The Hong Kong Genome Project (HKGP) aims to build a foundational resource for precision medicine in the Chinese population through large-scale genome sequencing and integrated analyses. Here we report findings from over 20,000 HKGP participants across two cohorts: a rare disease cohort including 2,227 patients with suspected genetic diseases and a population cohort including 18,261 participants undergoing genomic screening for medically actionable findings. The rare disease cohort achieved a diagnostic rate of 25%. When benchmarked against panels designed for European ancestries, the analysis revealed that 3.7% of the individuals in the population cohort had pathogenic or likely pathogenic variants associated with dominant disorders. While 48% of individuals were found to carry recessive disorder genes in the gene list based upon European ancestries, our analysis revealed that 38 additional clinically important genes would have been overlooked in the Chinese population. Pharmacogenomic analysis demonstrated that nearly all participants harbored at least one actionable phenotype, potentially informing nearly one million annual prescriptions in Hong Kong. The ongoing HKGP establishes a curated Hong Kong Chinese reference for clinically relevant genetic variation and serves as a blueprint for the implementation of precision medicine in underrepresented populations.