Explaining macroevolutionary divergence in light of population genetics requires understanding the extent to which the patterns of mutational input contribute to long-term trends. In the context of quantitative traits, mutational input is typically described by the mutational variance-covariance matrix, the M-matrix, which summarizes phenotypic variances and covariances introduced by new mutations per generation. However, as a summary statistic, the M-matrix does not fully capture all the relevant information from the underlying mutational architecture, and there exist a myriad of possible underlying mutational architectures that give rise to the same M-matrix. Using individual-based simulations, we demonstrate mutational architectures that produce the same M-matrix can lead to different levels of constraint on evolution and result in difference in within-population genetic variance, between-population divergence, and rate of adaptation. In particular, the rate of adaptation and that of neutral evolution are both reduced when a greater proportion of loci are pleiotropic. Our results reveal that aspects of mutational input not reflected by the M-matrix can have a profound impact on long-term evolution and suggest it is important to take them into account in order to connect patterns of long-term phenotypic evolution to underlying microevolutionary mechanisms.