All individuals with classic FOP have malformations of the great toes and, in approximately 50% of patients, the thumbs. These changes in the skeleton are present at birth (congenital) and are the first clinical signs of this disorder. The most common skeletal malformation associated with FOP is a shortened great toe with a malformed distal first metatarsal and a missing or abnormal first phalanx and/or interphalangeal joint. Other malformations of the toes and fingers may include inward turning of the great toe toward the other toes (hallux valgus), abnormally short fingers and toes (microdactyly), and/or permanent fixation of the fifth finger in a bent position (clinodactyly). Other congenital signs of FOP include proximal medial tibial osteochondromas, malformation of the upper part of the spinal column (cervical vertebrae), and an abnormally short broad neck of the bone in the thigh that extends from the knee to the pelvis (femur).

Progressive bone formation in connective tissues (heterotopic ossification) usually occurs during early childhood, and progresses throughout life. The abnormal development of bone may occur spontaneously but often occurs following an episode of soft tissue injury or a viral illness. The first sign of heterotopic ossification is the appearance of firm tender swellings on certain parts of the body, especially the back, neck, and/or shoulders. These soft tissue swellings mature through a cartilage-to-bone (endochondral) pathway to form mature heterotopic bone. The ectopic bone growth usually involves tendons, ligaments, skeletal muscle tissue, and connective tissues such as fascia and aponeuroses. In many cases, pain and stiffness occurs in these areas. On some occasions, a low-grade fever may herald the development of these swellings. Although the swellings eventually regress, they usually harden into mature bone as they decrease in size.

In the affected areas, bone slowly replaces connective tissue. The neck, back, chest, arms, and legs are usually the first areas affected. The disease eventually affects the hips, ankles, wrists, elbows, shoulders, and/or jaw as well as the abdominal wall. In some affected individuals, the progression of bone development may be rapid; in others, the process may be gradual. Even among identical twins, the disease progression may vary greatly, reflecting different environment impacts such as traumatic episodes.

Chronic swelling in various parts of the body is a common physical characteristic of individuals with FOP. Swelling may occur coordinately with the abnormal bone formation that characterizes FOP, or it may occur when recently-formed bone presses on lymphatic vessels, obstructing the flow of tissue fluid. In addition, swelling may also be caused by a lack of pumping action within the hardened (ossified) muscle and can cause blood and tissue fluids to pool in a limb (e.g., arms and/or legs).

Abnormal development of bone eventually leads to stiffness and limited movement of affected joints. If the jaw is involved, affected individuals may have trouble eating and/or speaking. In addition, abnormal development of bone may lead to progressive deformity of the spine including side-to-side (scoliosis) and, in some cases, front-to-back curvature of the spine (kyphosis). As is the case for skeletal bone, the bone that develops in abnormal areas may fracture and then undergo fracture repair. As the disease progresses, individuals with FOP experience increasingly limited mobility that causes problems with balance, difficulty walking and/or sitting, and/or severely restricted movement.

FOP may eventually result in complete immobilization. Affected individuals may experience progressive pain and stiffness in affected areas, complete fusion of the spine, and/or pain in affected areas of the body caused by abnormal bony growths that compress the nerves in these areas (entrapment neuropathies). As mobility begins to deteriorate, affected individuals may exhibit an increased susceptibility to respiratory infection or right sided congestive heart failure. Hearing impairment is seen in approximately 50% of affected individuals. In some cases of more severe forms of variant FOP, individuals may exhibit hair loss or mild cognitive delay.