Abstract Factors and possible constraints to extremely large spread of effective climate sensitivity (ECS) ranging about 2.1–10.4 K are examined by using a large-member ensemble of quadrupling CO2 experiments with an atmospheric general circulation model (AGCM). The ensemble, called the multiparameter multiphysics ensemble (MPMPE), consists of both parametric and structural uncertainties in parameterizations of cloud, cumulus convection, and turbulence based on two different versions of AGCM. The sum of the low- and middle-cloud shortwave feedback explains most of the ECS spread among the MPMPE members. For about half of the perturbed physics ensembles (PPEs) in the MPMPE, variation in lower-tropospheric mixing intensity (LTMI) corresponds well with the ECS variation, whereas it does not for the other half. In the latter PPEs, large spread in optically thick middle-cloud feedback over the equatorial ocean substantially affects the ECS, disrupting the LTMI–ECS relationship. Although observed LTMI can constrain uncertainty in the low-cloud feedback, total uncertainty of the ECS among the MPMPE cannot solely be explained by the LTMI, suggesting a limitation of single emergent constraint for the ECS.