The pathophysiological basis for progressive cardiac conduction disorder (PCCD) and idiopathic ventricular fibrillation (iVF) often remains unknown. While a genetic origin has been anticipated, only a few gene mutations associated with these diseases were reported so far. Using a candidate gene approach, we identified in a patient with PCCD and iVF a heterozygous mutation in the KCNK17 gene which encodes the two-pore domain potassium (K_2P) channel TASK-4. The identified mutation (p. G88R, glycine to arginine exchange) is located in a highly conserved protein domain in the first extracellular loop of TASK-4 and was absent in ethnically-matched, unrelated controls (n = 379). In two-electrode voltage-clamp recordings the TASK4-G88R mutation generated three-fold increased outward currents. Chemiluminescence assays and live cell imaging demonstrated that this gain-of-function is caused by an altered channel gating, since surface expression of TASK4-G88R was not altered. The gain-of-function is not caused by an altered extracellular pH-sensitivity of the mutant TASK-4 channels. Strikingly, the gain-of-function of G88R is dominant-active and confers to co-expressed wild-type channels. Finally, two mutations (G88E, G88K) similarly resulted in a gain-of-function, indicating that the glycine residue at position 88 is a structural determinant for channel gating at the outer vestibule. Summarizing, we identified the TASK-4 residue 88 (glycine) as an important site for normal gating behavior and showed that a dominant-active gain-of-function mutation (p. G88R) in TASK-4 is associated with PCCD and iVF. Our data highlight that cardiac K_2P channels might have a more prominent role in the generation of cardiac arrhythmias as initially expected.