot Function:
Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.
UniProtKB/Swiss-Prot CatalyticActivity:
5,10-methylenetetrahydrofolate + NAD(+) = 5,10-methenyltetrahydrofolate + NADH.
UniProtKB/Swiss-Prot CatalyticActivity:
5,10-methenyltetrahydrofolate + H(2)O = 10-formyltetrahydrofolate.
UniProtKB/Swiss-Prot BiophysicochemicalProperties:
Kinetic parameters: KM=202 uM for NAD {ECO:0000269 PubMed:16100107}; KM=352 uM for NADP {ECO:0000269 PubMed:16100107};

Gene Ontology (GO) - Molecular Function for MTHFD2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000287 magnesium ion binding IMP 16100107
GO:0003824 catalytic activity IEA --
GO:0004477 methenyltetrahydrofolate cyclohydrolase activity TAS --
GO:0004487 methylenetetrahydrofolate dehydrogenase (NAD+) activity TAS --
GO:0004488 methylenetetrahydrofolate dehydrogenase (NADP+) activity IEA,IMP 16100107
genes like me logo Genes that share ontologies with MTHFD2: view
genes like me logo Genes that share phenotypes with MTHFD2: view

Animal Models for MTHFD2 Gene

MGI Knock Outs for MTHFD2:

Animal Model Products

CRISPR Products

miRNA for MTHFD2 Gene

miRTarBase miRNAs that target MTHFD2

Inhibitory RNA Products

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for MTHFD2

Clone Products

No data available for Enzyme Numbers (IUBMB) , Phenotypes From GWAS Catalog , Human Phenotype Ontology , Transcription Factor Targets and HOMER Transcription for MTHFD2 Gene

Localization for MTHFD2 Gene

Subcellular locations from UniProtKB/Swiss-Prot for MTHFD2 Gene


Subcellular locations from

Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for MTHFD2 gene
Compartment Confidence
extracellular 5
mitochondrion 5
cytosol 2

Gene Ontology (GO) - Cellular Components for MTHFD2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005615 extracellular space HDA 22664934
GO:0005739 mitochondrion IBA,ISS 8218174
GO:0005759 mitochondrial matrix TAS --
GO:0005829 NOT cytosol IBA --
genes like me logo Genes that share ontologies with MTHFD2: view

No data available for Subcellular locations from the Human Protein Atlas (HPA) for MTHFD2 Gene

Pathways & Interactions for MTHFD2 Gene

genes like me logo Genes that share pathways with MTHFD2: view

Gene Ontology (GO) - Biological Process for MTHFD2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0006730 one-carbon metabolic process IBA --
GO:0008152 metabolic process IEA --
GO:0046653 tetrahydrofolate metabolic process IDA 8218174
GO:0046655 folic acid metabolic process TAS --
GO:0055114 oxidation-reduction process IEA --
genes like me logo Genes that share ontologies with MTHFD2: view

No data available for SIGNOR curated interactions for MTHFD2 Gene

Drugs & Compounds for MTHFD2 Gene

(7) Drugs for MTHFD2 Gene - From: DrugBank and HMDB

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
NADH Approved Nutra Target 0
Formic acid Approved, Experimental, Investigational Pharma 0
Water Approved Pharma 0
Magnesium Approved Nutra 0
ATP Investigational Nutra Agonist, Activator, Full agonist, Antagonist, Potentiation, Pore Blocker 0

(7) Additional Compounds for MTHFD2 Gene - From: HMDB

Name Synonyms Role CAS Number PubChem IDs PubMed IDs
  • 10-Formyl-THF
  • 10-Formyltetrahydrofolic acid
  • 10-Formyl-(6Rs)-tetrahydrofolic acid
  • 10-Formyl-H4pteglu1
  • 10-Formyl-tetrahydrofolate
5,10-Methenyltetrahydrofolic acid
  • 5,10-Methenyl-THF
  • 5,10-Methenyltetrahydrofolate
  • anhydro-Leucovorin
  • anhydro-Leucovorin a
  • Anhydroleucovorin
  • (6R)-5,10-Methylenetetrahydrofolate
  • (6R)-5,10-Methylenetetrahydrofolic acid
  • 5,10-Methenyltetrahydropteroylglutamate
  • 5,10-Methylene-6-hydrofolate
  • 5,10-Methylene-6-hydrofolic acid
  • 5'-Adenylphosphoric acid
  • Adenosine 5'-diphosphate
  • ADENOSINE-5'-diphosphATE
  • H3ADP
  • 5'-Adenylphosphate
Full agonist, Agonist, Partial agonist, Antagonist, Gating inhibitor 58-64-0
Hydrogen Ion
  • H+
  • H(+)
  • Hydrogen cation
  • Hydron
  • Proton
genes like me logo Genes that share compounds with MTHFD2: view

