MTHFR

methylenetetrahydrofolate reductase

Basic information

Region (hg38): 1:11785723-11806455

Links

ENSG00000177000 ∙ NCBI:4524 ∙ OMIM:607093 ∙ HGNC:7436 ∙ Uniprot:P42898 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• homocystinuria due to methylene tetrahydrofolate reductase deficiency (Supportive), mode of inheritance: AR
• homocystinuria due to methylene tetrahydrofolate reductase deficiency (Strong), mode of inheritance: AR
• homocystinuria due to methylene tetrahydrofolate reductase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Homocystinuria due to MTHFR deficiency	AR	Biochemical; Cardiovascular; Hematologic	Medical therapy (eg, with folate, betaine, riboflavin, hydroxycobalamin) can be effective; In individuals with heterozygous variants, there may be an increased risk of thrombophilia, and considerations may be warranted in certain situations	Biochemical; Cardiovascular; Hematologic; Neurologic	3889647; 1998339; 1866027; 1627352; 8456826; 7920641; 7647779; 7726158; 7564788; 8691945; 8826441; 8892013; 8940272; 8994411; 9133512; 9341863; 9244205; 9372726; 9068801; 9878639; 10323741; 10384377; 10536004; 10679944; 10862840; 10923034; 10961793; 11508552; 11170082; 11274424; 11938441; 12142069; 12673793; 15896655; 15979034; 16145688; 16216822; 17409006; 18658082; 18708589; 19697151; 20236116; 20356773; 20850942; 22578003; 22646290; 22665071; 22721898; 22773907; 22807619; 22856671; 22947400; 23124942
Variants in MTHFR may interact with variants in other genes, such as F5 to result in susceptibility to hematologic manifestations

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MTHFR gene.

• Homocystinuria due to methylene tetrahydrofolate reductase deficiency (59 variants)
• Neural tube defects, folate-sensitive (14 variants)
• Abnormality of metabolism/homeostasis (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTHFR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	1	268	6	276
missense	4	28	157	8	3	200
nonsense	20	19				39
start loss	2	1				3
frameshift	25	21				46
inframe indel	1	3	7			11
splice donor/acceptor (+/-2bp)	4	20				24
splice region	1	3	6	40	1	51
non coding	3	1	45	117	30	196
Total	59	94	210	393	39

Highest pathogenic variant AF is 0.0000131

Variants in MTHFR

This is a list of pathogenic ClinVar variants found in the MTHFR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-11786035-G-GT		Neural tube defects, folate-sensitive	Benign (Jun 14, 2016)
1-11786191-A-G		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11786602-ATTTT-A		Neural tube defects, folate-sensitive	Likely benign (Jun 14, 2016)
1-11786602-ATTTTTTTT-A		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11786602-A-ATT		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11786618-TTTTG-T		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11788023-G-A		Homocystinuria due to methylene tetrahydrofolate reductase deficiency	Conflicting classifications of pathogenicity (Feb 01, 2024)
1-11788203-CCTT-C		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11788224-C-T		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11789149-G-A		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11789662-T-C		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11789977-CA-C		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11790308-T-G		Homocystinuria due to methylene tetrahydrofolate reductase deficiency	Benign (Jan 15, 2025)
1-11790307-G-GGGTA		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11790310-T-TAAG		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11790505-CA-C		Neural tube defects, folate-sensitive	Uncertain significance (Jun 14, 2016)
1-11790562-G-C			Likely benign (Aug 01, 2022)
1-11790639-G-A			Likely benign (Feb 01, 2023)
1-11790673-C-T			Uncertain significance (Jul 29, 2014)
1-11790681-C-G		Intellectual disability • Homocystinuria due to methylene tetrahydrofolate reductase deficiency • Neural tube defects, folate-sensitive	Conflicting classifications of pathogenicity (Mar 16, 2024)
1-11790681-C-T		Homocystinuria due to methylene tetrahydrofolate reductase deficiency	Likely benign (Dec 08, 2022)
1-11790682-A-G		Homocystinuria due to methylene tetrahydrofolate reductase deficiency • Neural tube defects, folate-sensitive	Likely pathogenic (Dec 21, 2023)
1-11790683-T-C		Homocystinuria due to methylene tetrahydrofolate reductase deficiency	Likely benign (Aug 20, 2024)
1-11790692-C-T		not specified • Homocystinuria due to methylene tetrahydrofolate reductase deficiency • Inborn genetic diseases • Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Thrombophilia due to thrombin defect;Neural tube defects, folate-sensitive;Schizophrenia	Benign/Likely benign (Jan 20, 2025)
1-11790693-G-A		not specified • Homocystinuria due to methylene tetrahydrofolate reductase deficiency • MTHFR-related disorder	Benign (Feb 01, 2025)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTHFR	protein_coding	protein_coding	ENST00000376592	11	21198

