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Summary Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations., Highlights • Arrhythmia was a hallmark phenotype in E99K hiPSC-CMs, provoked by altered [Ca2+] • Monoallelic expression of E99K cardiac actin affects only half the cell population • Severe phenotypes in father's E99K hiPSC-CMs suggest influence of age & epigenetics • Mechanistic insight facilitated drug rescue with combined dantroline/ranolazine, In this article Smith, Denning and colleagues show that the E99K-ACTC1 cardiac actin mutation is a central cause of HCM, but the three-way interaction between the primary genetic lesion, background genetics, and donor patient age may influence the pathogenic phenotype. Pharmacological rescue experiments demonstrated dual dantroline/ranolazine to be an effective treatment.