Hyaluronic acid (HA) is abundantly present in the extracellular matrix (ECM) and reported to have a functional role during embryonic development. Among ECM components, HA has one of the fastest rates of turnover and is facilitated by hyaluronidases (HYALs). HYAL1 and HYAL2 are the predominant HYALs associated with the HA catabolism in somatic tissues. HYAL2 being a GPI-anchored cell-surface hyaluronidase is presumed to generate HA fragments (10-20 kDa) from large-sized extracellular HA (>200 kDa) followed by further degradation in the lysosomes into tetrasaccharides. Hyal2 knockout (KO) mice displayed craniofacial abnormalities and severe pre-weaning lethality. High frequency ultrasound of Hyal2 KO mouse hearts revealed atrial dilation and 50 % of Hyal2 KO mice exhibited a triatrial heart (cor triatriatum). Two separate mutations- K148R and P250L in HYAL2 were found to be associated with syndromic cleft palate. Recently, whole exome sequencing revealed seven new HYAL2 variants and we hypothesized that these gene variants interfere with the cellular role of HYAL2 by affecting its stability and cell-surface localization. Very low or a complete absence of expression were observed from the variants and the cell-surface localization of HYAL2 were severely compromised. Our biochemical analysis confirms that these seven variants are novel HYAL2 mutations. Levels of HA during different stages of embryonic development are finely regulated. The action of HYAL2 towards HA removal can be explained by the excessive accumulation of HA in Hyal2 KO mouse tissues. But, assaying the activity of HYAL2 directly has been a challenge in the field likely due to the lack of enough information on its mechanism of action. We speculate that HYAL2’s activity is regulated to allow its activation only at specific times. Searching for possible interacting protein partners of HYAL2 can provide mechanistic insight into the HYAL2 regulation. We employed proximity labeling system to report a library of possible interactors of HYAL2 that can be further validated experimentally to delineate their cellular function in the HYAL2 interactome. The results reported herein, define an extensive network of interactions of HYAL2 that may facilitate identification of HYAL2 regulators which can be pivotal to assay the activity of HYAL2 in the future.