Single nucleotide polymorphisms (SNPs), including PNPLA3 rs738409 and SERPINA1 rs17580, have been identified as risk modifiers in the progression fatty liver disease (alcoholic (ALD) or non-alcoholic (NAFLD)). While PNPLA3 has been studied in various settings, the value of both SNPs has so far not been addressed in a real-world cohort of subjects referred for a diagnostic work-up of liver disease. Thus, liver disease severity was assessed in 1257 consecutive patients with suspected ALD or NAFLD at the time of referral to a tertiary center. Advanced chronic liver disease (ACLD) was present in 309 (24.6%) patients and clinically significant portal hypertension (CSPH) was present in 185 (14.7%) patients. The PNPLA3 G-allele was independently associated with a higher liver stiffness measurement (LSM; adjusted B: 2.707 (1.435–3.979), p p p = 0.004). While the SERPINA1 Z-allele was not associated with a higher LSM or the presence of ACLD, it was independently associated with higher odds of CSPH (aOR: 2.122 (1.067–4.218), p = 0.032). Associations of the PNPLA3 G-allele and the SERPINA1 Z-allele with CSPH were maintained independently of each other. The presence of both risk variants further increased the likelihood of ACLD and CSPH.