The specific pathogenesis of FOP is not yet clear. This is because the early phenotype is easily confused with other diseases. Common misdiagnosis include cancer (bone sarcomas), aggressive juvenile fibromatosis, and fibrous dysplasia.​ 

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FOP typically starts off with a mutation in the ACVR1/ALK2 gene. A variety of mutations can occur that lead to FOP, including Q207E, G328W, R258S​, and R206H. The most common of the mutations listed is the R206H gain of function mutation  .

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Normally, this gene encodes for a BMP receptor, the activin A1 receptor type. This receptor is an important player in the bone morphogenetic protein (BMP) signalling pathway. The mutations listed occur in regions involved in receptor regulation such as the Gs and protein kinase domains. Thus, these mutations can lead to the over activation of the BMP signalling pathway and cause inappropriate bone formation in soft tissue. Overall, they disrupt the process of normal tissue repair.​

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Tissue inflammation, which occurs due to pro inflammatory cytokines and mast cells, recruit immune cells and mesenchymal progenitors. Normally, this would eventually lead to regular tissue repair. However, when the BMP signalling pathway is dysregulated and over activated, the recruited mesenchymal progenitors abruptly differentiate into chondrocytes and osteoblasts, forming bone.

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​​​Loss of inhibition by FKBP12 inhibitory proteins also keeps the ACVR1/ALK2 gene weakly active even without BMP stimulation. This drives heterotopic ossification and episodic bone formation in soft tissue which accumulates over time, leading to progressive disability.

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Accordingly, abnormal activation of SMAD1/5/8 downstream of ACVR1 contributes to enhanced ossification processes​, leading to crosstalk with other signalling pathways like TGF beta which exacerbates the disease  .

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