Abstract Background and Aims Individuals with heterozygous pathogenic variants in COL4A3/COL4A4 or also known as autosomal dominant Alport syndrome (ADAS) are increasingly diagnosed and show a wide spectrum of disease. Factors contributing to these different outcomes are not well understood. Here we study a cohort of patients with pathogenic (P) or likely pathogenic (LP) variants in COL4A3/COL4A4 with slow and rapid progression to evaluate risk factors associated with the condition. Method A retrospective observational multicenter study was performed in a cohort of individuals with heterozygous P and LP in COL4A3/COL4A4. Criteria were established to classify patients into rapid (RP) and slow progression (SP) (Fig. 1). In this study, we compared both cohorts and identified risk factors of rapid progression using T-score for numeric variables or Chi square for categoric variables. For the numerical variables that were correlated with RP, a cut-off point was established fitting the data with a regression curve. Further analyses are ongoing. Results A total of 374 patients were studied, the progression of the disease was classified in 135 individuals: 82 with RP (60.7%) and 53 SP (39.3%). The remaining patients couldn't be classified due to age or missing data during follow-up. The mean age at diagnosis of classified patients was 46.61 years (SD 17.46), with 65% being women. Genetic variant distribution was COL4A3 38%, COL4A4 58%, and digenic 4%. At diagnosis, 72% of patients had albuminuria or proteinuria (mean age of diagnosis: 50 years). Among these, 52.7% had ACR or PCR greater than 300 or 500 mg/gCr, with mean ACR at 445.92 mg/gCr (SD 587.54, max 2240 mg/g) and mean PCR at 968.38 (SD 1422, max 10633). 94% individuals had hematuria (mean age at diagnosis: 36.27 years). Forty-nine patients (36%) had CKD G-5, with a mean age of diagnosis of 53.08 years (SD 12.42). The mean eGFR was 67.56 (SD 30.56 ml/min). Results of kidney biopsy were available for 51 patients. 73 individuals had hypertension (HTN) with a mean age at diagnosis of 46.30 years (SD 13.81). A total of 82 patients responded to personal habits questionnaire. With all the variables studied, a total of 4 main variables were associated with RP. Conclusion The main variables associated with a worse outcome in individuals with heterozygous pathogenic variants in COL4A3/COL4A4 is the presence of albuminuria/proteinuria, HTN, age at diagnosis of HTN and age at diagnosis of the disease. Smoking has also been associated with a worse outcome when an exposure time over 11.8 years. More studies are still needed to understand the reasons for the huge phenotypic variability of this condition.