CYP2A6 rs28399508: Understanding Your Genetic Variant
The rs28399508 variant is a genetic change in the CYP2A6 gene associated with altered enzyme activity. This variant is linked to slower metabolism of substances like nicotine and certain medications, which can lead to interindividual differences in how the body processes these compounds.
What each genotype means
Normal CYP2A6 enzyme activity
You carry two copies of the common reference allele at this locus, typically associated with standard baseline CYP2A6 enzymatic function. Individuals with this genotype generally exhibit expected rates of nicotine breakdown and clearance of medications primarily processed by CYP2A6, such as letrozole and tegafur. If you are taking or considering medications metabolized by this pathway, always discuss standard dosing and monitoring with your clinician or pharmacist.
Found in the vast majority of people worldwide, including over 90% of individuals of European, African, and American ancestries, and roughly 80% to 90% of East Asian populations.
Intermediate CYP2A6 enzyme activity
You carry one copy of the decreased-function missense variant c.1412T>C (often designated in pharmacogenetic haplotype panels as CYP2A6*7 or *10). Population studies show that having one copy moderately reduces overall CYP2A6 activity, which can lead to slower clearance of nicotine and altered pharmacokinetics for drugs like letrozole or tegafur. If you are prescribed letrozole or other CYP2A6-metabolized therapies, consult your physician or pharmacist before making any changes to your medication regimen.
Carried by approximately 10% to 18% of individuals of East Asian ancestry, but present in fewer than 1% of European and African populations.
Poor CYP2A6 enzyme activity
You carry two copies of the decreased-function variant allele, which is associated with markedly reduced or impaired CYP2A6 enzymatic activity. Research demonstrates that homozygous individuals metabolize nicotine much more slowly than normal metabolizers and may experience elevated drug concentrations or altered active metabolite formation when taking medications like letrozole or tegafur. Because altered metabolism can affect therapeutic efficacy and side-effect profiles, discuss drug selection and dosing directly with your clinician or pharmacist.
Observed in roughly 0.5% to 1% of individuals of East Asian ancestry and is extremely rare (well below 0.1%) in European, African, and other global populations.
What is the rs28399508 Variant?
The rs28399508 variant is a specific change in the DNA sequence of the CYP2A6 gene, often identified as a missense mutation (c.1412T>C, p.Leu471Ser). This variant is recognized in scientific literature for its association with non-functional or reduced-function alleles, such as those related to the CYP2A6*4 or *7 classifications. When this variant is present, it can lead to a significant reduction in the enzyme's ability to perform its normal chemical tasks. Because the CYP2A6 gene provides instructions for making an enzyme that breaks down various substances, changes in this gene can alter the speed at which these substances are cleared from the body. Understanding this variant requires looking at how it affects the protein structure and, consequently, the metabolic efficiency of the enzyme in different individuals.
The Role of the CYP2A6 Gene
The CYP2A6 gene encodes a member of the cytochrome P450 superfamily of enzymes, which are primarily responsible for the metabolism of a wide range of endogenous and exogenous compounds. In the liver, the CYP2A6 enzyme plays a critical role in the biotransformation of nicotine into cotinine. Beyond nicotine, this enzyme is also involved in the metabolism of various therapeutic drugs, including letrozole, which is used in certain cancer treatments. Because the activity of this enzyme varies significantly between people, it is a major focus in the field of pharmacogenomics. Genetic variations that reduce the function of this enzyme can lead to slower clearance of these substances, potentially resulting in higher concentrations of the drug or compound in the bloodstream for longer periods than would be expected in individuals with fully functional enzyme activity.
Research and Clinical Associations
Research into rs28399508 and related CYP2A6 variants has primarily focused on their impact on nicotine metabolism and smoking behavior. Studies have consistently shown that individuals carrying variants associated with reduced CYP2A6 function exhibit slower nicotine metabolism, often measured by the nicotine metabolite ratio. While the evidence linking this specific variant to clinical outcomes is considered limited, the broader category of CYP2A6 genetic polymorphisms is well-documented in the context of pharmacogenomics. It is important to note that while genetic associations are observed in research settings, they do not serve as a diagnostic tool for individual health outcomes. The impact of this variant can be influenced by other genetic and environmental factors, meaning that the presence of the variant does not guarantee a specific clinical response to any medication or substance.
Population Frequency and Distribution
The frequency of the rs28399508 variant varies significantly across different ancestral populations. Data indicates that the minor allele frequency (MAF) is notably higher in East Asian populations, typically ranging between 0.05 and 0.10. In contrast, the variant is much less common in European and African populations, where the MAF is generally reported to be below 0.005. These differences highlight the importance of considering ancestry when evaluating the potential impact of genetic variants. Because the variant is more prevalent in certain groups, the clinical implications of reduced CYP2A6 activity may be more frequently observed or studied within those specific populations. Researchers continue to investigate these disparities to better understand how genetic diversity contributes to global differences in drug response and metabolic health.
What This Information Means for You
Learning about a genetic variant like rs28399508 can be an educational experience, but it is not a substitute for professional medical advice. If you are concerned about how your body processes a specific medication or if you are interested in how your genetics might influence your response to substances, the most important step is to consult with a healthcare provider or a pharmacist. They can interpret your genetic information in the context of your overall health, medical history, and current treatments. Never make changes to your medication regimen or health habits based solely on genetic test results without first discussing them with a clinician. Genetic information is just one piece of a complex puzzle, and a professional can help you understand what is relevant to your specific situation and what is not.
How common is this variant?
The variant has a minor allele frequency of approximately 0.05-0.10 in East Asian populations, while it is rare (MAF < 0.005) in European and African populations.
Frequently asked questions
Does this variant mean I cannot metabolize nicotine?
No, this variant is associated with slower metabolism, not a complete inability to process nicotine. It means your body may clear nicotine from your system at a different rate than someone without the variant.
Should I get tested for this variant before taking medication?
Routine testing for this specific variant is not standard practice for most medications. You should discuss any concerns about drug metabolism or side effects with your doctor, who can determine if testing is appropriate for your specific treatment plan.
Can I change my CYP2A6 activity level?
Your genetic makeup is fixed, but your overall metabolic health is influenced by many factors, including diet, other medications, and lifestyle. A healthcare provider can help you manage your health based on your individual needs.
Is this variant linked to cancer risk?
Some research explores the link between CYP2A6 variants and cancer risk due to the enzyme's role in metabolizing carcinogens. However, these associations are complex and not fully understood; you should speak with a medical professional regarding your personal risk factors.
Sources & further reading
Educational information only, last refreshed 10/17/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Functional splice-site variant defining CYP2A6*20 associated with significantly reduced enzyme activity and slower nicotine and coumarin clearance.
Defining functional variant for the CYP2A6*2 allele (L160H) causing defective nicotine C-oxidation and slower metabolic nicotine clearance.
Defines the non-functional CYP2A6*2 allele (p.Leu160His) conferring absent nicotine C-oxidation activity and slow nicotine metabolism.
Functional variant in CYP2A6 defining the *9 allele with decreased transcriptional activity and reduced rate of nicotine metabolism.
Associated with the CYP2A6 locus and variation in rate of nicotine metabolism and cigarette consumption.
Functional polymorphism defining the CYP2A6*9 reduced-function promoter variant causing slower nicotine and cotinine metabolism.