Desmin is a muscle-specific intermediate filament protein, which plays a significant role in providing structural integrity of cardiomyocytes by connecting different cell organelles and multi-protein complexes.1 Pathogenic DES mutations cause different cardiomyopathies and skeletal myopathies.2 The most obvious hallmark of pathogenic DES mutations is an aberrant cytoplasmic desmin accumulation.3 However, driven by a broad clinical application of next-generation sequencing techniques and advanced classification criteria, the number of variants of unknown significance increased significantly during the last years. Especially, the impact of DES variants within the N-terminal head domain on the filament assembly is widely unknown.