Allelic Nomenclature and Haplotyping

Pharmacogenes are described not by single variants alone but by named haplotypes - combinations of variants inherited together - using a star-allele system in which the reference allele is *1 and each defined variant haplotype receives its own number. This shared naming convention lets laboratories, databases, and guidelines refer to the same allele unambiguously. This topic addresses how pharmacogene haplotypes are defined, named, and assembled into diplotypes.

Definition

Allelic nomenclature for pharmacogenes is the standardized naming of haplotypes - sets of sequence variants inherited together on the same chromosome - typically using a gene name followed by an asterisk and a number (a star allele); haplotyping is the process of determining which haplotypes an individual carries.

Scope

The topic covers the star-allele (asterisk) nomenclature, the concept of a haplotype as a set of co-inherited variants, the process of haplotyping and calling a diplotype from genotype data, and the role of curated nomenclature resources in keeping allele definitions consistent. It is reference material on naming conventions and does not provide drug-specific guidance.

Core questions

• What is a haplotype, and how does it differ from a single variant?
• How does the star-allele system name pharmacogene haplotypes?
• How is a person's diplotype determined from genotyping data?
• Why is a shared, curated nomenclature necessary across laboratories and databases?

Key concepts

• Haplotype (co-inherited set of variants)
• Star (asterisk) allele nomenclature
• Reference allele (*1) and defined variant alleles
• Diplotype (pair of haplotypes)
• Haplotype phasing and diplotype calling
• Curated allele-definition resources

Mechanisms

A pharmacogene haplotype is defined by one or more sequence variants that travel together on a chromosome; each distinct, recognized haplotype is given a star-allele label, with *1 conventionally denoting the reference (normal-function) allele. Determining an individual's diplotype means identifying the two haplotypes they carry, which requires resolving which variants lie on the same chromosome (phasing) - straightforward when variants uniquely define an allele, but more complex when several variants must be considered together. Curated databases maintain the definitions, so that the same star allele means the same set of variants everywhere it is used, and each allele can be linked to an assigned function.

Clinical relevance

Consistent allele nomenclature is the foundation that lets metabolizer-phenotype prediction and gene-drug guidelines be applied reproducibly, because a phenotype call depends on correctly identifying the haplotypes present. As reference content this topic explains the naming and haplotyping system; it does not give prescribing instructions, which belong to validated clinical guidelines applied by qualified clinicians.

Epidemiology

The set of haplotypes seen and their frequencies differ across ancestral populations, and some star alleles are common in one population while rare in another; comprehensive nomenclature resources aim to capture this diversity so that haplotyping is accurate across groups.

History

Star-allele naming originated with the cytochrome P450 enzymes and was maintained for years through dedicated allele-nomenclature pages. In 2018 stewardship of the human CYP allele nomenclature moved into the Pharmacogene Variation (PharmVar) Consortium, which now serves as a central, versioned repository of pharmacogene haplotype definitions, working alongside knowledge resources such as PharmGKB.

Key figures

• Andrea Gaedigk
• Magnus Ingelman-Sundberg
• Teri Klein
• Michelle Whirl-Carrillo

Seminal works

• gaedigk-2017
• whirl-carrillo-2012

Frequently asked questions

What does a star allele such as CYP2C19*2 mean?

It is a named haplotype: a defined combination of sequence variants in the CYP2C19 gene that has been catalogued and assigned a number and a function, allowing laboratories and guidelines to refer to it consistently.

Why does haplotyping require more than reading individual variants?

Because an allele is defined by which variants are inherited together on the same chromosome, determining a haplotype may require phasing - working out the combination present - rather than just listing each variant in isolation.