preprint · medRxiv
Clinical genotyping tools based on European reference data often fail to represent genetic variation found in sub-Saharan African populations. A new curated, machine-readable catalogue addresses this by defining nine actionable alleles across six important pharmacogenes: CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP3A5, and NAT2. The resource was created by reanalysing 661 high-coverage whole genomes from seven African populations. When compared with the existing PharmCAT tool, which failed completely to call CYP2D6 diplotypes from standard variant-only files, the catalogue's reduced-position strategy successfully identified hundreds of carriers of the CYP2D6 *17 and *29 variants. High frequencies of specific variants directly influence prescribing risks for widely used medications including efavirenz, tramadol, tacrolimus, and isoniazid. These results demonstrate that effective pharmacogenomic decision support in African clinical settings requires population-specific allele definitions and software strategies tailored to standard genomic data formats.
Standard clinical genetic tests frequently miss critical drug-response variants common in African populations. Because these undetected variants influence how individuals process vital medications, such as pain relief, immunosuppressive drugs, and treatments for HIV and tuberculosis, tailored reference catalogues are essential. Ensuring clinical tools account for African genetic diversity prevents misdiagnosis of drug response and helps clinicians prescribe safer, more effective treatments.
The machine-readable catalogue can be integrated into clinical pharmacogenomic testing platforms and decision-support software used by diagnostic laboratories and healthcare providers. It is an applied, tested digital resource validated on existing genomic datasets, though real-world clinical implementation would require software integration into clinical workflows. Diagnostic developers targeting African healthcare systems or diverse patient populations can utilise these allele definitions to improve test accuracy for drugs like efavirenz, tramadol, and tacrolimus.
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Abstract Sub-Saharan African populations carry pharmacogenomic alleles poorly represented in the European-derived reference panels underlying most clinical genotyping tools. We present a curated, machine-readable catalog of nine actionable alleles across six pharmacogenes ( CYP2D6 , CYP2B6 , CYP2C9 , CYP2C19 , CYP3A5 , NAT2 ) with African-specific frequency ranges, functional annotations, and evidence levels derived from reanalysis of 661 high-coverage whole-genome sequences across seven 1000 Genomes Project African populations. Direct comparison against PharmCAT v3.4.0 shows that CYP2D6 produces zero diplotype calls (0/661 samples callable) due to monomorphic reference positions absent from standard variant-only VCF output, a known limitation whose consequences for African allele carriers had not been reported. afripharmagen ’s reduced-position strategy identifies 243 CYP2D6 *17 and 134 CYP2D6 *29 carriers from the same input. For CYP2B6 , CYP2C9 , CYP2C19 , and NAT2 , both tools show concordance of 95–100%. Frequency gradients ( CYP2B6 *6: 30–50%; CYP2D6 *17: 15–35% in West Africa; CYP3A5 *1: 60–95%) translate directly into prescribing risk for efavirenz, tramadol, tacrolimus, and isoniazid. Pharmacogenomic decision support in African settings must incorporate population-specific allele definitions and input-format-aware strategies.
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DOI: 10.64898/2026.08.25.26361354
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