Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structura predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe pheno- types can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domainand the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides po- tential evidence for a possible correlation between the severity of the phenotypes of HSP with the ex- tension of the changes in the protein structures of atlastin. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structura predictions could not detect gross changes in the mutant protein. And, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G> A (p.G410R), in a Structural progntions showed that the Tibetan activator nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan part of the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembr ane region of the molecule. Our results indicate that severe pheno- types can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides ten-tenality evidence for a possible correlation between the severity of the phenotypes of HSP with the ex-tension of the changes in the protein structures of atlastin.