HLA-DRB1 gene is important for controlling antigen peptides presentation to T cell Receptor that encodes salivary sIgA secretion, in turn, preventing Streptococcus mutants’ colonization in dental caries mechanism. The study investigated the Novel Mutation of HLA-DRB1 Gene in Salivary sIgA Secretion. It tested 30 patients high (>300ng/mL) and 30 patients low (<300ng/mL) salivary sIgA level, in high sIgA group: 5 patients match with variant HLA-DRB*1209; 25 with the same SNPs in the Exxon 2 of HLA-DRB1 on nt295 (GC) and nt303(CG) resulting in missense mutation on codon 99 from aspartate to histidine and silent mutation on codon 102. D99H affects protein function. On low salivary sIgA group, 9 patients had two deletions of base 136 and base 153. The frame shift resulted in a premature stop codon 61 amino acids downstream: 10 patients had substitutions of G to T (nucleotide position 313); A to T (nucleotide position 314). This group also had 2 deletions of base 136 and 153, leading to frame shift and premature stop codon; nine patients had substitution of G to T (nucleotide position 312) and A to T (nucleotide 314). The variants produced a truncated protein and the mutations. This confirmed HLA-DRB1 as gene involved in dental caries mechanism and SNPs that may help understand the structure and function of the protein.