Finally, the extensively replicated synonymous variant rs738408 in PNPLA3—a gene central to NAFLD pathogenesis— is located within a highly conserved, epigenetically active hepatic region and alters COMP1/other transcription factor motifs, providing a molecular link between genetic variation, hepatic lipid metabolism, and elevated ALT. Here, PNPLA3 is linked to metabolic dysfunction-associated steatotic liver disease.