Transcripts for MTHFD2 Gene

mRNA/cDNA for MTHFD2 Gene

Unigene Clusters for MTHFD2 Gene

Methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase:
Representative Sequences:

CRISPR Products

Inhibitory RNA Products

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for MTHFD2

Clone Products

Alternative Splicing Database (ASD) splice patterns (SP) for MTHFD2 Gene

ExUns: 1a · 1b · 1c ^ 2 ^ 3a · 3b ^ 4a · 4b ^ 5 ^ 6 ^ 7a · 7b · 7c ^ 8a · 8b ^ 9a · 9b · 9c · 9d ^ 10 ^ 11a · 11b · 11c
SP1: - - - -
SP2: - - -
SP3: - - - - - -
SP4: - - - - - - -
SP6: - - -
SP7: - - - - - - - - - - - -

Relevant External Links for MTHFD2 Gene

GeneLoc Exon Structure for
ECgene alternative splicing isoforms for

Expression for MTHFD2 Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and CGAP SAGE for MTHFD2 Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

Protein differential expression in normal tissues from HIPED for MTHFD2 Gene

This gene is overexpressed in Liver (48.5) and Breast (6.1).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for MTHFD2 Gene

NURSA nuclear receptor signaling pathways regulating expression of MTHFD2 Gene:


SOURCE GeneReport for Unigene cluster for MTHFD2 Gene:


Evidence on tissue expression from TISSUES for MTHFD2 Gene

  • Nervous system(4.8)
  • Liver(4.6)
  • Intestine(4.4)
  • Thyroid gland(4.2)
  • Blood(3.6)
  • Eye(3)
  • Lung(2.1)
genes like me logo Genes that share expression patterns with MTHFD2: view

No data available for mRNA differential expression in normal tissues , Protein tissue co-expression partners , mRNA Expression by UniProt/SwissProt and Phenotype-based relationships between genes and organs from Gene ORGANizer for MTHFD2 Gene

Orthologs for MTHFD2 Gene

This gene was present in the common ancestor of eukaryotes.

Orthologs for MTHFD2 Gene

Organism Taxonomy Gene Similarity Type Details
(Pan troglodytes)
Mammalia MTHFD2 34 33
  • 99.43 (n)
(Canis familiaris)
Mammalia MTHFD2 34 33
  • 89.81 (n)
(Bos Taurus)
Mammalia MTHFD2 34 33
  • 89.33 (n)
(Mus musculus)
Mammalia Mthfd2 16 34 33
  • 85.62 (n)
(Rattus norvegicus)
Mammalia Mthfd2 33
  • 84.53 (n)
(Monodelphis domestica)
Mammalia -- 34
  • 83 (a)
(Ornithorhynchus anatinus)
Mammalia -- 34
  • 76 (a)
(Gallus gallus)
Aves MTHFD2 34 33
  • 77.53 (n)
(Anolis carolinensis)
Reptilia -- 34
  • 80 (a)
tropical clawed frog
(Silurana tropicalis)
Amphibia mthfd2 33
  • 74.45 (n)
(Danio rerio)
Actinopterygii mthfd2 34
  • 76 (a)
LOC101886265 33
  • 70.23 (n)
African malaria mosquito
(Anopheles gambiae)
Insecta AgaP_AGAP004677 33
  • 62.01 (n)
fruit fly
(Drosophila melanogaster)
Insecta Nmdmc 34 35 33
  • 57.21 (n)
baker's yeast
(Saccharomyces cerevisiae)
Saccharomycetes ADE3 34
  • 13 (a)
(Hordeum vulgare)
Liliopsida Hv.8473 33
(Triticum aestivum)
Liliopsida Ta.3377 33
(Oryza sativa)
Liliopsida Os.7067 33
sea squirt
(Ciona savignyi)
Ascidiacea Cin.890 33
sea squirt
(Ciona intestinalis)
Ascidiacea Cin.890 33
Species where no ortholog for MTHFD2 was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Ashbya gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • Alicante grape (Vitis vinifera)
  • alpha proteobacteria (Wolbachia pipientis)
  • amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • beta proteobacteria (Neisseria meningitidis)
  • bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • common water flea (Daphnia pulex)
  • corn (Zea mays)
  • E. coli (Escherichia coli)
  • filamentous fungi (Aspergillus nidulans)
  • Firmicute bacteria (Streptococcus pneumoniae)
  • fission yeast (Schizosaccharomyces pombe)
  • green algae (Chlamydomonas reinhardtii)
  • honey bee (Apis mellifera)
  • K. lactis yeast (Kluyveromyces lactis)
  • loblloly pine (Pinus taeda)
  • malaria parasite (Plasmodium falciparum)
  • medicago trunc (Medicago Truncatula)
  • moss (Physcomitrella patens)
  • orangutan (Pongo pygmaeus)
  • pig (Sus scrofa)
  • rainbow trout (Oncorhynchus mykiss)
  • rice blast fungus (Magnaporthe grisea)
  • schistosome parasite (Schistosoma mansoni)
  • sea anemone (Nematostella vectensis)
  • sea urchin (Strongylocentrotus purpuratus)
  • sorghum (Sorghum bicolor)
  • soybean (Glycine max)
  • stem rust fungus (Puccinia graminis)
  • sugarcane (Saccharum officinarum)
  • thale cress (Arabidopsis thaliana)
  • tomato (Lycopersicon esculentum)
  • toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • worm (Caenorhabditis elegans)

