Fig. 3: Protein-coding variant effects in SVEP1 on ADP platelet activation, protein domains and cross-species conservation of 229G, 2702D and surrounding sequence.

Association of aggregated rare deleterious coding variants in SVEP1 and ADP-induced platelet aggregation. P values in panel A are from two-sided score tests with no adjustment for multiple testing. A Using a leave-one-out approach, we identified a rare coding variant (rs61751937) that explains most of the association. The first orange dot represents the overall gene-based test including the full set of 64 variants. Subsequent orange dots represent the -log10(P) of the gene-based test when the specific labeled variant was left out, and blue bars represent minor allele frequency of specific variant being left out. B Schematic protein structure of SVEP1. rs61751937 substitutes glycine for arginine at position 229. Another variant in SVEP1 has been associated with coronary artery disease which substitutes glycine for aspartic acid at position 2702. C Using UniProt, a total of 98 orthologs were identified for the largest human SVEP1 protein isoform and aligned. Alignments were visualized in MAFFT (v.7, https://mafft.cbrc.jp/alignment/server/, Katoh et al. 2017)⁵⁹ with ClustalW coloring. Both amino acids 229G and 2702D are highly conserved across diverse species, as well as their surrounding protein domains. The sequence identifiers and genus and species are given in Supplementary Data 3.