In conclusion, our data showed that rt269I type versus rt269L type is more prone to overall genome mutations, particularly in the Pol region in genotype C2 infections, and is more prevalent in signature NS mutations related to lowered HBV DNA replication, HBsAg and HBeAg secretion, potential NAr variants and HCC, perhaps via IFN-I mediated enhanced inflammation. Here, CPSF4 is linked to hepatocellular carcinoma.