*4.2. Class 0 Mutations*

Various databases based on genome and transcriptome sequences list an enormous number (over 1000) of mutations and polymorphisms in the *ABCG2* gene. These also include the synonymous mutations and the genetic variants in the non-coding regions, but from a practical point of view, we focus here primarily on non-synonymous singlenucleotide polymorphisms (SNPs) in the coding region. A comprehensive collection of mutations in ABC proteins, including those of ABCG2, is available at http://abcmutations. hegelab.org/ (accessed on 9 February 2021) [98,99]. This database (named ABCMdb) summarizes not only the naturally occurring but also the artificially generated genetic variants, and annotates them with relevant literature data. Inclusion of artificial mutations in such databases is of great help in gaining insights into structure-function relationships and in designing future experiments.

One group of ABCG mutations can be formed from those that do not affect the function, expression, and trafficking considerably (marked as Class 0). A characteristic representative of this group is the frequent missense polymorphism V12M (rs2231137) [49,100]. The minor allele frequency (MAF) of this SNP falls between 0.19 and 0.33 in the Asian populations and is around 0.06 in Europe [101,102]. Other members of this class are K360del and T434M [103,104]. The specific cellular events affected by the mutations of each group are depicted in Figure 1, whereas detailed data on the major representatives of the various SNP categories are provided in Table 1.

**Figure 1.** Classification of ABCG2 variants based on the cellular defects caused by the various mutations and polymorphisms. Green arrows—mRNA and protein trafficking, orange arrows—ABCG2 mediated transport, blue arrow—ABCG2-mediated transport with altered substrate preference.



PM, plasma membrane; NBD, nucleotide-binding domain; TMH, transmembrane helix; CL, cytoplasmic loop; EL, extracellular loop; n.d., no data; ?, unknown; \* in Caucasians, \*\* observed in a small cohort of patients with hyperuricemia or gout.
