Intracranial saccular aneurysms (IAs) are balloon-like or small berry defects in the wall of the major intracranial artery. Both environmental and genetic factors have been linked to the formation of IAs, but genetic risk factors of IAs are largely unknown. To identify additional genes responsible for IA development, whole exome sequencing of the patients from seven selected families was performed. One of the identified variants found in all five affected members of one family was a missense mutation in the highly conserved triple-helix region of the collagen COL22A1 isoform, the function of which has not been previously known. This mutant variant was examined in zebrafish embryonic and adult models. We demonstrated that COL22A1 is expressed in adjacent to the eyes, in the cranial tissues, in the myotendinous junctions, and in perivascular cells in the head region of the embryos. Early global overexpression of the human mutant but not wild-type COL22A1 in the zebrafish embryos interfered with epiboly movements during gastrulation due to the retention of the mutant protein in the cytoplasmic domain that led to an induction of Endoplasmic reticulum stress response. Inducible overexpression of the human mutant protein at a later stage resulted in the increased percentage of embryos with hemorrhages compared with the wild type protein. These data further suggest that the mutation has a deleterious dominant effect. We then used TALEN-engineered nucleases to generate a loss-of-function mutant in zebrafish col22a1. The homozygous null mutants were viable as adults but exhibited increased abnormal blood accumulations in the eyes and cranial regions, suggestive of hemorrhages. In addition, hemorrhages were present in the trunks of these adults caused by rupture of blood vessels. Furthermore, adult mutants are more susceptible to excessive forced overload cardiac stress than wild type siblings and have increased number of hemorrhages. We also demonstrated that the homozygous embryos show increased sensitivity to cardiovascular stress and exhibit greater frequency of intracranial hemorrhages, which can be partially rescued by the transient expression of wild type human COL22A1. The mutant embryos also exhibited increased vascular permeability as demonstrated by 10 kDa dextran injection into the circulation of 3 and 4-day post fertilization embryos. Our results argue that the function of COL22A1 is important in maintaining vascular integrity and that mutations in COL22A1 are one of genetic causes for intracranial aneurysms in humans.