Objectives <p>To investigate the genetic polymorphisms associated with febrile seizures (FS) in children from Vijayapura District, Karnataka, South India. Also to identify novel or known pathogenic variants using whole exome sequencing (WES), explore clinical profiles, and assess associations with family or past history of FS.</p> Methods <p>This observational study included 50 children aged 6 mo to 6 y presenting with FS at Shri B.M. Patil Medical College, Vijayapura. After excluding those with neurological deficits or atypical seizure etiologies, peripheral blood samples were collected. DNA was extracted, and exon-specific primers were designed. PCR products were subjected to Sanger sequencing, and WES was performed on 12 cases. Clinical characteristics were recorded, and statistical analysis was done using SPSS v20.</p> Results <p>Among 50 children, the most common age group was 1–2 y (50%), with males accounting for 56%. Family history and past history of FS were present in 38% and 40% respectively. Typical FS were more common (76%). WES revealed novel or rare variants, including variants of uncertain significance (VUS), in GABRG2, SEMA6B, and KCNQ2. While KCNQ2 (6%) and CPA6 (2%) pathogenic/likely pathogenic variants have known associations with FS, the SEMA6B variants observed (30%) are primarily VUS, and their functional or causal role in FS remains uncertain. No significant association was found between seizure type and family or past history.</p> Conclusions <p>This pilot study underscores the genetic heterogeneity of FS and identifies SEMA6B as a potentially relevant gene in South Indian children. WES may be a valuable tool for unraveling FS pathogenesis, especially in region-specific populations.</p>