KLHL24 is a cullin 3-based E3 ubiquitin ligase substrate adaptor that regulates protein turnover through targeted ubiquitination and degradation 1. Its primary function is maintaining intermediate filament stability and degradation balance essential for skin integrity 1. As part of the BCR(KLHL24) E3 ubiquitin ligase complex, KLHL24 mediates ubiquitination of keratin 14 (KRT14) and controls its levels during keratinocyte differentiation 1. In cardiac tissue, KLHL24 degradation substrates include multiple intermediate filament proteins—desmin, synemin, and vimentin—whose excessive degradation drives pathology 2. Pathogenic mutations (primarily start-codon variants) produce stabilized KLHL24 truncations with abolished autoubiquitination, leading to excessive substrate degradation 1. This gain-of-function mechanism causes epidermolysis bullosa simplex with cutaneous fragility and recently recognized cardiomyopathy presentations 3. KLHL24 mutations are associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular non-compaction, with autosomal dominant and recessive inheritance patterns documented 456. KLHL24-associated cardiomyopathy involves intermediate filament degradation, mitochondrial dysfunction, and fibrotic remodeling 2. The ClinGen Expert Panel assigned KLHL24 moderate evidence classification for HCM causation 45.