Single nucleotide polymorphisms (SNP) are responsible for genetic mutations. We studied genetic molecular variations and found an association of oral cancer with SNP of Adenylate Cyclase 2 (ADCY2) rs252546 and complement C7 (C7) rs1450656 genes in people of Southern Punjab, Pakistan. The study involves 100 cases of oral cancer and 100 healthy individuals. ADCY2 is found as a membrane-associated enzyme and C7 is involved in innate immunity. The process of genotyping was carried out by Tetra ARMS Primer PCR. The genetic variant of ADCY2 rs252546 has allelic origin G/A and C7 rs1450656 with C/T. The statistical analysis showed that the 51-60 years age group is significantly associated with oral cancer. The allelic frequency of ADCY2 rs252546 and C7 rs1450656 was calculated through Hardy Weinberg equilibrium. The homozygous mutant allele G of ADCY2 was more prevalent in cases and C allelic genotype was equally found in cases and controls. Other demographic and polymorphic studies indicated a significant association of variants of ADCY2 and C7 with oral cancer in the local population of Punjab. Variations in ADCY2 and C7 can be used as potential biomarkers and biological targets for oral cancer management strategies.