What you carry at this position in your DNA and what research says about it.
Folate Metabolism and Heart Risk: 5/10 evidence, 24 publications.
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Sample genotype (not yours): G/G
Typical Cardiovascular and Lymphoma Risk
Two copies of the common G allele provide standard SHMT1 enzyme localization and typical baseline health risks. However, this genotype is linked to a less favorable response to certain colon cancer chemotherapies.
What this genotype means: Typical baseline cardiovascular risk; Typical baseline lymphoma risk; Reduced response to FOLFIRI and bevacizumab chemotherapy.
Sample genotype (not yours): A/A
Increased Cardiovascular and Lymphoma Risk
Two copies of the variant A allele alter SHMT1 enzyme localization, which can elevate cardiovascular and lymphoma risks. Conversely, this genotype predicts a highly favorable response to specific chemotherapies.
What this genotype means: Elevated cardiovascular risk when paired with MTHFR variants; Increased risk of non-Hodgkin lymphoma; Significantly better response to FOLFIRI and bevacizumab chemotherapy.
Sample genotype (not yours): G/A
Typical Health Risk with Enhanced Chemotherapy Response
One copy of the variant A allele maintains typical baseline health risks while offering potential benefits during specific cancer treatments. This intermediate state balances standard folate metabolism with altered drug sensitivity.
What this genotype means: Typical baseline cardiovascular risk; Typical baseline lymphoma risk; Improved response to FOLFIRI and bevacizumab chemotherapy.
Gene function and biological role
Gene Function: The SHMT1 gene encodes serine hydroxymethyltransferase 1, a key cytoplasmic enzyme in the folate-mediated one-carbon metabolism pathway [1]. This enzyme catalyzes the reversible conversion of tetrahydrofolate and serine to 5,10-methylenetetrahydrofolate and glycine [2]. By generating 5,10-methylenetetrahydrofolate, it provides the essential substrate required by the MTHFR enzyme to produce active methylfolate [1]. This biochemical step is critical for cellular methylation, DNA synthesis, and the clearance of homocysteine [3]. Disruptions in this pathway can lead to elevated homocysteine levels, which is a known risk factor for cardiovascular disease [1].
Variant Impact: The rs1979277 variant, also known as C1420T or p.Leu474Phe, is a missense mutation in the twelfth exon of the SHMT1 gene [1]. This genetic change substitutes the amino acid leucine with phenylalanine at codon 474 of the enzyme [4]. This structural alteration affects the intracellular localization of the SHMT1 enzyme, shifting it away from its typical cytoplasmic sites [1]. Consequently, the availability of 5,10-methylenetetrahydrofolate is reduced, which can impair downstream folate metabolism and DNA synthesis [3]. This functional limitation is particularly pronounced when dietary folate intake is low or when other folate pathway variants are present [1].
Key Insight: The cardiovascular risk associated with this variant is highly dependent on another common gene, MTHFR, demonstrating how multiple genetic factors interact to shape heart health. Additionally, while the variant allele is linked to higher health risks, it unexpectedly predicts a significantly better survival rate and treatment response during certain colon cancer chemotherapies.
Location: SHMT1. Chromosome 17 · 17p11.2 · 18.3 Mb
Estimated prevalence by population
Global 48.6%; European 46.8%; African 42.9%; East Asian 85.7%; South Asian 66.1%; Americas 56.6%; Ashkenazi 45.3%; Finnish 45.7%; Middle Eastern 50.1%; Amish 46.4%.
Estimated GG genotype frequency.
Global 41.8%; European 43.2%; African 45.2%; East Asian 13.8%; South Asian 30.4%; Americas 37.3%; Ashkenazi 44.0%; Finnish 43.8%; Middle Eastern 41.4%; Amish 43.5%.
Estimated GA genotype frequency.
Global 9.6%; European 10.0%; African 11.9%; East Asian 0.6%; South Asian 3.5%; Americas 6.1%; Ashkenazi 10.7%; Finnish 10.5%; Middle Eastern 8.6%; Amish 10.2%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Cardiovascular & Metabolic
Heart Disease
Cardiovascular Risk. Evidence: 3/10. Source: PMID 21178087. Typical Risk.
