What you carry at this position in your DNA and what research says about it.
Folate Processing: 6/10 evidence, 9 publications.
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Sample genotype (not yours): A/A
Reduced Folate Conversion and Higher Drug Sensitivity
Two copies of the A allele are linked to lower DHFR enzyme levels, which can slow down the conversion of synthetic folic acid into active folate. This genotype is also associated with an increased risk of side effects from certain folate-blocking medications.
What this genotype means: Slower conversion of synthetic folic acid; Increased risk of pemetrexed toxicity; Altered response to methotrexate therapy.
Sample genotype (not yours): A/G
Moderately Reduced Folate Conversion
A single copy of the A allele is associated with a moderate reduction in DHFR enzyme production. This can slightly lower the efficiency of converting synthetic folic acid and increase sensitivity to certain medications.
What this genotype means: Moderately slower folic acid processing; Slightly increased risk of pemetrexed side effects.
Sample genotype (not yours): G/G
Typical Folate Conversion and Standard Drug Sensitivity
Two copies of the G allele represent the typical genetic profile, supporting efficient conversion of synthetic folic acid into active folate. This genotype is associated with standard sensitivity to folate-blocking medications.
What this genotype means: Efficient conversion of synthetic folic acid; Standard sensitivity to folate-blocking drugs.
Gene function and biological role
Gene Function: The DHFR gene encodes dihydrofolate reductase, a key enzyme in the folate metabolic pathway. This enzyme is responsible for converting dihydrofolate into tetrahydrofolate, which is the active form of vitamin B9 needed for cell division and growth [1]. It also plays a vital role in converting synthetic folic acid from fortified foods and supplements into a usable form [2]. Proper functioning of this pathway is essential for DNA synthesis, red blood cell production, and keeping homocysteine levels in check [1]. Because of its role in DNA replication, DHFR is a primary target for several chemotherapy and immunosuppressive drugs [3].
Variant Impact: The rs1650697 variant is located in the promoter region of the DHFR gene, where it influences how much of the enzyme is produced. The minor A allele is associated with decreased expression of the DHFR gene, leading to lower levels of the enzyme [4]. This reduction can impair the body's ability to efficiently process synthetic folic acid and recycle folate [4]. Conversely, the major G allele is associated with typical promoter activity and standard enzyme levels [5]. This genetic variation can also alter sensitivity to medications that target the folate pathway, such as chemotherapy drugs [3].
Read on the Folate Processing page
Key Insight: This variant sits in the promoter region of the DHFR gene, meaning it acts like a volume dial that controls how much folate-processing enzyme your body produces.
Location: DHFR. Chromosome 5 · 5q14.1 · 80.7 Mb
Estimated prevalence by population
Global 4.8%; European 5.9%; African 0.8%; East Asian 10.9%; South Asian 9.3%; Americas 5.6%; Ashkenazi 6.2%; Finnish 7.7%; Middle Eastern 3.7%; Amish 1.9%.
Estimated AA genotype frequency.
Global 31.6%; European 36.8%; African 15.9%; East Asian 44.3%; South Asian 42.4%; Americas 36.1%; Ashkenazi 37.4%; Finnish 40.0%; Middle Eastern 31.0%; Amish 23.6%.
Estimated AG genotype frequency.
Global 63.6%; European 57.2%; African 83.3%; East Asian 44.8%; South Asian 48.3%; Americas 58.3%; Ashkenazi 56.3%; Finnish 52.3%; Middle Eastern 65.3%; Amish 74.6%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Nutrition & Metabolism
Vitamin & Mineral Metabolism
Folate Metabolism. Evidence: 3/10. Source: PMID 20472929. Reduced.
Pharmacogenomics
Chemotherapy Response
Pemetrexed Sensitivity. Evidence: 5/10. Source: PMID 24732178. Higher Toxicity Risk.
Immunosuppressant & Biologic Response
Methotrexate Response. Evidence: 5/10. Source: PMID 29210328. Reduced Efficacy.
Neurology & Mental Health
Neurodevelopmental Traits
Cortical Thickness. Evidence: 6/10. Source: PMID 34910505. Increased.
Showing effects for A/G genotype
Folate Metabolism. Evidence: 3/10. Source: PMID 20472929. Moderately Reduced.
Methotrexate Response. Evidence: 5/10. Source: PMID 29210328. Typical Response.
Cortical Thickness. Evidence: 6/10. Source: PMID 34910505. Slightly Increased.
Showing effects for G/G genotype
Folate Metabolism. Evidence: 3/10. Source: PMID 20472929. Typical.
Pemetrexed Sensitivity. Evidence: 5/10. Source: PMID 24732178. Typical Sensitivity.
Cortical Thickness. Evidence: 6/10. Source: PMID 34910505. Typical.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Lower levels of the DHFR enzyme can restrict the body's capacity to process synthetic folic acid from supplements and fortified foods [1]. This can result in an accumulation of unmetabolized folic acid in the bloodstream and a relative shortage of the active folate forms needed for cellular repair [1]. Additionally, this genetic profile is linked to a higher risk of clinical toxicity when undergoing chemotherapy with pemetrexed [2]. Research also indicates that pediatric leukemia patients with this genotype may experience lower survival rates when treated with methotrexate protocols [3]. On a structural level, this genotype is associated with variations in brain cortical thickness [4].
Slower conversion of synthetic folic acid; Increased risk of pemetrexed toxicity; Altered response to methotrexate therapy.
Sample genotype: AG (Heterozygous)
Having one copy of each allele typically results in intermediate DHFR enzyme activity, falling between the typical and highly reduced levels [1]. While the body can still process folate, the conversion of synthetic folic acid into its active, usable form may be less efficient than in those with the typical genotype [1]. This intermediate status is also associated with an elevated risk of experiencing adverse side effects during pemetrexed chemotherapy [2]. However, unlike the double-A genotype, this heterozygous profile has not been strongly linked to reduced survival rates during methotrexate therapy [3]. Subtle changes in brain cortical structure have also been noted in genetic studies [4].
Moderately slower folic acid processing; Slightly increased risk of pemetrexed side effects.
Sample genotype: GG (Homozygous)
Standard levels of the DHFR enzyme allow the body to efficiently process synthetic folic acid from fortified foods and dietary supplements [1]. This efficient conversion supports healthy DNA synthesis, cellular repair, and normal homocysteine metabolism [1]. Individuals with this genotype generally exhibit a typical, baseline response to folate-targeting therapies like pemetrexed and methotrexate, without the elevated toxicity risks seen in carriers of the A allele. Brain cortical thickness measurements in individuals with this genotype represent the typical baseline population standard [2]. Additionally, clinical databases indicate that this common genetic variant does not pose an independent risk for familial adenomatous polyposis.
Efficient conversion of synthetic folic acid; Standard sensitivity to folate-blocking drugs.
Variants with shared genetic architecture
rs11545078 · GGH Gene · Chr 8 · Methotrexate Toxicity
rs1051266 · SLC19A1 Gene · Chr 21 · Folate and Drug Response
rs1801131 · MTHFR Gene · Chr 1 · Folate Metabolism
118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.
The genetic architecture of human cortical folding.
Content updated August 2026.
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