Point mutations responsible for hypo- and afibrinogenemia are yielding new insights into amino acid side chains involved in the molecular processing, assembly, secretion, and domain stability of fibrinogen. Reverse phase chromatography, isoelectric focussing, electrospray mass spectrometry, and tryptic peptide mass mapping have shown that chains with heterozygous mutations of gamma 284 Gly-->Arg, B beta 316 Asp-->Tyr and gamma 371 Thr-->Ile are absent from plasma fibrinogen. The nonexpression of these mutations appears to result from perturbation of the five-stranded beta sheet of the D domain. We propose that this is due to retention of the variant in the endoplasmic reticulum and that in turn this leads to hypofibrinogenemia. Other mutations effect intracellular proteolysis and chain assembly. For example the mutation, A alpha 20 Val-->Asp, makes the protein a substrate for furin, which removes the first 19 residues of the A alpha chain as the mature molecule transits the trans golgi complex. Transient expression of gamma 153 Cys-->Arg chains together with A alpha and B beta chains suggests this mutation might perturb chain assembly, and the incorporation of mutations of B beta 353 Leu-->Arg or B beta 400 Gly-->Asp into intracellular fibrinogen precludes its subsequent export from host cells expressing fibrinogen genes. The graded severity of the hypo- and afibrinogenemias associated with homozygous A alpha chain truncations suggest the absolute minimal requirement for molecular assembly is the formation of the C terminal disulfide ring of the coiled coil.