The mitral valve prolapse (MVP) affects about 3% of the population and remains one of the most common indications for valvular surgery. Although the genetic basis of MVP is acknowledged since we identified FLNA (Filamin-A; FlnA) as the first gene responsible for this life threatening disease, the genes involved and identified remain scarce. To identify new genes and genetic variants, we performed whole exome sequencing of 20 familial cases of isolated MVP. In a family suffering a mild form of MVP, we found a non-synonymous rare variant in the Rac1 specific GTPase Activating Protein ARHGAP24 gene encoding ARHGAP24-D92N mutant protein. Interestingly, ARHGAP24 protein was previously shown to interact with FlnA and was thus named FilGAP. Also, our previous studies established the potential involvement of FilGAP and small GTPases (RhoA, Rac1) in FlnA-associated MVP. Complete exon sequencing of ARHGAP24 in 95 additional MVP patients identified, according to genetic databases, 3 other non-synonymous rare sequence variations encoding FilGAP-R95Q; P417H and T481M mutants. Based on this genetic analysis, HEK293 cells were used to analyze the effects of theses mutations. The role of FilGAP is to decrease Rac1 activity and we showed that all the mutations identified are loss of function mutations mutated leading to increase Rac1 activity. Increased spreading of mutant FilGAP expressing cells corroborates this increase in Rac activity. In addition, we showed FlnA poorly co-immunoprecipitates FilGAP-P417H and T481M suggesting reduced FlnA/FilGAP interaction might be the molecular mechanism responsible for the loss of function of these two mutations. The molecular mechanism involved for the two other mutations (R92Q and D92N) is under investigations. Together, we identified a new gene involved, like FlnA, in cellular mechanical stress response pathway suggesting common physiopathological mechanisms are at work in FilGAP and FlnA associated valvulopathy.