{"variant":{"rsid":"rs1801133","gene":"MTHFR","name":"C677T (Ala222Val, exon 4)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): G reference, A variant. MTHFR is on the minus strand, so A here is the T of c.665C>T, known as C677T.","effect":"Reduces enzyme thermostability. 677TT homozygotes have ~30% of normal MTHFR activity; 677CT heterozygotes ~65% (lymphocyte extracts, Frosst et al., Nat Genet 1995). ClinVar (VCV000003520): aggregate classification drug response (methotrexate toxicity), reviewed by an expert panel; a DPWG guideline found insufficient evidence for an MTHFR–methotrexate gene–drug interaction (van der Pol et al., Eur J Hum Genet 2024). Submissions for individual conditions conflict.","frequency_note":"677T allele (A on the plus strand) ~37% in Europeans, ~47% in Admixed Americans, ~9% in Africans (1000 Genomes, Ensembl).","reading":{"assembly":"GRCh37","chromosome":"1","position":11856378,"reference_allele":"G","variant_allele":"A","gene_strand":"minus","countable":true,"strand_ambiguous":false,"sources":[{"label":"dbSNP rs1801133","url":"https://www.ncbi.nlm.nih.gov/snp/rs1801133"},{"label":"Ensembl GRCh37 rs1801133","url":"https://grch37.ensembl.org/Homo_sapiens/Variation/Explore?v=rs1801133"}]},"alphamissense":{"note":"AlphaMissense's computational prediction of how this amino-acid change affects the protein. It is not a clinical (ACMG/ClinVar) classification, not a measure of disease risk and not evidence about drug response: alleles with established effects can score likely_benign, and common alleles that cause no disease can score likely_pathogenic. The effect field says what is established. Google DeepMind states that AlphaMissense is not validated or approved for clinical use. It does not override ClinVar's drug-response classification or the DPWG finding cited in effect.","is_clinical_classification":false,"am_class":"likely_pathogenic","score":0.632,"score_note":"Rounded to 3 decimals from the published value.","thresholds":"AlphaMissense bins from the paper: likely_benign below 0.34, ambiguous 0.34 to 0.564, likely_pathogenic above 0.564","protein_variant":"A222V","uniprot_id":"P42898","source":{"label":"AlphaMissense (Cheng et al., Science 2023), AlphaMissense_hg19, Zenodo record 10813168, CC BY 4.0","url":"https://doi.org/10.5281/zenodo.10813168"}},"sources":[{"label":"ClinVar — MTHFR gene entries","url":"https://www.ncbi.nlm.nih.gov/clinvar/?term=MTHFR%5Bgene%5D"},{"label":"Frosst et al., Nat Genet 1995 (MTHFR C677T: reduced, thermolabile enzyme activity in lymphocyte extracts; higher plasma homocysteine in homozygotes)","url":"https://pubmed.ncbi.nlm.nih.gov/7647779/"},{"label":"ClinVar VCV000003520","url":"https://www.ncbi.nlm.nih.gov/clinvar/variation/3520/"},{"label":"van der Pol et al., Eur J Hum Genet 2024 (DPWG guideline: ABCG2/HLA-B and allopurinol, MTHFR and folic acid/methotrexate)","url":"https://pubmed.ncbi.nlm.nih.gov/36056234/"}]},"gene":{"symbol":"MTHFR","name":"5,10-Methylenetetrahydrofolate reductase","url":"https://deepdna.ai/api/v1/genes/MTHFR"},"meta":{"disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information.","api_version":"2026-09-20","docs":"https://deepdna.ai/docs/","status":"live","data_as_of":"2026-10-25T21:32:19.251Z","freshness":"https://deepdna.ai/api/v1/freshness"}}