UNLABELLED: While variant is an adverse prognosis factor in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), current clinical prognosis and variation feature analysis of alterations remain limited. We evaluated 333 MDS/AML patients with mutations, single nucleotide polymorphisms (SNPs), and wild-type to characterize clinical features and identify prognostic factors using next-generation sequencing (NGS) data. Interpretation requires caution due to sample size limitations, particularly in subgroup analyses. Multivariate analysis identified age, gender, cytogenetic risk, transplantation, white blood cell (WBC) count, status, and variant allele frequency (VAF) > 40% as independent prognostic factors. Patients with mutations ( = 45) had significantly worse overall survival (OS) and disease-free survival (DFS) (2-year OS: 34.94%; DFS: 38.26%) compared to those with SNPs ( = 84; 2-year OS: 77.25%; DFS: 87.54%;  < 0.001) and wild-type patients ( = 204; 2-year OS: 63.25%; DFS: 70.72%;  < 0.05). Notably, SNP carriers exhibited comparable or superior survival to wild-type patients. Focusing on the mutated cases, we identified as a possible disadvantageous prognosis factor among the coexistent gene mutations of , suggesting that a potential dual-gene (-) mutation signature is associated with shorter survival. Therapeutic analysis revealed that transplantation improved survival in variant patients compared to chemotherapy alone, supporting its role as an effective intervention. Our findings highlight the prognostic significance of alterations in MDS/AML and underscore the importance of karyotype risk stratification, post-transplant relapse prevention, and mutation monitoring to optimize outcomes. Future studies with larger cohorts are needed to validate these results. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00792-z.