Through global collaboration with a Nigerian health center (funded in part by the Pharmacogenomics Global Research Network), our study investigated the impact of sub-Saharan African-specific CYP2D6 alleles on risperidone metabolism. We discovered that *17 shows double the activity of normal-function alleles, while *29 behaves more like a no-function allele—findings that contradict the results reported for other substrates. These findings could spark a whole new paradigm in clinical pharmacogenetics by pushing us towards the consideration of substrate specificity for CYP2D6. Importantly this work, that prioritized a historically understudied population, gets us one step closer to more equitable precision medicine.