A general probabilistic fatigue crack growth prediction methodology for accurate and efficient damage prognosis is proposed in this paper. This methodology consists two major parts. First, the realistic random loading is transformed to an equivalent constant amplitude loading process based on a recently developed mechanism model. This transformation avoids the cycle-by-cycle calculation of fatigue crack growth under variable amplitude loading. Following this, an inverse first-order reliability method (IFORM) is used to evaluate the fatigue crack growth at an arbitrary reliability level. Inverse FORM method does not require a large number of function evaluations compared to the direct Monte Carlo simulation. Computational cost is significantly reduced and the proposed method is very suitable for real-time damage prognosis. Numerical examples are used to demonstrate the proposed method. Various experimental data under variable amplitude loading are collected and model predictions are compared with experimental data for model validation.