SRP071249 PRJNA301897 Saccharomyces cerevisiae Genome sequencing Cryptic genetic variants that do not typically influence traits can interact with each other and mutations to unexpectedly show phenotypic effects. The genetic and molecular basis of this phenomenon, which is known as 'phenotypic capacitance' (or 'capacitance'), remains incompletely understood. Here, we provide detailed new insights into capacitance by genetically dissecting 17 independent instances of the same cryptic phenotype in a yeast cross. Roughly half of the cases involve a spontaneous mutation in a 'capacitor' gene uncovering sets of cryptic variants. These capacitating mutations differ in the total number and specific identities of cryptic variants they interact with to induce the same phenotypic change. However, we also show that capacitance can arise without functional disruption of capacitors due to higher-order genetic interactions that only involve cryptic variants. Our results may be relevant to other species and disease, as most of the capacitating mutations and cryptic variants identified in our study are components of the evolutionarily conserved and oncogenic Ras signaling pathway. Saccharomyces cerevisiae