CYP2D6 rs3892039: Understanding the *4 Non-Functional Allele
The rs3892039 variant is a specific genetic change within the CYP2D6 gene that defines the non-functional *4 allele. This variant is associated with impaired metabolism of numerous clinically prescribed medications, including certain antidepressants, tamoxifen, and codeine.
What each genotype means
Typical enzyme baseline
You carry two copies of the reference allele at this position, meaning you do not have the non-functional CYP2D6*4 splice defect variant. Assuming you do not carry other CYP2D6 variants or structural gene deletions, your body is expected to break down CYP2D6-metabolized medications normally. Always consult your doctor or pharmacist prior to making any medication or dosage changes.
Carried by approximately 60% to 70% of individuals of European ancestry and over 95% of individuals of East Asian ancestry.
Decreased enzyme activity
You carry one copy of the variant allele defining the non-functional CYP2D6*4 allele, which disrupts normal pre-mRNA splicing. Depending on the functional status of your second CYP2D6 allele, research associates this genotype with intermediate or reduced metabolism for medications like antidepressants, tamoxifen, and certain opioids. You should discuss your specific pharmacogenomic results with a prescribing clinician or pharmacist to guide safe medication choices.
Found in roughly 25% to 35% of people of European ancestry, but in fewer than 2% to 4% of individuals of East Asian ancestry.
Poor metabolizer status
You carry two copies of the CYP2D6*4 defining variant, which typically eliminates CYP2D6 enzyme activity because both copies produce non-functional proteins. In clinical studies, individuals with this genotype process many common drugs—including certain antidepressants, beta-blockers, and pain medications—very slowly, or fail to convert prodrugs like codeine and tamoxifen into their active forms. Discuss these results with your healthcare provider or pharmacist, as alternative medications or standard dosage adjustments are frequently recommended.
Carried by approximately 3% to 5% of individuals of European descent, but is rare (well under 1%) in East Asian populations.
What is the rs3892039 Variant?
The rs3892039 variant is a single-nucleotide polymorphism (SNP) located within the CYP2D6 gene. In the context of pharmacogenomics, this specific change is a hallmark of the CYP2D6*4 allele. This allele is classified as a 'null' or non-functional variant, meaning that the genetic instructions it provides do not result in a working enzyme. Because the CYP2D6 enzyme is responsible for breaking down or activating a significant portion of commonly prescribed drugs, the presence of this variant can lead to significant differences in how an individual processes these medications. When an individual carries two copies of non-functional alleles, they are often categorized as a 'poor metabolizer,' which may lead to altered drug concentrations in the blood compared to individuals with fully functional enzyme activity.
The Role of the CYP2D6 Gene
The CYP2D6 gene encodes a member of the cytochrome P450 superfamily of enzymes. These enzymes are primarily located in the liver and are essential for the metabolism of a wide array of substances, including approximately 25% of all clinically used drugs. CYP2D6 is particularly notable for its high level of genetic variability, which contributes to the diverse ways people respond to treatments for pain, depression, and cancer. For some drugs, the enzyme is required to convert an inactive 'prodrug' into its active form; for others, it is responsible for clearing the drug from the body. When the gene is non-functional, as is the case with the *4 allele, the body may fail to activate a drug properly, leading to a lack of therapeutic effect, or it may fail to clear a drug, potentially increasing the risk of side effects.
Research and Clinical Evidence
Research into rs3892039 and the *4 allele is extensive, particularly within the field of pharmacogenomics. Clinical guidelines from organizations like the Clinical Pharmacogenetics Implementation Consortium (CPIC) highlight the importance of this variant when prescribing medications such as codeine or tamoxifen. For example, in individuals who are poor metabolizers due to *4, codeine may not be converted into morphine effectively, resulting in inadequate pain relief. Conversely, for other drugs, the inability to metabolize the medication can lead to toxic accumulation. While the association between this variant and altered drug metabolism is well-established, the clinical impact can be complex and depends on the specific drug, the patient's overall genetic profile, and other environmental factors. Evidence is considered strong for its role in drug metabolism, though clinical application should always be guided by a healthcare professional.
Population Frequency
The frequency of the rs3892039 variant varies significantly across different global populations. It is most prevalent in European populations, where the minor allele frequency can reach approximately 15-20%. In contrast, the variant is much less common in East Asian populations, where it is typically found at frequencies of less than 2%. These differences underscore the importance of considering ancestry when evaluating the potential impact of pharmacogenetic variants. Because the *4 allele is a major contributor to the 'poor metabolizer' phenotype in European-descended populations, it is a primary focus of clinical testing in those groups. Understanding these population-specific frequencies helps clinicians and researchers better predict the prevalence of drug-metabolism phenotypes in different communities.
What You Can Do With This Information
If you have information about your CYP2D6 genotype, it is important to view it as one piece of a larger clinical puzzle. This information is not a diagnosis and does not predict your health outcomes in isolation. If you are concerned about how your body processes a specific medication, the most important step is to discuss your genetic results with your doctor or a pharmacist. They can interpret these findings in the context of your current health, other medications you may be taking, and your medical history. Never change your medication dosage or stop taking a prescribed drug based on genetic test results without consulting your healthcare provider. Pharmacogenetic testing is a tool to help clinicians personalize treatment plans, but it should always be used in conjunction with professional medical judgment.
How common is this variant?
The minor allele frequency is approximately 15-20% in European populations, while it is less than 2% in East Asian populations.
Frequently asked questions
What does it mean to be a CYP2D6 poor metabolizer?
A poor metabolizer has two non-functional copies of the CYP2D6 gene, meaning they produce little to no active enzyme. This can lead to reduced effectiveness of certain drugs or an increased risk of side effects because the body cannot process the medication as expected.
Does having the *4 allele mean I cannot take any medications?
No, it does not mean you cannot take medications. It simply means that for certain specific drugs processed by the CYP2D6 enzyme, your doctor may need to adjust the dosage or choose an alternative medication to ensure safety and effectiveness.
Should I get tested for the CYP2D6 *4 allele?
Genetic testing for CYP2D6 is typically ordered by a healthcare provider when there is a clinical need to understand why a patient is not responding to a medication or is experiencing unexpected side effects. You should discuss the necessity of such testing with your doctor.
Is the *4 allele the only variant that affects CYP2D6?
No, the CYP2D6 gene is highly polymorphic, meaning there are many different variants and alleles that can affect enzyme function. The *4 allele is just one of many that researchers and clinicians track.
Sources & further reading
Educational information only, last refreshed 10/12/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant is a key marker for the CYP2D6*10 allele, which results in reduced enzymatic activity and altered metabolism of various psychiatric and analgesic medications.
Defines the CYP2D6*17 allele (p.Thr107Ile), which exhibits reduced enzyme activity towards substrates like codeine and certain antidepressants.
Defines the CYP2D6*29 variant (p.Val338Met) conferring decreased metabolic capacity, primarily observed in populations of African descent.
Promoter variant defining the CYP2D6*41 allele, associated with reduced enzyme expression and decreased metabolic capacity for various drugs.
Defines the CYP2D6*6 deletion variant (1707delT) leading to a premature stop codon and loss of enzyme function.
Defines the non-functional CYP2D6*41 splice defect associated with intermediate metabolizer phenotype affecting codeine, tamoxifen, and SSRI metabolism.