CYP2D6 rs5030865: Medication Metabolism and Star Alleles
The rs5030865 variant is a single nucleotide polymorphism located within the CYP2D6 gene on chromosome 22. In pharmacogenomics, this position corresponds to key missense alterations (such as c.505G>A and c.505G>T) that define altered-function star alleles, including CYP2D6*14, *8, and related nonfunctional haplotypes like *7 and *114. Because CYP2D6 metabolizes roughly a fifth of clinically prescribed drugs, variation at this site can impact how quickly a person activates or eliminates certain medications.
What each genotype means
| Genotype | What the research suggests | Reading |
|---|---|---|
| GG | The homozygous reference genotype indicates the absence of the rs5030865 missense substitution on both chromosome copies. Individuals with this genotype produce standard glycine at residue 169, which is typical for functional CYP2D6 alleles like *1 or *2. Overall CYP2D6 enzymatic activity will depend on the presence or absence of other known variants across the gene. | Informational |
| GA | This heterozygous genotype indicates one copy of the c.505G>A substitution, which characterizes alleles such as CYP2D6*14 or CYP2D6*114. Carrying this variant on one chromosome can reduce or eliminate function from that allele, contributing to an intermediate or poor metabolizer status depending on the paired allele. A clinical pharmacogenomic panel is typically needed to determine full diplotype phasing. | Higher attention |
| AA | This rare homozygous alternative genotype indicates that both copies of the CYP2D6 gene harbor the missense variant at this position. Individuals with this profile typically experience reduced or complete loss of CYP2D6 catalytic activity from these alleles, predisposing them to poor clearance of standard substrates or reduced activation of prodrugs. Dosing and drug choice adjustments may be recommended under expert medical supervision. | Higher attention |
Variant Identity and Genomic Location
The single nucleotide polymorphism rs5030865 is positioned in exon 3 of the cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene, mapped to the long arm of chromosome 22 at 22q13.2. At the molecular level, this site features a nucleotide transition typically noted as NM_000106.6:c.505G>A or related substitutions like c.505G>T (legacy position 1758G>A/T). These nucleotide changes lead to missense substitutions, such as glycine being replaced by arginine at codon 169 (p.Gly169Arg). In the standard nomenclature organized by the Pharmacogene Variation (PharmVar) Consortium, variants at rs5030865 serve as core defining markers for specific haplotype definitions, including the decreased-function CYP2D6*14 allele, the CYP2D6*8 allele, and related complex nonfunctional or reduced-function alleles like CYP2D6*114 and *7. Due to the high sequence similarity of the CYP2D6 locus to nearby pseudogenes, clinical testing often uses targeted genotyping assays or long-read sequencing to assign this position accurately within a wider haplotype context.
The Role of the CYP2D6 Enzyme
The CYP2D6 gene encodes an essential member of the liver's cytochrome P450 mixed-function oxidase system. Although CYP2D6 makes up only a small fraction of the total hepatic cytochrome P450 protein content, it is responsible for the phase I oxidative metabolism of roughly 20 to 25 percent of all clinically approved pharmaceuticals. Substrates processed by CYP2D6 span multiple drug classes, such as selective serotonin reuptake inhibitors, tricyclic antidepressants, typical and atypical antipsychotics, beta-blockers, antiemetics like ondansetron, the prodrug tamoxifen used in oncology, and opioid analgesics such as codeine and tramadol. The CYP2D6 enzyme functions either by converting active drugs into inactive forms for bodily clearance or by bioactivating prodrugs into their therapeutic compounds. Disruptions in the primary amino acid sequence of the enzyme, such as those caused by coding variants at rs5030865, can compromise the catalytic pocket or overall protein folding, leading to reduced or absent enzymatic activity.
