CYP3A5 rs4646473: What Your Genotype Means
The rs4646473 variant is a genetic marker located within the CYP3A5 gene, which encodes an enzyme responsible for metabolizing various medications. It is primarily studied for its association with the clearance rates of tacrolimus, an immunosuppressant drug used in transplant medicine.
What each genotype means
High CYP3A5 enzyme expression
This genotype is associated with the CYP3A5*1/*1 status, which leads to high expression of the CYP3A5 enzyme. Individuals with this profile typically clear the medication tacrolimus more rapidly and may require higher doses to reach therapeutic blood levels. Please discuss your specific dosing requirements with your clinician or pharmacist.
This genotype is most common in individuals of African ancestry and is relatively rare in European and East Asian populations.
Intermediate CYP3A5 enzyme expression
This genotype corresponds to the CYP3A5*1/*3 status, resulting in intermediate expression of the CYP3A5 enzyme. You may metabolize tacrolimus faster than non-expressers, potentially requiring dose adjustments to maintain target drug concentrations. Always consult your healthcare provider or pharmacist regarding your medication management.
This genotype is found at varying frequencies globally, appearing in approximately 13-17% of European populations and significantly higher proportions in other ethnic groups.
Low or absent enzyme expression
This genotype is associated with the CYP3A5*3/*3 status, which is characterized by a lack of functional CYP3A5 enzyme expression. Because you do not produce this enzyme, you may require lower doses of tacrolimus to achieve therapeutic levels compared to expressers. Please coordinate with your clinical team to ensure your medication dosage is appropriate for your genetic profile.
This is the most frequent genotype in most ethnic populations, carried by the vast majority of individuals of European descent.
Understanding the CYP3A5 Gene
The CYP3A5 gene provides instructions for creating the cytochrome P450 3A5 enzyme. This enzyme is part of a large family of proteins primarily found in the liver and intestines that help break down, or metabolize, foreign substances, including many prescription drugs. In the context of pharmacogenomics, CYP3A5 is highly significant because its activity levels vary greatly between individuals. This variability is often determined by specific genetic variants that dictate whether a person produces a functional enzyme or a truncated, non-functional version. Because this enzyme plays a major role in the metabolic pathway of tacrolimus—a drug used to prevent organ rejection—understanding an individual's CYP3A5 status is a key component of personalized medicine strategies in transplant care.
The Role of rs4646473 in Drug Metabolism
The rs4646473 variant is closely linked to the expression levels of the CYP3A5 enzyme. Research indicates that genetic variations in this region can influence whether a patient is classified as a 'CYP3A5 expresser' or a 'non-expresser.' Expressers possess functional enzyme activity, which leads to faster metabolism and clearance of tacrolimus from the bloodstream. Conversely, non-expressers lack this functional enzyme, resulting in slower drug clearance. Because tacrolimus has a narrow therapeutic index—meaning the difference between an effective dose and a toxic dose is small—these differences in metabolism are clinically relevant. Patients who are rapid metabolizers may require higher doses to maintain therapeutic drug levels, while those with lower metabolic activity may require lower doses to avoid potential side effects or toxicity.
Evidence and Clinical Application
The evidence linking CYP3A5 genotypes to tacrolimus pharmacokinetics is well-established in clinical literature. Organizations like the Clinical Pharmacogenetics Implementation Consortium (CPIC) have published guidelines that incorporate CYP3A5 status into dosing recommendations for tacrolimus. While the association between genotype and drug clearance is strong, the clinical impact on outcomes like graft rejection or survival can be complex and influenced by other factors, including age, weight, and other medications. It is important to note that while genetic testing provides valuable data, it is only one piece of the clinical puzzle. Clinicians use this information alongside therapeutic drug monitoring to adjust dosages. If you are a transplant recipient or are scheduled for a procedure involving tacrolimus, you should discuss the relevance of pharmacogenetic testing and any potential dose adjustments directly with your transplant team or clinical pharmacist.
How common is this variant?
The frequency of CYP3A5 genotypes varies significantly across global populations, with the non-expresser phenotype being the most common in many groups, except among individuals of African ancestry where expresser genotypes are more prevalent.
Frequently asked questions
Does my CYP3A5 genotype change over time?
No, your genetic sequence for the CYP3A5 gene is inherited and remains constant throughout your life. While your genotype does not change, your clinical needs may evolve based on your health status and other medications.
Can I use this test to predict all drug reactions?
No, this genetic variant is specific to the metabolism of certain drugs like tacrolimus. It does not predict your response to all medications, as different drugs are processed by different enzymes in the body.
Should I ask my doctor for a CYP3A5 test?
If you are a transplant patient or are prescribed tacrolimus, you may ask your clinician if pharmacogenetic testing is appropriate for your care. Decisions regarding testing should always be made in consultation with your medical team.
What does it mean to be a 'rapid metabolizer'?
Being a rapid metabolizer means your body breaks down a specific drug faster than average. In the case of tacrolimus, this may mean you require a higher dose to keep the drug at a therapeutic level in your blood.
Sources & further reading
Educational information only, last refreshed 10/3/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Defines the non-functional CYP3A5*3 allele, dictating CPIC guideline-based dosing adjustments for tacrolimus in solid-organ transplant recipients.
Defines the CYP3A5*3 splice-altering variant that leads to absent CYP3A5 activity and dictates dosing requirements for the immunosuppressant tacrolimus.