CYP2C19 is a very important gene in the field of pharmacogenomics. It encodes a cytochrome P450 enzyme that metabolises many commonly prescribed medicines, including proton pump inhibitors, antiepileptic drugs and antiplatelet agents such as clopidogrel. *CYP2C19* is highly polymorphic: **39 haplotypes have been characterised by their impact on drug metabolism.** This *CYP2C19* genetic heterogeneity is associated with significant pharmacokinetic variation between individuals, which impacts on drug efficacy and the risk of adverse effects.

"The CYP2C19 gene is highly polymorphic; the Pharmacogene Variation Consortium (PharmVar) has currently defined over 35 star (*) allele haplotypes, including rare gene deletions (https://www.pharmvar.org/gene/CYP2C19)." The guideline further notes that these alleles are assigned functional categories (normal, decreased, no function, increased) which are used to predict metabolizer status and influence drug response.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. **CYP2C19 genetic variation impacts the metabolism of many drugs** and has been associated with both efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized.

"The CYP2C19 gene is highly polymorphic with 37 known variant star (*) alleles, including rare copy number variants (i.e., gene deletions)." Alleles "are categorized into functional groups as follows: normal function (e.g., CYP2C19*1), decreased function (e.g., CYP2C19*9), no function (e.g., CYP2C19*2 and *3), and increased function (e.g., CYP2C19*17)." This functional grouping is used to assign metabolizer phenotypes that affect the rate of drug metabolism.

"The CYP2C19 gene has more than 35 star alleles defined by PharmVar, including rare gene deletions (CYP2C19 Allele Definition Table)." The article emphasizes that clinically relevant alleles are grouped by function (normal, decreased, no function, increased) and that genotype–phenotype tables are used to infer metabolizer status which in turn affects the metabolism of multiple drugs.

The Pharmacogene Variation Consortium (PharmVar) catalogues genetic variation of pharmacogenes by haplotypes termed star (*) alleles… **CYP2C19 genetic variation impacts the metabolism of many drugs** and has been associated with both efficacy and safety issues. PharmVar has recently catalogued the **CYP2C19*36 and *37 alleles**, which represent full and partial (with including at least exon 1) CYP2C19 gene deletions, respectively, further increasing the number of known CYP2C19 alleles.

The CYP2C19 gene is located on chromosome 10q23.33 and to date, 39 alleles and 2000 SNPs have been identified (Shao et al., 2020). Intriguingly, the CYP2C19 gene is highly polymorphic, leading to changes in enzymatic activity, therapeutic responses, and/or adverse drug reactions.

NCBI’s Gene entry for CYP2C19 (Gene ID 1557) states that this cytochrome P450 enzyme is involved in the metabolism of several important therapeutic agents. It lists multiple variant alleles such as CYP2C19*2 and other loss-of-function alleles, and links to PharmVar and dbSNP resources that catalogue the different CYP2C19 star alleles impacting enzyme activity and drug response.

"Like many other CYP450 superfamily members, the CYP2C19 gene is highly polymorphic, with >25 known variant alleles (http://www.cypalleles.ki.se/cyp2c19.htm)." The paper notes that the wild-type *CYP2C19*1 allele is associated with functional metabolism, whereas variant alleles such as *2–*8 confer reduced or absent enzymatic activity that can significantly alter activation of clopidogrel and other substrates.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. **CYP2C19 genetic variation impacts the metabolism of many drugs** and has been associated with both efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. The table lists numerous **CYP2C19* star alleles** (e.g. *2 suballeles such as *2A–*2E) with their nucleotide changes, functional effects (such as "splicing defect" or amino acid changes), and references, illustrating the extensive genetic variability of CYP2C19 and the range of functional consequences for enzyme activity.

The known CYP2C19 star (*) alleles are cataloged by the Pharmacogene Variation (PharmVar) Consortium (https://www.pharmvar.org/gene/CYP2C19, last accessed …). Clinical genotyping recommendations depend on which alleles are included; the article discusses **selection of CYP2C19 alleles for clinical testing**, noting that multiple alleles with no function, decreased function, normal function, or increased function contribute to variable metabolism of CYP2C19 substrates.

CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of all medications. CYP2C19 and CYP2D6 are of particular clinical relevance, as they are highly polymorphic and implicated in the metabolism of numerous widely prescribed drugs. CYP2C19*2 (rs4244285) is the most common allelic variant in Caucasians and results in aberrant splicing and loss-of-enzyme activity. In contrast, the regulatory polymorphism rs12248560 defining CYP2C19*17 increases transcriptional activity and causes the ultrarapid CYP2C19 metabolism.

The CYP2C19 Allele Definition Table provides star (*) allele definitions used by CPIC. It lists numerous **CYP2C19 star alleles**, their defining variants, and assigned functional status (normal, decreased, no function, increased, uncertain), which are used to predict metabolizer phenotype. The documentation notes that allele definitions are based on PharmVar CYP2C19 GeneFocus and structural variation information, reflecting the high genetic variability of CYP2C19 relevant to drug metabolism.

