Abstract <p>Aggregation analysis of rare genetic variants at the level of biological pathways is a promising approach for investigating predisposition to multifactorial diseases. The aim of this study was to investigate the contribution of the cumulative burden of rare, potentially pathogenic (high-impact, HI) variants to the development of life-threatening complications of COVID-19. We performed a gene set analysis for 77 COVID-19 patients with whole-exome sequencing data. Gene sets were compiled using the AMIGO Gene Ontology database for creating gene sets related to sepsis, acute kidney injury (AKI), pulmonary embolism (PE), and other conditions (<i>n</i> = 21). The contribution of HI variants was assessed using the Cochran–Mantel–Haenszel method. The analysis revealed a central role for ion transport genes and extracellular matrix organization genes in the pathogenesis of most complications. The largest number of associated biological processes was identified for acute kidney injury (AKI) and pulmonary embolism (PE). Sepsis was associated only with blood coagulation genes. No associations were found with genes of innate or adaptive immunity. Our data support the hypothesis that genetic predisposition to severe complications from SARS-CoV-2 infection is more likely associated with vulnerability of fundamental homeostatic processes under conditions of systemic inflammation rather than with variability in the immune response. This opens up prospects for searching for new therapeutic targets aimed at correcting ionic balance and tissue remodeling.</p>