The BMPR2 c.1171G>A variant is a missense variant predicted to cause substitution of alanine to threonine at amino acid position 391 (p.(Ala391Thr)). The variant was absent in gnomAD v.4.1.0, so PM2_supporting is met (but not BA1, BS1 nor BS2). Computational predictor REVEL score is 0.86, which is ≥0.75, and AlphaMissense = 0.9729, so PP3 is met and BP4 is not met. This variant is located in the kinase domain (aa 203-504), hence PM1 is met. It does not affect known critical or non-critical amino acids. The variant has been reported in at least two presumably unrelated individuals with IPAH from French (PMID: 18356561) and Spanish cohorts (PMID: 33007923). Another individual with IPAH was reported in Machado et al. (2009) (PMID:19555857) but it was not clear whether it referred to the same individual as in PMID: 18356561, and another report of the French cohort (PMID: 25429696) likely referred to the same individual as in PMID: 18356561. Hence, PS4_supporting was met as the variant was found in >1 PAH patient. PP1, PS2, PM6 were not met due to the absence of co-segregation data. Experimental evidence demonstraed abolished BMPR2-SMAD signaling via a BRE2-Luc vector luciferase assay in murine embryonic endothelial cells that included appropriate controls and replicates (PS3 met). A different missense variant affecting the same amino acid, c.1172C>A p.(Ala391Asp), was reported in an IPAH individual (PMID: 31727138) but was scored as VUS (PM1, PM2_supporting, PM5_supporting, PP3) thus, PM5 was not met. In summary, this variant meets the criteria to be classified as a likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024).