Although some “disease modifiers” (Figure 3), including clinical (i.e., presence and clustering of the metabolic traits) [71], biological (transaminases levels) [92] and genetic (PNPLA3, TM6SF2, HSD17B13) [93,94] factors allow for a “general” estimation of the HCC risk, these approaches are not accurate enough to justify the implementation of the screening strategies in the absence of cirrhosis. The gene discussed is PNPLA3; the disease is Cirrhosis.