In this issue of JEM, Bergson et al. (https://doi.org/10.1084/jem.20240827) identified variants in HMCN1 that co-segregate with and account for variations in disease severity in individuals with a diagnosis of epidermolysis bullosa simplex (EBS) resulting from pathogenic variants in KRT14. The authors show that hemicentin-1 binds keratin 14 at the protein level and that silencing HMCN1 expression disrupts the organization of K14-containing filaments in epidermal keratinocytes and their attachment to the extracellular matrix. These findings address the clinical heterogeneity observed in EBS, a rare genetic skin disorder, with general implications for all genodermatoses.