We developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient’s standardized phenotypic features and subjects the data to interactome network-based prioritization. This algorithm was thoroughly benchmarked using a synthetic patient-cohort, and was subsequently tested on a widely heterogeneous prospective, real-world series of 135 families affected by Hereditary Spastic Paraplegia (HSP) and/or Cerebellar Ataxia (CA). Data available in this repository: A Pheno dataset containing 82 patients with the causal gene and associated patient HPO terms. A ClinVar dataset containing 66,800 pathogenic variants in a VCF file. Benchmark: The optimal number of HPOs required for gene prioritization in 82 patients from a real-world cohort. Benchmark: The results of prioritizing known and candidate disease genes using ClinPrior in 66,800 synthetic WES analysed.