In addition to the normal CYP2C19*1 allele, the CYP2C19 gene can have up to 35 different alleles (named in order of discovery), many of which are associated with altered enzyme function, resulting in poor, intermediate, rapid, or ultra-rapid drug metabolism. The group’s recommended tier-two CYP2C19 alleles are *4A, *4B, *5, *6, *7, *8, *9, *10, and *35. Their recommendations are divided into a tier-one minimum set of alleles and a tier-two set of alleles for extended panels.

In a study of over 2.2 million individuals, the authors state: "The well-characterized variants of CYP2C19 are the increased-function allele *17 (c.-806C>T) and the no-function alleles *2 (c. 681G>A) and *3 (c. 636G>A)." They report overall frequencies of *2, *3, and *17 as 15.2%, 0.3%, and 20.4%, respectively, and note that these common alleles, together with other rarer alleles, are used to classify metabolizer status and influence rates of medication metabolism.

"Alleles are categorized into functional groups as follows: normal function (e.g., CYP2C19*1), decreased function (e.g., CYP2C19*9), no function (e.g., CYP2C19*2), and increased function (e.g., CYP2C19*17)." The guideline reiterates that CYP2C19 is highly polymorphic and that variation in these alleles leads to normal, intermediate, poor, rapid, or ultrarapid metabolizer phenotypes, which in turn influence drug exposure and response.

Multiple variations (polymorphisms) in the CYP2C19 gene have been associated with clopidogrel resistance, a condition in which the drug clopidogrel is less effective than normal in people who are treated with it. The normal version of the gene, written as CYP2C19*1, provides instructions for producing a normally functioning CYP2C19 enzyme. The two most common CYP2C19 gene polymorphisms associated with clopidogrel resistance (known as CYP2C19*2 and CYP2C19*3) result in the production of a nonfunctional CYP2C19 enzyme that is unable to activate clopidogrel. One change in the CYP2C19 gene (known as CYP2C19*17) increases the enzyme's ability to metabolize drugs; individuals with two copies of CYP2C19*17 are typically classified as ultra-rapid metabolizers.

ClinPGx manually curates pharmacogenomic articles and maps alleles from those articles to **PharmVar core alleles**, where they exist. It notes that "PharmVar genes with core alleles" are maintained and that "A full list of variants that define each star allele is curated and published" by ClinPGx for genes like CYP2C19, underscoring the large number of functionally distinct CYP2C19 alleles impacting drug metabolism.

A Diasorin white paper on CYP2C19 testing states: "Up to 34 different variations in the gene sequence have been described for CYP2C19." It further explains that every individual has two CYP2C19 alleles and that the combination of these alleles (genotype) determines the overall level of CYP2C19 enzyme activity (phenotype), affecting how rapidly medications are metabolized. It notes that alleles *4 to *10 are relatively rare, with frequencies typically less than 1%.

Defective CYP2C19*2 and CYP2C19*3 alleles are characterized by a splice mutation and a stop codon, respectively, and account for most of the poor metabolizer alleles. Genetic variants in CYP2C19 can alter enzyme activity and thereby influence the metabolism of drugs that are CYP2C19 substrates.

The CPIC gene page for CYP2C19 states that there are gene-specific tables for "CYP2C19 allele definition, allele functionality, frequency and diplotype-phenotype tables" supporting CPIC guidelines. These materials classify CYP2C19 alleles into functional categories and provide guidance on how different genotypes affect predicted metabolizer status and hence drug metabolism.

The ClinPGx entry for CYP2C19*2 explains that this star allele is defined by key splicing variants 12662A>G (rs12769205) and 19154G>A (rs4244285) and an amino acid change I331V (rs3758581). It describes CYP2C19*2 as a loss-of-function allele associated with reduced enzyme activity and poor metabolizer status, illustrating how specific alleles modulate medication metabolism rates.

CYP2C19 is a highly polymorphic cytochrome P450 enzyme. Many **single nucleotide variants, splicing variants and deletions** in the CYP2C19 gene have been identified, and new allelic variants continue to be described. These genetic variants are grouped into star (*) alleles that are assigned functional categories (no function, decreased function, normal function, increased function, or uncertain function). The combination of alleles in an individual’s genotype allows prediction of metaboliser phenotype, ranging from poor to ultra-rapid metaboliser.

CYP2C19 Allele Definition Table. Variant mapping to star alleles; allele mapping to the human genome reference sequence GRCh38, the RefSeq Gene sequence, and the Human Cytochrome P450 Allele Nomenclature database. The table lists currently defined CYP2C19 star alleles, many of which are associated with altered function of the enzyme, including no function, decreased function, normal function, and increased function alleles.