Background: Oral cancer accounts for 2 to 4% of all cancer and 90% of oral cancer cases are squamous cell carcinoma. Apart from etiological factors genetic factors also play an important role in oncogenesis. The common type of sequence variations is single nucleotide polymorphisms (SNPs), described as a change in the coding and amino acids sequence in the related proteins which could confer protective or lethal effects on the organism. Objective: To analyze the genetic variation in the CA9 gene (rs2071676) and to compare allele frequencies in different populations worldwide. The rs2071676 variant of the CA9 gene is a missense variant that results in the substitution of the amino acid methionine in place of valine. Methods: Genotype frequencies of the SNP rs2071676 were collected from the Ensembl database for different populations and the deviations were analyzed. Furthermore, the expression profile of the CA9 gene in HNSCC was assessed using in-silico tools. The survival of patients based on the expression of the CA9 gene was also assessed. Results: The present study identified deviations in allele frequencies for rs2071676 polymorphism between different populations. The minor allele frequency in the ancestral population or the African population was found to be much lower than the other populations such as American, East Asian, and South Asian, where both the alleles showed similar frequencies. Conclusion: The significant deviation between allele frequencies in different groups provides clues about the positive selection of these alleles in certain populations. This led us to further investigate the plausibility of association of the CA9 gene with HNSCC. The intriguing facts observed from the study could aid in revealing the association between the CA9 gene and the progression of oral cancer.