摘要Founder events influence recessive diseases in highly endogamous populations.Several Indian populations have experienced significant founder events due to strict endogamy.However,the clinical implications of it remain underexplored.Therefore,we perform whole-exome sequencing of 281 individuals from four South Indian populations,characterized by high IBD scores.Our study reveals a high inbreeding rate of 59％across the populations.We identify～29.2％of the variants that are exclusively present in a single popu-lation and uncover 1284 unreported exonic variants,underscoring the underrepresentation of Indian populations in global databases.Among these,23 are predicted to be deleterious,all of which are present in a heterozygous state;they may be pathogenic when homozygous,an expected phenomenon in endogamous populations.Approximately 16％-33％of the identified pathogenic variants showed signifi-cantly higher occurrence rates compared with the South Asian populations from 1000 Genomes dataset.Pharmacogenomic analysis revealed distinct allele frequencies of variants in CYP450 and non-CYP450 genes,highlighting heterogeneous drug responses and associated risks.We report a high prevalence of ankylosing spondylitis in Reddy population,linked to the HLA-B*27∶04 allele and strong founder effect.Our findings highlight the need for extensive genomic research in understudied Indian populations for a better understanding of disease risk and evolving strategies for precision and preventive medicine.