Whilst the underlying principles of precision medicine are comparable across the globe, genomic references, health practices, costs and discrimination policies differ in Asian settings compared to the reported initiatives involving European-derived populations. We have addressed these variables by developing an evolving reference base of genomic and phenotypic data and a framework to return medically significant variants to consenting research participants applicable for the Asian context. Targeting 10,000 participants, over 2000 Singaporeans, with no known pre-existing health conditions, have consented to an extensive clinical health screen, family health history collection, genome sequencing and ongoing follow-up. Genomic variants in a subset of genes associated with Mendelian disorders and drug responses are analysed using an in-house bioinformatics pipeline. A multidisciplinary team reviews the classification of variants and a research report is generated. Medically significant variants are returned to consenting participants through a bespoke return-of-result genomics clinic. Variant validation and subsequent clinical referral are advised as appropriate. The design and implementation of this flexible learning framework enables a cohort of detailed phenotyping and genotyping of healthy Singaporeans to be established and the frequency of disease-causing variants in this population to be determined. Our findings will contribute to international precision medicine initiatives, bridging gaps with ethnic-specific data and insights from this understudied population.