The enormous number of variants of unknown significance in humans as well as allelic variation of causative mutations result in a high degree of interindividual variance in clinical presentation of disease. Genotype-phenotype correlations for allelic variations are therefore hard to identify by genetics alone. This also applies to rare diseases, where a mixture of splice-site, nonsense/frameshift and missense point mutations in combination with putative modifiers define penetrance and severity of disease. To analyze interindividual variation in phenotypic severity and assign pathogenic mechanisms to different disease phenotypes we analyze the impact of allelic variance on protein interaction networks, using ciliopathies, a group of rare diseases as a paradigm. Combining CRISPR-Cas based knock-down, affinity proteomics to isolate protein interactions, quantitative mass-spectrometry and computational modeling (Boldt et al., Nature Comm. 2016) we analyze the impact of mutations on protein-protein interaction networks. This allows to identify variants that affect molecular functions relevant to disease pathogenesis, and exclude those that are not. (Beyer et al., Mol.Cell.Prot 2018). CRISPR-Cas mediated gene-editing can further be used to study the impact of a specific variance in a protein of interest under physiological and in pathophysiological conditions. This allows analysis of genetic threshold effects of specific variants like missense mutations within protein interaction networks. We can further investigate the role of protein diversity generated through splice events and gene-regulatory-activities. The versatility of the approach enables a multiplicity of possible investigations linking functional proteomic analysis to human molecular genetics as well as identify pathogenic mechanisms for individual clinical features.