CYP2A6 rs28399509: Understanding This Genetic Variant
The rs28399509 variant is a specific genetic change located within the CYP2A6 gene, which encodes an enzyme responsible for metabolizing various substances. This variant is associated with the CYP2A6*8 allele, which has been linked to decreased catalytic activity for certain medications.
What each genotype means
Typical CYP2A6 enzyme activity
You carry two copies of the standard reference allele for this site in the CYP2A6 gene. Research indicates this genotype is associated with normal baseline enzyme function and typical clearance rates for CYP2A6-metabolized substrates such as tegafur and nicotine, assuming no other variants are present. Always consult a physician or pharmacist to discuss any questions regarding personal medication response and dosing.
Found in over 95% of individuals in East Asian populations and in more than 99% of European and other global ancestries.
Intermediate CYP2A6 enzyme activity
You carry one copy of the decreased-function A allele, which defines the CYP2A6*8 star allele (p.Arg365Gln). Studies show that individuals with this heterozygous genotype generally exhibit reduced catalytic clearance of specific CYP2A6 substrates, though current clinical evidence remains limited. Because this variant may alter drug metabolism, discuss your medication regimen and dosing options with your clinician or pharmacist.
Carried by approximately 2% to 6% of individuals of East Asian ancestry and is very rare or absent in European and African populations.
Significantly reduced CYP2A6 activity
You carry two copies of the decreased-function A allele corresponding to the CYP2A6*8 haplotype. Research suggests this genotype leads to substantially reduced or impaired catalytic activity toward CYP2A6-metabolized medications, including prodrugs like tegafur. If you are prescribed medications cleared or activated by CYP2A6, share these results with your doctor or pharmacist to assess whether individualized dosing adjustments are advised.
Extremely rare across all global populations, occurring in fewer than 1 in 1,000 individuals of East Asian descent and practically undetected in other ancestries.
What is rs28399509?
The rs28399509 variant is a single nucleotide polymorphism (SNP) found within the CYP2A6 gene, located on chromosome 19. In the context of pharmacogenomics, this specific variant serves as a defining marker for the CYP2A6*8 allele. This allele involves a coding change, specifically a p.Arg365Gln amino acid substitution, which alters the structure of the resulting enzyme. Because the CYP2A6 enzyme is a critical component of the cytochrome P450 system, changes to its genetic sequence can influence how efficiently the body processes certain compounds. Researchers track these variants to better understand why individuals may experience different responses to medications or environmental toxins. While rs28399509 is a recognized marker, it is important to note that it is just one of many variations within this complex gene, and its clinical impact depends on the overall genetic profile of an individual.
The Role of the CYP2A6 Gene
The CYP2A6 gene provides instructions for making an enzyme that plays a significant role in the metabolism of nicotine, coumarin, and several pharmaceutical drugs. By hydroxylating these substances, the enzyme helps the body break them down so they can be eliminated. Because of its role in nicotine metabolism, the activity level of this enzyme is often studied in relation to smoking behaviors and tobacco-related health risks. Beyond nicotine, the enzyme is involved in the processing of specific medications, such as the chemotherapy drug tegafur. When the gene carries variants that reduce the enzyme's catalytic activity, the body may process these substrates more slowly than expected. This can lead to higher concentrations of the drug in the bloodstream, potentially increasing the risk of side effects or requiring dosage adjustments. Understanding these metabolic pathways is a cornerstone of personalized medicine, aiming to tailor treatments to an individual's unique genetic makeup.
Research and Evidence Strength
The evidence linking rs28399509 to altered drug metabolism is currently classified as limited. While studies have identified this variant as a defining feature of the CYP2A6*8 allele, the functional consequences can vary depending on the specific substrate being metabolized. Research indicates that this variant may result in significantly decreased catalytic activity for certain medications, such as tegafur. However, the clinical significance of this reduction is not fully established for all potential substrates. Because the evidence is limited, it is not currently used as a standard diagnostic tool for routine clinical decision-making. Instead, it remains a subject of ongoing pharmacogenomic research. If you are concerned about how your genetics might affect your response to a specific medication, it is essential to discuss this with your healthcare provider or a clinical pharmacist, who can interpret your results in the context of your overall health and treatment plan.
Population Frequency
The frequency of the rs28399509 variant varies significantly across different ancestral groups. According to population-scale sequencing data, this variant is primarily detected in East Asian populations, where the minor allele frequency (MAF) typically ranges from approximately 0.01 to 0.03. In contrast, the variant is considered rare or absent in European lineages. These differences highlight the importance of considering ancestry in pharmacogenomic studies, as the prevalence of specific metabolic variants is not uniform globally. Understanding these population-specific frequencies helps researchers design more inclusive studies and ensures that clinical guidelines are relevant to diverse groups of people. If you are interested in your own genetic status regarding this variant, it is important to remember that population averages do not predict individual outcomes, and genetic testing should always be interpreted by a qualified professional.
What You Can Do With This Information
Genetic information regarding variants like rs28399509 is intended for educational purposes and should not be used to make independent medical decisions. If you have received genetic testing results that mention this variant, the most important step is to share this information with your doctor or a pharmacist. They can determine if your specific genotype is relevant to any medications you are currently taking or may be prescribed in the future. You cannot use this information to diagnose yourself or to adjust your medication dosages on your own, as doing so could be dangerous. Instead, use this knowledge to facilitate a productive conversation with your healthcare team. They can provide context on whether your genetic profile warrants a change in therapy or if standard dosing remains appropriate for your needs. Always prioritize professional medical advice over self-interpretation of genetic data.
How common is this variant?
The rs28399509 variant has a minor allele frequency of approximately 0.01 to 0.03 in East Asian populations and is rare in European lineages.
Frequently asked questions
What does it mean to be a 'poor metabolizer' for CYP2A6?
A poor metabolizer has genetic variants that significantly reduce the activity of the CYP2A6 enzyme. This means the body breaks down certain drugs or substances more slowly, which can lead to higher levels of the drug in the blood.
Should I get tested for CYP2A6 variants?
Routine testing for CYP2A6 is not standard for the general population. You should only consider testing if your doctor determines it is necessary to guide the dosing of a specific medication you are prescribed.
Can this variant affect my smoking habits?
Because CYP2A6 is involved in nicotine metabolism, some research suggests that variants in this gene can influence smoking behavior. However, this is a complex trait influenced by many genetic and environmental factors.
Is rs28399509 the same as CYP2A6*8?
Yes, rs28399509 is a defining coding polymorphism for the CYP2A6*8 allele. It is the specific genetic marker used to identify this particular star allele in research and testing.
Where can I find more information about my specific genotype?
You should consult with a genetic counselor or your primary healthcare provider. They can help you understand your results and explain how they might impact your clinical care.
Sources & further reading
Educational information only, last refreshed 9/16/2026. 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.