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.21e-10	0.913	125699	0	49	125748	0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.896	342	392	0.873	0.0000251	4306
Missense in Polyphen		124	156.37	0.793		1746
Synonymous	-1.37	182	160	1.14	0.0000106	1283
Loss of Function	1.90	20	31.5	0.634	0.00000167	338

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000274	0.000264
Middle Eastern	0.000326	0.000326
South Asian	0.000261	0.000261
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co- substrate for homocysteine remethylation to methionine. {ECO:0000269|PubMed:25736335}.
• Disease: DISEASE: Methylenetetrahydrofolate reductase deficiency (MTHFRD) [MIM:236250]: Autosomal recessive disorder with a wide range of features including homocysteinuria, homocysteinemia [MIM:603174], developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders. {ECO:0000269|PubMed:10679944, ECO:0000269|PubMed:20236116, ECO:0000269|PubMed:25736335, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:7726158, ECO:0000269|PubMed:8940272, ECO:0000269|PubMed:9781030}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:10323741, ECO:0000269|PubMed:7564788, ECO:0000269|PubMed:8826441}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Schizophrenia (SCZD) [MIM:181500]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:15729744, ECO:0000269|PubMed:18583979}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Fluoropyrimidine Pathway, Pharmacodynamics;Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;One carbon pool by folate - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;S-Adenosylhomocysteine (SAH) Hydrolase Deficiency;Methionine Metabolism;Folate malabsorption, hereditary;Methionine Adenosyltransferase Deficiency;Glycine N-methyltransferase Deficiency;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Hypermethioninemia;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Methotrexate Action Pathway;Folate Metabolism;Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type;Cystathionine Beta-Synthase Deficiency;Glycine Metabolism;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate-Alcohol and Cancer Pathway Hypotheses;Fluoropyrimidine Activity;Folate Metabolism;One carbon donor;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;One carbon metabolism and related pathways;Ethanol effects on histone modifications;Folate metabolism;Metabolism;folate transformations I;Metabolism of folate and pterines;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.909

Intolerance Scores

• loftool: 0.210
• rvis_EVS: 0.09
• rvis_percentile_EVS: 60.71

Haploinsufficiency Scores

• pHI: 0.131
• hipred: N
• hipred_score: 0.379
• ghis: 0.548

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	Medium
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Mthfr
• Phenotype: liver/biliary system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; skeleton phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype

Gene ontology

• Biological process: response to hypoxia;neural tube closure;cellular amino acid metabolic process;methionine metabolic process;one-carbon metabolic process;blood circulation;methionine biosynthetic process;regulation of histone methylation;response to vitamin B2;tetrahydrofolate interconversion;response to amino acid;S-adenosylmethionine metabolic process;folic acid metabolic process;homocysteine metabolic process;response to folic acid;oxidation-reduction process;response to interleukin-1;heterochromatin maintenance
• Cellular component: cytosol;synapse
• Molecular function: methylenetetrahydrofolate reductase (NAD(P)H) activity;protein-containing complex binding;flavin adenine dinucleotide binding;NADP binding;FAD binding;modified amino acid binding