CYP2C19 rs72549304 (*5 Allele): Drug Metabolism Guide
The single nucleotide polymorphism rs72549304 is a rare genetic variant in the CYP2C19 gene that defines the star allele CYP2C19*5. This missense change (c.1297C>T, p.Arg433Trp) leads to a completely non-functional drug-metabolizing enzyme. As a result, carriers have reduced capacity to process key medications, including the antiplatelet drug clopidogrel and proton pump inhibitors.
What each genotype means
Normal enzyme activity
This genotype represents the most common state where the CYP2C19 gene does not carry the inactivating *5 mutation. Individuals with this profile are typically expected to have normal metabolic function for medications processed by this enzyme, such as clopidogrel or certain proton pump inhibitors. Please discuss any medication dosing or concerns with your clinician or pharmacist.
This is the most common genotype, found in the vast majority of the global population.
Reduced enzyme activity
This genotype indicates you carry one copy of the CYP2C19*5 variant, which is a non-functional allele. Research suggests that carrying one such loss-of-function allele may lead to reduced enzyme activity, potentially affecting how your body processes specific drugs like clopidogrel. Please consult your healthcare provider or pharmacist to determine if this impacts your current medication regimen.
This genotype is very rare, with the *5 allele occurring at a frequency of less than 0.1% globally.
Poor metabolizer status
This genotype indicates you carry two copies of the CYP2C19*5 variant, which is classified as a completely inactivating mutation. Individuals with this profile are considered poor metabolizers, meaning they may not effectively activate certain medications like clopidogrel, which could reduce the drug's intended antiplatelet effect. It is essential to discuss this genetic finding with your clinician or pharmacist to ensure your treatment plan is appropriate for your metabolism.
This genotype is extremely rare and has been primarily reported in isolated cases within European and East Asian cohorts.
What Is rs72549304 and Where Is It Located?
The variant rs72549304 represents a single nucleotide variation located within exon 9 of the cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene on chromosome 10q24. At the molecular level, it involves a substitution of cytosine (C) to thymine (T) at coding position 1297 (c.1297C>T). This alteration leads to an amino acid substitution of arginine to tryptophan at codon 433 (p.Arg433Trp). In pharmacogenomic nomenclature established by the Pharmacogene Variation (PharmVar) Consortium and curated by resources like PharmGKB, this specific sequence variation serves as the defining marker for the CYP2C19*5 star allele. Because the altered residue is essential to the structural integrity and catalytic activity of the hemoprotein, the resulting protein lacks normal catalytic capability.
The Biological Role of the CYP2C19 Enzyme
CYP2C19 encodes a membrane-bound monooxygenase localized primarily to the endoplasmic reticulum of liver hepatocytes. It is an essential member of the cytochrome P450 superfamily, responsible for the biotransformation and clearance of roughly 10% of commonly prescribed therapeutic compounds. Substrates of CYP2C19 include antiplatelet agents such as clopidogrel, proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, and pantoprazole, as well as several tricyclic antidepressants, selective serotonin reuptake inhibitors, and anticonvulsants. For some drugs, such as proton pump inhibitors, CYP2C19 acts primarily to clear the active medication from circulation. For prodrugs like clopidogrel, the enzyme is critical for bioactivation into the active metabolite required to inhibit platelet aggregation.
Pharmacogenomic Impact and Evidence Strength
Pharmacogenomic consensus guidelines from bodies such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) classify CYP2C19*5 as a validated 'no-function' allele. However, because rs72549304 is extremely rare compared to the classic loss-of-function alleles (*2 and *3), direct clinical trial data evaluating outcomes specifically in *5 carriers remain limited. Instead, CPIC assigns metabolic status by grouping *5 together with other completely inactivating alleles. Carriers of one non-functional allele are predicted to be intermediate metabolizers, while individuals carrying two non-functional alleles are classified as poor metabolizers. In poor metabolizers, standard doses of clopidogrel generate significantly lower levels of active drug, potentially leading to treatment resistance, whereas standard doses of PPIs can lead to elevated circulating drug concentrations.
