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 population and uncovered 1284 unreported exonic variants, underscoring the underrepresentation of Indian populations in global databases. Among these, 23 are predicted to be deleterious, all present in heterozygous state may be pathogenic when homozygous, an expected phenomenon in endogamous populations. Approximately 16%-33% of the identified pathogenic variants showed significantly higher occurrence rates compared to 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 HLA-B*27:04 allele and strong founder effect. Our findings highlight the need for extensive genomic research in understudied Indian populations for better understanding of disease risk and evolving strategies for precision and preventive medicine.