CYP2D6 rs28399436: Drug Metabolism and Genotype Meaning
The rs28399436 polymorphism is a single-nucleotide variant located within the human cytochrome P450 2D6 (CYP2D6) gene locus. In pharmacogenomic nomenclature, it is recognized as a defining marker for the non-functional CYP2D6*4.004 suballele. Carrying this variant is associated with reduced metabolic clearance of medications processed by CYP2D6, such as codeine, tamoxifen, and select psychotropic therapies.
What each genotype means
Normal enzyme activity
This genotype is associated with the functional CYP2D6 enzyme activity typically observed in the general population. It does not contain the specific non-functional variant associated with the CYP2D6*4.004 suballele. Please discuss any medication-related concerns or dosing questions with your clinician or pharmacist.
This is the most common genotype observed across all major global populations.
Reduced enzyme activity
This genotype includes one copy of the variant associated with the non-functional CYP2D6*4.004 suballele, which may lead to reduced metabolic clearance of certain medications like codeine or tamoxifen. Because this is a single-copy variant, your overall enzyme function depends on the activity of the other inherited allele. Please discuss your medication response and potential dosing adjustments with your clinician or pharmacist.
Carried by roughly 2% to 6% of people of European ancestry; it is significantly less common in East Asian and African populations.
Decreased enzyme function
This genotype indicates the presence of two copies of the variant associated with the non-functional CYP2D6*4.004 suballele, which is linked to decreased metabolic clearance of specific psychotropic and pain medications. Individuals with this profile may experience altered drug efficacy or side effects due to slower processing of these substances. Please consult with your clinician or pharmacist to review your medication regimen and ensure appropriate dosing.
This genotype is rare, occurring in approximately 0.01% to 0.1% of European populations and is extremely rare in other global ancestries.
Understanding rs28399436 and the CYP2D6 Gene
The single nucleotide polymorphism rs28399436 resides in the CYP2D6 gene on chromosome 22. This gene encodes cytochrome P450 family 2 subfamily D member 6, a primary hepatic phase-I drug-metabolizing enzyme. The CYP2D6 region is structurally complex, featuring extensive sequence homology with the adjacent pseudogene CYP2D7, as cataloged by resources like [ClinPGx](https://www.clinpgx.org/vip/PA166170264/overview) and the [National Genomics Education Programme](https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/cyp2d6/). Rather than acting strictly in isolation, rs28399436 is cataloged as part of a specific haplotype—the CYP2D6*4.004 suballele. This suballele combines non-coding variations with the well-known core missense substitution c.100C>T (p.Pro34Ser). In star-allele nomenclature curated by the Pharmacogene Variation Consortium (PharmVar), variants that form part of the CYP2D6*4 lineage result in severely impaired or absent enzymatic activity, contributing to altered drug breakdown.
Biological Role in Medication Breakdown
The CYP2D6 enzyme is responsible for the clearance or biotransformation of approximately 20% to 25% of clinically prescribed medications, including opioid analgesics, selective serotonin reuptake inhibitors, tricyclic antidepressants, and selective estrogen receptor modulators like tamoxifen. Because CYP2D6*4 and its suballeles lack enzymatic activity, individuals possessing these variants exhibit impaired conversion of prodrugs into active metabolites or reduced clearance of active compounds. For instance, codeine requires bioactivation by CYP2D6 into morphine to deliver pain relief, while tamoxifen depends on conversion into endoxifen for optimal therapeutic action. When active CYP2D6 function is lacking, prodrugs may prove ineffective, while substrates that rely on CYP2D6 for metabolic inactivation may accumulate, increasing the likelihood of dose-dependent adverse reactions as detailed in clinical guidelines curated by [ClinPGx](https://www.pharmgkb.org/page/cyp2d6RefMaterials).
