Population genetics of human NFKB1 and NFKB1 variants in patients with CVID or related conditions. (A) The distribution of consensus negative selection (CoNeS) for genes underlying autosomal recessive (AR) IEI, AD IEI, and AR/AD IEI. NFKB1 (red line) falls within the category of AD IEI. (B) Intolerance to functional variation along the NFKB1 genic region, as measured by the subRVIS percentiles. The protein domains were annotated with the Conserved Domain Database (CDD). The subregions were defined as the regions within the gene aligning with the CDD and the unaligned regions were the regions lying between CDD alignments. The numbers in parentheses indicate the ID of the sequence in the CDD. (C) Schematic illustration of NFKB1 variants in the NFKB1 gene. Variants tested LOF, hypomorphic, and neutral are colored red, orange, and blue, respectively. New variants identified in this study are underlined.