Intellectual disability (ID) is a progressive disorder that affects around 1–3% of the world's population. The heterogeneity of intellectual disability makes it difficult to diagnose as a complete disease. Genetic factors and major mutations play a noticeable role in the development and progression of ID. There is a high need to explore novel variants that may lead to new insights into the progressive aspects of ID. In the current course of study, 31 samples of ID from different studies available on GEO (GSE77742, GSE74263, GSE90682, GSE98476, GSE108887, GSE145710, and PRJEB21964) datasets were taken for the study. These datasets were analyzed for differential gene expression and single nucleotide polymorphism (SNPs). The SNPs of high impact were compared with the differentially expressed genes. Comparison leads to the identification of the priority gene ie NPR3 gene. The identified priority gene further was evaluated for the effect of the mutation using a Mutation Taster. Structure comparison analysis of the wild and mutated proteins of the NPR3 gene was further carried out by UCSF Chimera. Structural analysis reveals the anomalies in protein expression affecting the regulations of the NPR3 gene. These findings identified a novel nonsense mutation (E222*) in the downregulated NPR3 gene that leads to anomalies in the regulation of its protein expression. This missense mutation reveals a major role in causing ID. Our study concludes that the decrease in the expression of the NPR3 gene causes delayed sensory, motor, and physiological functions of the human brain leading to neurodevelopmental delay that causes ID.