Genetic variants at the interferon lambda (IFNL) locus have been associated with several human phenotypes in both disease and health. In chronic hepatitis C virus (HCV) infections, where the IFNL variants were first identified to be associated with response to interferon-α-ribavirin therapy, the available data clearly suggests that the causal variant could be the dinucleotide polymorphism rs368234815 that causes an open reading frame-shift in the IFNL4 gene resulting in expression of a functional IFN-λ4, a new type III IFN. In other human diseases/phenotypes where IFNL variants have been recently associated with, the causal mechanism remains unclear. In vitro evidence has shown that other IFNL variants (rs28416813, rs4803217) may regulate expression of another type III IFN, IFN-λ3. Therefore, expression of a functional IFN-λ4 and quantitative differences in IFN-λ3 expression are two potential causal mechanisms behind the observed phenotypes. Since these two potential causal mechanisms involve features of mutual exclusivity and overlapping functions, it is difficult to differentiate one from the other, in vivo, in absence of other implicating evidences. In addition, the strong linkage disequilibrium (LD) observed in many populations at the IFNL locus makes it difficult to tease out the actual functional/causal variants responsible for the phenotypes. The non-synonymous single nucleotide polymorphism rs117648444 that alters the activity of IFN-λ4 and the LD structure in the IFNL region which leads to a confounding effect of rs117648444 on other IFNL variants, provide us with additional tools in case-control studies to probe the role of IFN-λ4.