Gain-of-function BRAF variants leading to an increase in kinase activity are most commonly associated with cardio-facio-cutaneous syndrome; however, gain-of-function variants that result in reduced kinase activity and impaired stimulation of MAP 2K1/2 and ERK1/2 phosphorylation have also been observed [101, 105]. The gene discussed is MAPK3; the disease is cardiofaciocutaneous syndrome.