Evolution for MTHFD2 Gene

Gene Tree for MTHFD2 (if available)
Gene Tree for MTHFD2 (if available)
Evolutionary constrained regions (ECRs) for MTHFD2: view image

Paralogs for MTHFD2 Gene

Paralogs for MTHFD2 Gene

(4) SIMAP similar genes for MTHFD2 Gene using alignment to 7 proteins:

  • B4DY35_HUMAN
  • B9A062_HUMAN
  • F8WF06_HUMAN
  • F8WF89_HUMAN
  • Q7Z650_HUMAN
genes like me logo Genes that share paralogs with MTHFD2: view

Variants for MTHFD2 Gene

Sequence variations from dbSNP and Humsavar for MTHFD2 Gene

SNP ID Clin Chr 02 pos Variation AA Info Type
rs1000372634 -- 74,209,471(+) T/C intron_variant
rs1001042753 -- 74,202,066(+) A/G intron_variant
rs1001105800 -- 74,212,389(+) C/T intron_variant
rs1001138361 -- 74,211,683(+) A/G intron_variant
rs1001409300 -- 74,208,327(+) G/A intron_variant

Structural Variations from Database of Genomic Variants (DGV) for MTHFD2 Gene

Variant ID Type Subtype PubMed ID
nsv1117245 CNV tandem duplication 24896259
nsv834261 CNV loss 17160897
nsv961419 CNV duplication 23825009

Variation tolerance for MTHFD2 Gene

Residual Variation Intolerance Score: 33.8% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 1.14; 23.12% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for MTHFD2 Gene

SNPedia medical, phenotypic, and genealogical associations of SNPs for

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for MTHFD2 Gene

Disorders for MTHFD2 Gene

Additional Disease Information for MTHFD2

Genetic Association Database
Human Genome Epidemiology Navigator
ATLAS of Genetics and Cytogenetics in Oncology and Haematology

No disorders were found for MTHFD2 Gene.

No data available for MalaCards , UniProtKB/Swiss-Prot and Genatlas for MTHFD2 Gene

Publications for MTHFD2 Gene

  1. Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase. (PMID: 16100107) Christensen KE … Mackenzie RE (The Journal of biological chemistry 2005) 3 4 22 58
  2. Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase. (PMID: 2587219) Peri KG … Mackenzie RE (Nucleic acids research 1989) 2 3 4 58
  3. Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor. (PMID: 27899380) Gustafsson R … Stenmark P (Cancer research 2017) 3 4 58
  4. Genetic susceptibility to distinct bladder cancer subphenotypes. (PMID: 19692168) Guey LT … EPICURO/Spanish Bladder Cancer Study investigators (European urology 2010) 3 44 58
  5. A Large-scale genetic association study of esophageal adenocarcinoma risk. (PMID: 20453000) Liu CY … Christiani DC (Carcinogenesis 2010) 3 44 58

Products for MTHFD2 Gene

Sources for MTHFD2 Gene

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