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Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population. Agency for Science, Technology and Research (A*STAR) Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This study made use of data generated as part of the Singapore National Precision Medicine program funded by the Industry Alignment Fund (Pre-Positioning) (IAF-PP: H17/01/ a0/007). The participating study cohorts were supported by the following funding sources: (1) HELIOS study by grants from a Strategic Initiative at Lee Kong Chian School of Medicine, the Singapore Ministry of Health (MOH) under its Singapore Translational Research Investigator Award (NMRC/STaR/0028/2017) and the IAF-PP: H18/01/a0/016, (2) GUSTO study by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore MOH’s National Medical Research Council (NMRC) Singapore (NMRC/TCR/004-NUS/2008, NMRC/TCR/ 012-NUHS/2014) with additional funding provided by SICS and IAF-PP: H17/01/a0/005, (3) SEED study by NMRC/CIRG/1417/2015, NMRC/CIRG/ 1488/2018, NMRC/OFLCG/004/2018, (4) MEC study by NMRC grant 0838/2004, BMRC grant 03/1/27/18/216, 05/1/21/19/425, 11/1/21/19/678 to NUS and National University Health System (NUHS) Singapore, (5) PRISM cohort study by NMRC/CG/M006/2017_NHCS, NMRC/STaR/ 0011/2012, NMRC/STaR/0026/2015, EYE ACP-PRISM PRECISION MEDICINE INITIATIVE FUND 05/FY2020/EX/06-A41, Lee Foundation and Tanoto Foundation, (6) TTSH cohort study by NMRC/CG12AUG2017 and CGAug16M012. Additional funding support includes grants under National Research Foundation Singapore administered by the Singapore Ministry of Health’s National Medical Research Council to the following individuals: National Precision Medicine Programme (NPM) PHASE II FUNDING (MOH-000588) to W.K.L., National Medical Research Council Singapore Clinician-Scientist Award (NMRC/CSA-INV/0017/2017, MOH000654) to J.N., National Medical Research Council Singapore ClinicianScientist Award (CSAINV21Jun-0003) to S.S.J., and Clinician-Scientist Award Senior Investigator (NMRC/CSA-SI/0012/2017) to C-Y.C; as well as funding from Agency for Science, Technology, and Research (A*STAR) of Singapore to J. Liu