CYP2D6 rs28371699: What Your Genotype Means
The genetic variant rs28371699 is an intronic single nucleotide polymorphism located in the CYP2D6 gene. It marks the hypomorphic CYP2D6*41.002 suballele and is associated with altered mRNA splicing that causes decreased enzymatic activity. As a result, individuals carrying this variant may exhibit reduced metabolic clearance or activation of numerous widely prescribed CYP2D6-dependent medications.
What each genotype means
Normal enzyme activity
This genotype indicates the absence of the specific splicing defect associated with the CYP2D6*41 allele at this position. Individuals with this result typically possess fully functional CYP2D6 enzyme activity, assuming no other variants are present. Please discuss your medication response and any potential dosing adjustments with your clinician or pharmacist.
This is the most common genotype, found in the majority of individuals across most global populations.
Reduced enzyme activity
This genotype indicates you carry one copy of the variant associated with the CYP2D6*41 allele, which is known to cause reduced enzyme function due to a splicing defect. You may be classified as an intermediate metabolizer, meaning your body might process certain medications more slowly than average. Please discuss your medication response and any potential dosing adjustments with your clinician or pharmacist.
Carried by roughly 1 in 6 to 1 in 10 people of European ancestry; it is significantly less common in East Asian populations.
Decreased enzyme activity
This genotype indicates you carry two copies of the variant associated with the CYP2D6*41 allele, which is linked to reduced enzyme function. This may result in a decreased ability to metabolize certain drugs that rely on the CYP2D6 enzyme, potentially leading to altered drug levels in your system. Please discuss your medication response and any potential dosing adjustments with your clinician or pharmacist.
This genotype is relatively rare, occurring in a small percentage of individuals, primarily within European populations.
Variant Identity and Molecular Mechanism
The variant rs28371699 is located within the human cytochrome P450 family 2 subfamily D member 6 (CYP2D6) locus on chromosome 22. It tags an intronic nucleotide change (historically characterized as 2988G>A or c.985+39G>A in intron 6) defining the hypomorphic CYP2D6*41.002 suballele. Functionally, this nucleotide substitution introduces a splicing defect that shifts normal pre-mRNA processing, leading to diminished production of mature, full-length CYP2D6 mRNA. Because the primary coding sequence remains largely intact, the enzyme produced functions normally, but total protein abundance is notably reduced. Consequently, pharmacogenomic consortia like the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Pharmacogene Variation (PharmVar) Consortium categorize alleles bearing this change as decreased-function alleles.
The Biological Role of CYP2D6
The CYP2D6 enzyme is a major member of the hepatic cytochrome P450 monooxygenase system, responsible for the phase I biotransformation of approximately 20% to 25% of clinically used drugs. Despite contributing to only a modest fraction of total liver cytochrome P450 protein content, CYP2D6 metabolizes diverse therapeutic classes, including selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, beta-blockers, antiarrhythmics, and opioid analgesics like codeine and tramadol. CYP2D6 is not inducible by environmental exposures, making genetic variation the predominant determinant of its catalytic variability among individuals. Depending on their combination of functional, decreased-function, or null alleles, individuals are classified across a spectrum of metabolizer phenotypes ranging from poor to ultrarapid.
Pharmacogenomic Evidence and Clinical Associations
Clinical pharmacogenomics guidelines curated by CPIC and the Pharmacogenomics Knowledgebase (PharmGKB) assign specific activity scores to CYP2D6 alleles to forecast metabolizer status. Alleles tagged by rs28371699, such as *41, are typically assigned a reduced activity score (such as 0.5) compared to the fully functional reference allele (*1, score 1.0). In patients taking prodrugs that require CYP2D6 activation to produce therapeutic effects (for instance, codeine converting to morphine, or tamoxifen converting to endoxifen), carrying a decreased-function allele can lead to lower circulating active drug concentrations. Conversely, for drugs inactivated by CYP2D6, reduced clearance can cause higher plasma levels and elevated adverse effect risks. While association studies strongly link the overall *41 star allele haplotype to decreased metabolism, isolated evidence for rs28371699 outside the context of complete star allele profiling remains limited.
Ancestry and Global Population Distribution
The minor allele (A) for rs28371699 demonstrates substantial variation across continental populations. According to population genetics reference resources such as gnomAD and NCBI Medical Genetics Summaries, the minor allele frequency (MAF) is most prevalent in populations of European ancestry, where it typically ranges between 8% and 10%. In contrast, it is observed at much lower rates in East Asian populations, where the MAF is approximately 1% or lower. In East Asian ancestries, decreased CYP2D6 capacity is more commonly driven by distinct variants, such as the *10 core defining SNP. Understanding these ancestral variations is vital for clinical genetics laboratories when designing targeted pharmacogenetic panels to ensure accurate haplotype assignment across diverse patient demographics.
Navigating Results and Practical Guidance
Discovering an altered CYP2D6 genotype through commercial or research testing can offer interesting insights, but it is not a diagnosis and must be interpreted with caution. A single SNP such as rs28371699 only provides a partial view of the highly polymorphic CYP2D6 locus, which is also prone to extensive copy number variations, gene duplications, and non-functional gene deletions that can supersede a single point mutation's effect. Readers should never alter, stop, or adjust prescription dosages based on personal genomic data alone. Any medical considerations regarding drug efficacy, side effects, or dosing must be discussed with a qualified healthcare professional, physician, or clinical pharmacogenomics pharmacist who can consider comprehensive diplotype testing alongside other clinical factors.
How common is this variant?
The minor A allele occurs at a frequency of approximately 8% to 10% in populations of European ancestry, while it is observed at a substantially lower frequency of about 1% in East Asian populations.
Frequently asked questions
Does having the rs28371699 A allele mean I cannot take medications metabolized by CYP2D6?
No, carrying one or two copies of this variant does not mean you cannot take these medications. It simply suggests that your liver may metabolize certain CYP2D6-dependent drugs more slowly than average, which clinicians can manage through tailored drug choices or dose adjustments.
What is the difference between rs28371699 and the CYP2D6*41 allele?
The rs28371699 variant is a specific single nucleotide change within intron 6 that tags the CYP2D6*41.002 suballele. The term *41 refers to a broader haplotype family of reduced-function alleles that share this characteristic splicing defect along with other background markers.
Can I use direct-to-consumer genetic data to change my prescription dose?
You should never alter or stop your prescription medication based on raw direct-to-consumer genetic data. Many consumer platforms do not test for structural gene duplications or deletions, so any potential dosing adjustments must be evaluated by a healthcare provider using clinical-grade testing.
Why is CYP2D6 testing more complicated than other genetic tests?
The CYP2D6 region is structurally complex, featuring over one hundred distinct star alleles, whole-gene deletions, duplications, and hybrid structures formed with pseudogenes like CYP2D7. Evaluating a single variant like rs28371699 cannot fully capture a person's complete metabolizer phenotype without specialized diplotype and copy-number analysis.
Sources & further reading
Educational information only, last refreshed 9/8/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Get my report — $29Related variants in CYP2D6
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.