Recurrent spontaneous abortion (RSA) is one of the causes of infertility following fetus creation. This can lead to the reduction of the fertility rate in various populations. Collagens’ structure, their ratios to each other, and their connections to various receptors are some of the key players in successful fetus implantation. Among them, COL12A1 has a special role because of its very high expression in the uterus. Also, the CD44 protein as a cell adhesion molecule which is a receptor for some of the collagens plays a significant role in RSA. The aim of the study is to investigate the association of CD44-rs13347 and CoL12A1-rs970547 with RSA in a case-control base, and the impacts of COL12A1-rs970547 on protein structure. To genotype single nucleotide polymorphisms (SNPs) of the genes, the PCR-RFLP method was performed on the 124 RSA and 124 control samples. The results were analyzed by the binary-logistic regression method (p-value≤0.05). The SNPs’ effect on the proteins’ structure was analyzed by PSIPRED, HOPE, LOMET, and chimera-USF. Proteins signaling pathway and physical interaction between COL12A1 and CD44 were investigated by KEGG-pathway and GeneMANIA, respectively. Results showed that TT (P= 0.032) genotype of CD44-rs13347 increased the risk of RSA while the CT (P= 0.027) genotype of CD44-rs13347, TT (P= 0.044) genotype, and T (P= 0.019) mutant allele of COL12A1-rs970547 decreased the risk of RSA. Moreover, 3D structures investigation indicated that COL12A1-rs970547 may affect the structure of COL12A1 and its interaction with Integrins. The analysis of the signaling pathway and proteins’ physical interaction network also revealed the interaction of COL12A1 and CD44 with MMP2 and MMP9. On this base, we recommend that T allele of COL12A1-rs970547 has a protective feature against RSA, especially in homozygous form by improving their interaction with Integrins and probably MMPs, too. On the other hand, the CD44-rs13347 probably has an indirect influence on th
