A common fingerprint linking arrhythmia-associated variants N53I in EF2 (Holt et al., 2020) with D95V/H in EF3 and D131V/H/E in EF4 (Dal Cortivo et al., 2022) seems to be the fact that the single mutation can perturb to various extent protein tertiary structure, but all variants alter the protein intramolecular dynamics, affecting and destabilizing the N-terminal domain, which has been suggested to permit the functional recognition of RyR2 target via allosteric interactions (Westerlund and Delemotte, 2018; Dal Cortivo et al., 2022). Here, GUF1 is linked to Arrhythmia.