Precise pre-mRNA splicing is vital for appropriate protein translation where splice-disrupt variants may change the structure of transcripts and their encoded proteins, resulting in a complete loss of function or acquiring a new function. Splice-disrupt genomic variants are one of the causes of cancer-causing errors in gene expression. Little is known about splice-disrupt genomic variants. Here, pattern of splice-disrupt variants in different types of prostate cancer was investigated using huge deposited genomic variants in prostate cancer (21,842,764 variants). HLA-A, MSR1, and EGFR had the highest allele frequency of splice-disrupt variation in prostate cancer, castration-resistant prostate cancer, familial prostate cancer, and metastatic castration-resistant, respectively. Intron, followed by CDs and 3’UTR were enriched with the splice-disrupt mutations. Some splice-disrupt variants, on CDs of NCOR2, PTPRC, and CRP that were solely present in advanced metastatic castration-resistant prostate cancer. Damaging splice-disrupt variants were identified based on PolyPhen, SIFT, and GERP++ scores as well as clinical significance. Functional annotation of damaging splice-disrupt variants highlighted important cancer-associated functions including endocrine resistance, lipid metabolic process, steroid metabolic process, regulation of mitotic cell cycle, and regulation of metabolic process. This is the first study that profiles the splice-disrupt genomic variants and their target genes in prostate cancer.