Population Frequency and Diversity
Unlike CYP2C19*2 (prevalent across global populations) and CYP2C19*3 (frequently observed in East Asian ancestries), rs72549304 is a very rare deleterious variant. In large population sequencing datasets, such as the Genome Aggregation Database (gnomAD), the minor allele frequency (MAF) of the T allele is well below 0.001 globally. Although the *5 allele has historically been identified and described in small cohorts of European and East Asian descent, it is generally absent or found at negligible frequencies in most routine clinical screening panels, reflecting its status as an uncommon contributor to overall population-level metabolizer phenotypes.
Practical Implications: What This Means for You
Identifying the rs72549304 variant provides useful information regarding your genetic predisposition to drug metabolism, but it does not represent a medical diagnosis or disease risk on its own. Genetic results reflect only an inherited baseline; real-world drug response is also governed by age, liver function, drug-drug interactions, and concurrent health conditions. If a personal genetic test indicates the presence of the T allele, never start, stop, or alter medication dosages independently. Instead, share these findings with a licensed healthcare provider or clinical pharmacogeneticist, who can integrate your diplotype with established CPIC guidelines to optimize medication selection and dosing safely.
How common is this variant?
The minor T allele is exceptionally rare globally, with an estimated minor allele frequency (MAF) below 0.001 across worldwide populations. It has been primarily documented in isolated studies of European and East Asian cohorts, with homozygous TT individuals occurring only exceedingly rarely.
Frequently asked questions
What is the CYP2C19*5 allele?
The CYP2C19*5 allele is defined by the rs72549304 (c.1297C>T) single nucleotide variant. It causes a missense mutation (p.Arg433Trp) that renders the resulting CYP2C19 liver enzyme completely non-functional, reducing an individual's overall capacity to metabolize certain medications.
Does having rs72549304 affect how clopidogrel works?
Yes. Clopidogrel is an inactive prodrug that requires activation by the CYP2C19 enzyme to prevent blood clots. Carriers of inactivating alleles like *5 produce lower levels of the active drug, which may diminish its protective antiplatelet effects.
Why is CYP2C19 rs72549304 considered to have 'limited' evidence?
While molecular studies clearly demonstrate that the p.Arg433Trp change causes a complete loss of enzyme activity, rs72549304 is extremely rare in the general population. As a result, direct prospective clinical trial data specifically tracking outcomes in *5 carriers remain sparse compared to common variants like *2 or *3.
Should I adjust my medication if I have the CT or TT genotype?
No, you should never alter your medication regimen based solely on a commercial or preliminary genetic test. You should share your comprehensive pharmacogenomic report with your physician or pharmacist, who can interpret the entire CYP2C19 diplotype and adjust therapy using evidence-based CPIC guidelines.
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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Defines the CYP2C19*17 increased function allele, conferring rapid or ultrarapid metabolism for CPIC-actionable drugs including clopidogrel, PPIs, and SSRIs.
The CYP2C19*2 loss-of-function splicing defect results in impaired biotransformation of prodrugs including clopidogrel and altered clearance of proton pump inhibitors and select antidepressants.
Variant in the CYP2C19 locus associated with altered metabolism of clopidogrel and proton-pump inhibitors.
Defines the CYP2C19*8 loss-of-function variant (c.358T>C, p.Trp120Arg) which results in no enzymatic activity and impaired metabolism of CYP2C19 substrates.
Defines the non-functional CYP2C19*3 null allele resulting from a premature stop codon, leading to poor metabolism of drugs such as clopidogrel, escitalopram, and proton pump inhibitors.
Defines the CYP2C19*4 allele caused by an ATG start codon alteration that abolishes translation, resulting in reduced or absent drug metabolism capacity.