Why is a frameshift missense mutation more likely to have a severe effect on phenotype than a nucleotide-pair substitution missense mutation in the same protein? why is a frameshift missense mutation more likely to have a severe effect on phenotype than a nucleotide-pair substitution missense mutation in the same protein? a frameshift missense will cause the codons to be out of order, but a substitution missense does not change the order of the codons. a substitution missense mutation causes the protein to be shorter and thus non-functional. a substitution missense affects only one codon, but a frameshift missense affects all codons downstream of the frameshift. a frameshift missense mutation will cause an early stop codon, but a substitution missense might be silent.