The BMPR2 c.354T>C variant is a missense variant predicted to cause a cysteine to tryptophan substitution at amino acid position 118 (p.Cys118Trp). The variant is absent from gnomAD exomes v.2.1.1 controls and gnomAD genomes v3.0 (PM2_supporting). More than 4 unrelated pulmonary arterial hypertension probands were identified with this variant (PMID: 10973254, PMID: 32255665, PMID: 33007923, and PMID: 31727138) (PS4). In one multigenerational family, the variant segregated with PAH in at least 3 family members (PMID: 10973254) (PP1). BMPR2 p.Cys118Trp is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID: 9886286, PMID: 12221115, PMID: 12045205, PMID: 16429395) (PM1_strong). Several well-controlled in vitro functional assays provided variant-specific evidence of protein loss of function (PMID: 25688877, PMID: 12221115, and PMID: 32255665) (PS3). In silico prediction (REVEL =0.9279) is consistent with a pathogenic effect for this variant (PP3). Additionally, another variant in the same codon, BMPR2 (NM_001204.7):c.353G>A:(p.Cys118Tyr), was classified as likely pathogenic (PM5_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4, PM1_strong, PM2_supporting, PM5_supporting, PP3, PP1 (VCEP specification version v 1.1, 1/18/2024).