Clinical Evidence and Phenotype Associations
Evidence linking specific CYP2D6 functional disruptions to altered drug clearance is extensive, though evidence for the standalone rs5030865 variant remains qualified as limited to moderate because of its low frequency and role as part of broader multi-variant haplotypes. Organizations like the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) translate diplotypes into a standardized CYP2D6 activity score. Alleles bearing mutations at rs5030865 are classified as decreased-function or no-function alleles. Individuals carrying one or two nonfunctional alleles typically fall into intermediate metabolizer (IM) or poor metabolizer (PM) categories. In poor metabolizers, standard doses of active medications may accumulate to elevated plasma concentrations, raising the risk of adverse drug reactions or dose-dependent toxicities. Conversely, for prodrugs like codeine that require conversion by CYP2D6 into active morphine, deficient enzyme function frequently leads to reduced therapeutic efficacy and lack of pain relief.
Global Distribution and Population Frequency
The rs5030865 variant is globally uncommon, with overall minor allele frequencies estimated at less than 1% across major population datasets like gnomAD and the TOPMed program. Its distribution is also distinctly ancestry-specific. For instance, the CYP2D6*14 allele defined by the c.505G>A transition is primarily identified in individuals of East Asian ancestry, where it occurs at a reported frequency of approximately 0.3%, while remaining exceptionally rare or entirely undetected in European, African, and Indigenous American populations. In contrast, other no-function alleles like CYP2D6*4 dominate in populations of European descent, while alleles like *17 and *29 are frequent in individuals of African ancestry. Because of its overall scarcity, most individuals across world populations carry the homozygous reference genotype (GG), producing the standard wild-type glycine at position 169.
Interpreting Results and Clinical Application
A consumer or research genetic test that reports an individual's rs5030865 genotype provides only one piece of a complex biological puzzle. Because CYP2D6 activity is dictated by whole haplotypes, structural copy-number variations (such as gene deletions, duplications, or hybrid genes with CYP2D7), and co-inherited variants, a single variant cannot definitively confirm your overall metabolizer status. Furthermore, genetic testing is not a diagnosis and should never prompt anyone to stop, start, or modify the dosage of any prescribed medication independently. Medication metabolism is also influenced by environmental factors, kidney and liver function, patient age, and co-prescribed drugs that may inhibit or induce metabolic pathways. Any questions regarding CYP2D6 genetic results, drug interactions, or therapeutic dosing should be evaluated alongside a licensed physician or clinical pharmacogenomics specialist.
How common is this variant?
The rs5030865 variant is very rare globally, exhibiting a minor allele frequency of less than 0.01 across global reference populations. It is detected predominantly at low frequencies (around 0.3%) in East Asian populations and is exceptionally rare or absent in other ancestral groups.
Frequently asked questions
What does having an altered CYP2D6 genotype mean for my daily life?
Carrying an altered CYP2D6 variant does not cause physical symptoms or disease on its own. It only becomes biologically relevant when you take medications that rely on the CYP2D6 enzyme for breakdown or activation. In those specific scenarios, your body may process the drug slower or faster than average.
Does rs5030865 mean I am a poor metabolizer?
Not necessarily. Your overall metabolizer status (normal, intermediate, poor, or ultrarapid) depends on your complete CYP2D6 diplotype, which accounts for both inherited copies of the gene, including potential gene duplications or deletions. While rs5030865 is found in decreased-function and no-function alleles, a full clinical panel is required to assign your overall activity score.
Which medications are affected by the CYP2D6 enzyme?
CYP2D6 processes a large array of commonly prescribed drugs, including many antidepressants (like fluoxetine and venlafaxine), beta-blockers (such as metoprolol), antipsychotics, and pain medications (such as codeine and tramadol). It also plays a critical role in converting the breast cancer drug tamoxifen into its active metabolite.
Should I change my medication dosage based on my genetic results?
No, you should never alter or stop your medication regimen based on raw genetic data. Only a licensed physician, clinical pharmacist, or healthcare provider can appropriately evaluate whether genetic results warrant adjustments, taking into account your overall health, symptoms, and other medications.
Sources & further reading
Educational information only, last refreshed 9/9/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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