Cancer & Oncology
Blood Cancers
Lymphoma. Evidence: 3/10. Source: PMID 23913011. Typical Risk.
Colorectal Cancer
Colorectal Cancer. Evidence: 4/10. Source: PMID 23401104. Typical Risk.
Pharmacogenomics
Chemotherapy Response
Chemotherapy Response. Evidence: 5/10. Source: PMID 22044939. Decreased Response.
Immunosuppressant & Biologic Response
Methotrexate Toxicity. Evidence: 5/10. Source: PMID 18368069. Higher Side Effects.
Showing effects for A/A genotype
Cardiovascular Risk. Evidence: 3/10. Source: PMID 21178087. Increased Risk.
Lymphoma. Evidence: 3/10. Source: PMID 23913011. Increased Risk.
Chemotherapy Response. Evidence: 5/10. Source: PMID 22044939. Stronger Response.
Methotrexate Toxicity. Evidence: 5/10. Source: PMID 18368069. Lower Liver Damage.
Showing effects for G/A genotype
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Standard cellular localization of the SHMT1 enzyme is maintained, ensuring a steady supply of folate intermediates for downstream methylation processes [1]. Standard enzyme function helps keep baseline cardiovascular risks at typical levels, avoiding the elevated risks seen in variant carriers [1]. Similarly, the risk of developing non-Hodgkin lymphoma remains at the typical population baseline [2]. In the context of cancer treatment, clinical data indicates that this genotype is associated with a reduced response and shorter survival when treated with FOLFIRI and bevacizumab [3]. Additionally, pediatric leukemia patients with this genotype may experience a higher likelihood of abdominal pain when undergoing high-dose methotrexate therapy [4]. Ensuring adequate dietary folate and B-vitamin intake supports overall metabolic efficiency [1].
Typical baseline cardiovascular risk; Typical baseline lymphoma risk; Reduced response to FOLFIRI and bevacizumab chemotherapy.
Sample genotype: AA (Homozygous)
Altered cellular localization of the SHMT1 enzyme occurs, which limits the availability of key folate substrates required for proper methylation [1]. This metabolic restriction leads to an increased risk of cardiovascular disease, especially when combined with the MTHFR C677T variant [1]. The risk of developing non-Hodgkin lymphoma is also elevated, as impaired folate flow can compromise DNA synthesis and repair mechanisms [2]. On the other hand, this genotype is highly advantageous during certain cancer treatments, predicting superior survival and tumor response rates when undergoing FOLFIRI and bevacizumab chemotherapy [3]. Patients treated with methotrexate also benefit from a reduced likelihood of liver toxicity [4]. Supporting the methylation cycle with active folate and vitamin B6 can help mitigate the elevated cardiovascular risks associated with this genotype [1].
Elevated cardiovascular risk when paired with MTHFR variants; Increased risk of non-Hodgkin lymphoma; Significantly better response to FOLFIRI and bevacizumab chemotherapy.
Sample genotype: GA (Heterozygous)
Folate metabolism operates at a standard level because a single copy of the variant allele does not significantly impair overall methylation capacity [1]. Baseline cardiovascular risk remains typical and is not elevated unless severe nutritional deficiencies or other major genetic variants are present [1]. The risk for non-Hodgkin lymphoma also remains close to the typical population baseline [2]. However, in the event of metastatic colorectal cancer, carrying this single variant allele is associated with a significantly better response and prolonged survival when treated with FOLFIRI and bevacizumab [3]. Furthermore, patients undergoing methotrexate therapy show a decreased likelihood of experiencing treatment-induced liver damage [4]. Maintaining a balanced diet rich in folate and active B vitamins helps optimize this intermediate metabolic profile [1].
Typical baseline cardiovascular risk; Typical baseline lymphoma risk; Improved response to FOLFIRI and bevacizumab chemotherapy.
Variants with shared genetic architecture
rs1801133 · MTHFR Gene · Chr 1 · Folate Processing
rs1801198 · TCN2 Gene · Chr 22 · Vitamin B12 Transport
rs1805087 · MTR Gene · Chr 1 · Folate and Drug Metabolism
Content updated August 2026.
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