CYP2D6 rs5030864: The CYP2D6*8 Loss-of-Function Allele
The genetic variant rs5030864 is a single nucleotide polymorphism located within the human CYP2D6 gene on chromosome 22. In pharmacogenomics, this variant serves as the core defining mutation of the completely non-functional CYP2D6*8 star allele. Individuals carrying this variant produce a disrupted enzyme that contributes toward intermediate or poor drug metabolizer statuses for a wide range of therapeutic medications.
What each genotype means
Normal enzyme activity
This genotype represents the presence of the reference allele on both chromosomes, which is typically associated with normal CYP2D6 enzyme function. Individuals with this profile are generally expected to metabolize medications at standard rates, though other genetic factors can influence this. Please discuss any medication dosing concerns with your clinician or pharmacist.
This is the most common genotype globally, found in the vast majority of the population.
Reduced enzyme activity
This genotype indicates you carry one copy of the rs5030864 variant, which is associated with the non-functional CYP2D6*8 allele. You may have reduced capacity to metabolize certain drugs processed by the CYP2D6 enzyme compared to individuals without this variant. Please consult your healthcare provider or pharmacist regarding how this may affect your response to specific medications.
This genotype is rare, occurring in less than 1% of most European and American populations.
Poor drug metabolism
This genotype indicates you carry two copies of the rs5030864 variant, which defines the completely null CYP2D6*8 loss-of-function allele. Individuals with this profile are classified as poor metabolizers, meaning they may process certain medications significantly slower than average, potentially leading to higher drug levels in the blood. It is important to discuss this result with your clinician or pharmacist before starting or adjusting any medications metabolized by this enzyme.
This genotype is extremely rare globally, with a frequency significantly lower than 0.5% in most studied populations.
Genomic Location and the Nature of rs5030864
The rs5030864 variant is located in the CYP2D6 gene on chromosome 22q13.2. Pharmacogenetic nomenclature curated by resources such as the Pharmacogene Variation Consortium (PharmVar) and PharmGKB defines rs5030864 (commonly reported as c.505G>T or p.Gly169Ter) as the primary variant defining the CYP2D6*8 haplotype. The transition introduces a premature termination codon into the protein-coding sequence, leading to either nonsense-mediated mRNA decay or a truncated, entirely non-functional enzyme. CYP2D6 is part of a complex and highly homologous genomic region that includes pseudogenes like CYP2D7 and CYP2D8, making precise molecular sequencing and haplotype phasing essential for accurate genotype identification.
Biological Function of the CYP2D6 Enzyme
The CYP2D6 gene encodes the cytochrome P450 family 2 subfamily D member 6 enzyme, a predominantly hepatic hemoprotein responsible for metabolizing approximately 20% to 25% of clinically prescribed medications. These therapeutics span major drug classes, including selective serotonin reuptake inhibitors, tricyclic antidepressants, beta-blockers, antiarrhythmics, tamoxifen, and opioid prodrugs such as codeine and tramadol. The enzyme modifies foreign hydrophobic compounds to facilitate elimination or biotransforms inactive prodrugs into their active analgesic or therapeutic forms. When an allele such as CYP2D6*8 fails to produce a viable protein, overall clearing capacity decreases in proportion to the patient's diploid activity score.
Strength of Evidence and Pharmacogenomic Impact
Expert bodies such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) classify CYP2D6*8 as a definitive 'no function' allele, assigning it an enzymatic activity score of 0. However, because rs5030864 is exceedingly rare across most global populations, empirical in vivo pharmacokinetic studies evaluating *8 independently remain limited relative to common null alleles like *4 or *5. Clinical phenotypes are derived cumulatively: carrying one null allele alongside a normal-function allele (*1) results in an intermediate metabolizer status, whereas pairing it with another null allele produces a poor metabolizer phenotype, marked by reduced prodrug activation or heightened vulnerability to drug accumulation.
Population Distribution and Global Frequency
According to broad population genomic resources such as the Genome Aggregation Database (gnomAD) and allele frequency tables published by CPIC, rs5030864 is a very rare variant worldwide. Its global minor allele frequency is well below 0.005 (0.5%), with the highest observed occurrences concentrated in individuals of European and American ancestries, where frequencies generally remain beneath 0.05% to 0.1%. Due to this rarity, standard commercial Tier 1 clinical pharmacogenetic screening panels frequently omit rs5030864, as panels prioritize high-frequency variants to maximize clinical yield across broad populations.
Navigating Pharmacogenomic Results Responsibly
Understanding your rs5030864 genotype provides valuable context regarding your baseline hepatic metabolic capacity, but it represents only one component of medication response. A single SNP cannot provide an overall metabolizer status without comprehensive phasing across the entire CYP2D6 locus, including copy number variation assessments. Furthermore, environmental variables, diet, kidney function, and concomitant medications that inhibit or induce cytochrome enzymes can dramatically alter in vivo drug processing. Genetic data should never be used to initiate, stop, or change prescription drug dosages independently; any adjustments must be evaluated in collaboration with a licensed physician or clinical pharmacist.
How common is this variant?
The rs5030864 variant is globally rare with a minor allele frequency typically below 0.005 (<0.5%), observed mainly in European and American populations at frequencies well under 0.1%.
Frequently asked questions
What is the CYP2D6*8 allele?
CYP2D6*8 is a specific version of the CYP2D6 gene defined by the rs5030864 variant. It carries a nonsense mutation that halts protein synthesis, rendering the resulting enzyme completely non-functional.
Does carrying rs5030864 mean I am a poor drug metabolizer?
Not necessarily. Your overall metabolizer status depends on the combined activity of both CYP2D6 alleles inherited from your parents. Carrying one copy of rs5030864 results in an intermediate or normal metabolizer status if your second allele functions properly.
Why wasn't rs5030864 included on my standard genetic test?
Clinical testing guidelines often recommend testing only common variants to balance cost and efficacy. Because rs5030864 occurs at very low frequencies in most populations, many routine commercial testing panels do not routinely assay it.
Can I adjust my medication dosage if I have this variant?
No, you should never alter medication schedules or dosages based solely on raw genetic data. Personalized medication changes require formal clinical assessment, consideration of drug-drug interactions, and guidance from your physician or pharmacist.
Sources & further reading
Educational information only, last refreshed 9/7/2026. 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.