(A) Distribution of 1233 candidate SNVs binned into 89 exons of the CD91/LRP1 gene. Individual ligand binding domains are indicated. Interdomain regions that play no binding or membrane anchoring role are colored uniformly black. The inset figure shows the number of mutations per base in each domain. Vertical height of each bar indicates the number of SNPs falling within that exon. (B) Visualization of high-impact SNV –log(P value) score of change in stability energy between the SNV-altered CD91 and WT. Higher scores represent increased magnitude of change in stability energy compared with all other candidate SNVs. Red line was chosen at a Z score of 1.96, and points above this threshold have a P < 0.05. (C) Scatter plot of high-impact SNV effect on hsp90-CD91 binding interactions. Negative and positive scores represent increased binding or decreased ligand binding, respectively, in hsp90-altered CD91 receptors compared with WT reference binding energies. The 4 ligand binding domains of CD91 are color coded as indicated. Black arrows represent SNVs that appear in 4 individual patients with lung squamous cell carcinoma, and red arrows represent SNVs that appear in 4 individual patients with skin cutaneous melanoma. The position of each SNV is indicated by a number next to each arrow. (D and E) Stacked bar plot showing predicted high-impact SNVs in human samples of lung squamous cell carcinomas (D) or skin cutaneous melanoma (E) and the associated presence of CD8⁺ immune cells from transcriptomic data. RNA-Seq expression levels (in FPKM) are used as a proxy for CD8⁺ T cell presence. Solid bars indicate SNVs with –ΔΔG docking impact, and hatched bars indicate SNVs with +ΔΔG docking impact.