MOTIVATION: Accurately predicting the impact of single-point mutations on protein stability is crucial for elucidating molecular mechanisms underlying diseases in life sciences and advancing protein engineering in biotechnology. With recent advances in deep learning and protein structure prediction, deep learning approaches are expected to surpass existing methods for predicting protein thermostability. However, structure-based deep learning models, specifically convolutional neural networks, are affected by orientation biases, leading to inconsistent predictions with respect to the input protein orientation. RESULTS: In this study, we present OrgNet, a novel orientation-gnostic deep learning model using 3D convolutional neural networks to predict protein thermostability change upon point mutation. OrgNet encodes protein structures as voxel grids, enabling the model to capture fine-grained, spatially localized atomic features. OrgNet implements spatial transforms to standardize input protein orientations, thus eliminating orientation bias problem. When evaluated on established benchmarks, including Ssym and S669, OrgNet achieves state-of-the-art performance, demonstrating superior accuracy and robust performance compared to existing methods. AVAILABILITY AND IMPLEMENTATION: OrgNet is available at https://github.com/i-Molecule/OrgNet.