(A) Total unique germline and de novo variants reported in ClinVar [52] as ‘pathogenic’, ‘likely pathogenic’, ‘associated’ or ‘risk factor. Somatic gene variants, contiguous copy-number variants, and gene variants not accompanied by a human disease condition were excluded from these counts. It is important to note that some patient mutations reported in the scientific literature may not have been submitted or updated by authors to the ClinVar database at the time of writing and thus are not included here. Disease causing variants in more upstream MLKL signalling modulators including death receptors, pattern recognition receptors, interferons and the NF-κB pathway are not presented here but are described in recent reviews [87–90]. (B) Summed global Minor Allele Frequency (MAF) of Missense and Loss of Function (LOF) variants as annotated by gnomAD at time of writing, (n = >280 000 alleles sequenced) [54]. Missense and LOF alleles flagged as ‘low confidence’ or ‘variant quality/annotation dubious’, alleles unique to non-canonical transcripts (with exception of CFLAR, where both long and short forms were included) or alleles with MAFs > 0.5 were excluded. (C) The top 10 missense variants used in calculating summed missense allele frequency in (B) and their global allele frequency plotted according to position in protein. *TICAM1 pPro367dup MAF = 0.3.