State of Clinical Evidence and Star Allele Typing
The clinical evidence associating the broader CYP2D6*4 family with absent enzyme activity is robust and classified as high-level evidence by major pharmacogenomics consortia such as CPIC and DPWG. However, the specific evidence evaluating rs28399436 independently of other co-inherited variants is cataloged as limited. Because rs28399436 exists primarily within the CYP2D6*4.004 haplotype, routine clinical genotyping panels often test only the canonical splice site defect (*4 defining marker rs3892097) or the c.100C>T variant rather than distinguishing every individual suballele. Consequently, published literature attributes metabolic consequences to the entire composite diplotype rather than to rs28399436 in isolation. Interpreting this marker therefore requires comprehensive star-allele assignment that accounts for structural variants, gene duplications, and hybrid rearrangements.
Population Distribution and Ancestry Patterns
Allele frequencies for CYP2D6 variants display notable variation across ancestral backgrounds. The minor allele at rs28399436 is primarily observed in European-descent populations, where it typically occurs at a frequency of 1% to 3% (MAF ~0.01-0.03). In contrast, broad population sequencing efforts aggregated in resources such as [gnomAD](https://pmc.ncbi.nlm.nih.gov/articles/PMC9160216) show that the variant is rare or absent in East Asian, South Asian, and African populations. While East Asian ancestries more frequently carry decreased-function alleles like CYP2D6*10, the non-functional *4 lineage remains the predominant defective allele group among individuals of European ancestry. This geographic variation underscores the importance of ancestry considerations when evaluating clinical pharmacogenomic utility.
Navigating Results: What This Information Means for You
A genetic finding at rs28399436 provides information regarding inherited drug-metabolizing capacity, but it is not a diagnosis of any disease or a direct guarantee of drug response. Pharmacokinetics are governed by an individual's overall CYP2D6 diplotype (both inherited copies combined), as well as environmental factors such as drug-drug interactions. For example, co-administration of strong CYP2D6 inhibitors like fluoxetine or paroxetine can cause phenoconversion, temporarily turning a genetically normal metabolizer into a functional poor metabolizer. Readers should never alter, pause, or begin any prescription medication based on personal genetic results alone. Any adjustments to dosing or therapeutic strategy must always be evaluated in consultation with a qualified clinician or clinical pharmacist.
How common is this variant?
The minor allele frequency for rs28399436 is approximately 0.01 to 0.03 (1% to 3%) in European populations, while it is rare or virtually absent in African and East Asian ancestries.
Frequently asked questions
What does a variant in CYP2D6 mean for my everyday health?
Variants in the CYP2D6 gene do not typically cause symptoms, physical illness, or chronic disease on their own. Instead, they primarily influence how your liver enzymes process certain prescription medications. If you are not taking drugs metabolized by CYP2D6, the variant has little to no perceptible impact on daily life.
Does having rs28399436 mean pain medications like codeine won't work?
Codeine relies on active CYP2D6 enzymes to be transformed into morphine, the molecule that provides pain relief. If rs28399436 is part of an overall poor or intermediate metabolizer diplotype, your body may produce less active morphine, which can lead to reduced analgesic relief. A healthcare provider can review your genotype and recommend alternative pain relief options if necessary.
How does rs28399436 relate to the CYP2D6*4 allele?
In pharmacogenetic nomenclature, star (*) alleles represent specific sets of co-inherited variants called haplotypes. The rs28399436 variant is recognized as one of the defining markers for a specific subtype known as CYP2D6*4.004. Like the primary CYP2D6*4 allele, this suballele produces a non-functional enzyme.
Should I change my medication dose if I carry this variant?
No, you should never adjust, stop, or start any medication without direct clinical guidance. Clinical drug response depends on your full genetic diplotype, body weight, liver function, and concurrent medications. If you have questions about your pharmacogenomic report, discuss the results with your doctor or a clinical pharmacist.
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 CYP2D6*6 deletion variant (1707delT) leading to a premature stop codon and loss of enzyme function.