CYP2D6 rs72549305: Understanding the *6 Loss-of-Function Variant
The rs72549305 variant is a specific genetic change within the CYP2D6 gene that defines the nonfunctional *6 allele. This variant is associated with an impaired ability to metabolize various clinically important drugs, including certain beta-blockers, antidepressants, and opioids.
What each genotype means
Normal enzyme activity
This genotype represents the presence of two functional copies of the CYP2D6 gene, often referred to as the wild-type or *1/*1 status. Individuals with this profile typically exhibit normal metabolic capacity for drugs processed by this enzyme, such as certain antidepressants and beta-blockers. Please discuss any medication-related concerns or dosing adjustments with your clinician or pharmacist.
This is the most common genotype observed across most global populations.
Reduced enzyme activity
This genotype indicates you carry one functional copy of the gene and one copy of the rs72549305 variant, which is associated with the nonfunctional CYP2D6*6 allele. This may result in reduced metabolic capacity for specific medications, potentially leading to altered drug levels in your system. Please consult your healthcare provider or pharmacist to determine if this impacts your current or future medication management.
The minor allele associated with this variant is found at a frequency of approximately 0.01 in European populations and is considered rare in other ancestral groups.
Poor enzyme activity
This genotype indicates the presence of two copies of the rs72549305 variant, corresponding to the nonfunctional CYP2D6*6 allele. Individuals with this profile are classified as poor metabolizers, which may significantly impair the processing of various antidepressants, opioids, and beta-blockers. It is essential to discuss this genetic finding with your clinician or pharmacist, as it may necessitate alternative medication choices or dosage adjustments.
This homozygous genotype is very rare, occurring at a frequency consistent with the low prevalence of the minor allele in the general population.
What is the rs72549305 Variant?
The rs72549305 variant is a specific genetic marker located within the CYP2D6 gene, a highly polymorphic region of the human genome. In the context of pharmacogenomics, this variant is used to identify the CYP2D6*6 allele. The CYP2D6 gene provides instructions for making an enzyme that plays a critical role in the metabolism of approximately 25% of all clinically used medications. Because the gene is so variable, researchers use star (*) nomenclature to categorize different versions of the gene based on their functional impact. The *6 allele is classified as a nonfunctional allele, meaning that the enzyme produced by this version of the gene does not perform its intended metabolic work. When an individual carries this variant, it can significantly alter how their body processes drugs that rely on the CYP2D6 enzyme for activation or clearance.
The Role of the CYP2D6 Enzyme
The CYP2D6 enzyme is a member of the cytochrome P450 family, which are primarily responsible for breaking down substances in the liver. Unlike many other enzymes that can be induced or sped up by external factors, CYP2D6 is considered non-inducible, making an individual's genetic makeup the primary driver of their metabolic capacity. Medications processed by this enzyme include common antidepressants, antipsychotics, beta-blockers, and opioids like codeine or tramadol. Because the enzyme is essential for converting some drugs into their active forms or clearing them from the system, having nonfunctional alleles like *6 can lead to unexpected clinical outcomes. If a person has two nonfunctional copies of the gene, they are often categorized as a 'poor metabolizer,' which may result in higher-than-expected drug levels in the blood or, conversely, a lack of therapeutic effect if the drug requires the enzyme to become active.
Research and Clinical Evidence
The evidence linking the CYP2D6*6 allele (defined by rs72549305) to altered drug metabolism is well-established in pharmacogenomic literature. Clinical guidelines from organizations like the Clinical Pharmacogenomics Implementation Consortium (CPIC) categorize *6 as a no-function allele. Research indicates that individuals carrying this variant may experience adverse drug reactions or reduced efficacy when taking standard doses of CYP2D6-dependent medications. However, it is important to note that the clinical impact of this variant depends heavily on the other allele an individual carries on their second copy of the gene. Because the CYP2D6 gene is so complex, with over 170 known star alleles, the overall phenotype is determined by the combination of both inherited copies. While the association between *6 and reduced enzyme activity is strong, the clinical significance for any specific patient should always be evaluated by a healthcare professional who can consider the full genetic profile and current medication list.
Population Frequency and Distribution
Genetic variation in CYP2D6 is not distributed equally across the globe, and the frequency of the *6 allele is no exception. Current data suggests that the minor allele frequency for rs72549305 is approximately 0.01 in European populations, making it a relatively uncommon variant. In other global populations, this specific allele is considered rare. Because allele frequencies vary significantly by ancestry, the likelihood of carrying this nonfunctional variant depends on an individual's genetic background. Researchers continue to study these interethnic differences to improve the accuracy of pharmacogenomic testing across diverse groups. It is essential to recognize that while population statistics provide a broad overview, they do not predict the specific genotype of any single individual. Genetic testing is the only way to determine an individual's specific CYP2D6 status.
Managing Your Genetic Information
If you have received information about your CYP2D6 status, it is important to understand what you can and cannot do with these results. This information is a tool for your healthcare provider to help optimize medication selection and dosing, but it is not a diagnosis of any disease. You should never change, stop, or start any medication based on genetic test results without consulting your doctor or pharmacist. They are trained to interpret these findings in the context of your overall health, other medications you may be taking, and your clinical history. If you are concerned about how your body processes a specific drug, ask your clinician if pharmacogenomic testing is appropriate for your situation. By working closely with a medical professional, you can ensure that your genetic information is used safely and effectively to support your personalized treatment plan.
How common is this variant?
The rs72549305 variant has a minor allele frequency of approximately 0.01 in European populations and is considered rare in other global populations.
Frequently asked questions
What does it mean to be a CYP2D6 poor metabolizer?
A poor metabolizer has two nonfunctional copies of the CYP2D6 gene. This means their body processes certain medications much slower than average, which can increase the risk of side effects or reduce the effectiveness of drugs that need the enzyme to work.
Should I get tested for CYP2D6 variants?
Pharmacogenomic testing is typically recommended by doctors when a patient is starting a medication known to be processed by the CYP2D6 enzyme. You should discuss with your healthcare provider whether testing is necessary for your specific treatment plan.
Can I change my CYP2D6 genotype?
No, your genotype is inherited from your parents and remains the same throughout your life. It is a permanent part of your biological makeup.
Does having the *6 allele mean I will have side effects?
Not necessarily. While the *6 allele is associated with reduced enzyme function, whether you experience side effects depends on the specific medication, the dose, and your other genetic factors. Always consult your doctor regarding your specific risks.
Sources & further reading
Educational information only, last refreshed 9/17/2026. 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.
This variant defines the CYP2D6*4 non-functional allele, which causes impaired metabolism of numerous clinically prescribed medications including antidepressants, tamoxifen, and codeine.
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 non-functional CYP2D6*41 splice defect associated with intermediate metabolizer phenotype affecting codeine, tamoxifen, and SSRI metabolism.