Fulminant hepatitis B (FHBV) is a rare but severe outcome of acute hepatitis B virus infection. The severe liver injury is attributed to an exaggerated immune response directed at clearing virus by causing lysis of infected hepatocytes. Multiple factors could contribute to severity of the disease. Our study has shown that although there are no specific variant(s) linked to severity, there are clusters of variants in the cis-acting regulatory elements which can upregulate replication of FHBV strains. The most novel concept to come out of this study is that, most of these variants are not unique to FHBV sequences but they are significant when they occur in the form of 'motifs' or combinations; we showed that these multiple motifs are associated with a common functional effect.