Oral leukoplakia (OL), an oral potentially malignant disorder begins with a hyperplastic/hyperkeratotic stage at which no genome-scale somatic single nucleotide variant profiles have been described so far. We performed exome sequencing of five cases at this stage with no evidence of dysplasia to identify genetic alterations (exon-level copy number alterations, indels, and single nucleotide variants), their association with transcript levels and relationship with oral cancer susceptibility. Pathway enrichment analysis of genes associated with tobacco chewing and age-related mutation signatures, transcripts with variants predicted to be functionally damaging and those with significantly altered levels have all indicated the involvement of focal adhesion, ECM–receptor interactions, regulation of cytoskeleton and DNA repair. Two novel mutations identified in FAT1 tumor suppressor gene were associated with decreased transcript levels. In addition, 16 expressed cancer driver genes contained functionally damaging variants. Many of the affected genes were also reported in dysplastic OL lesions. The presence of variants in cancer driver genes and those shared with oral dysplasias possibly provide a basis for further progression and increased susceptibility to oral cancer.