Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, characteristic facies (hypertelorism, downward-slanting palpebral fissures), congenital heart defects (e.g., pulmonary stenosis, hypertrophic cardiomyopathy), and developmental delays. Approximately 50% of NS cases are caused by heterozygous mutations in PTPN11 encoding Src homology 2 domain-containing phosphatase 2 (SHP-2).The pathogenesis of the disease involves the phosphorylation of several proteins. In a Han Chinese NS pedigree exhibiting characteristic facies and growth retardation, whole-exome sequencing identified a heterozygous PTPN11 mutation (NM_001330437.2: c.923A>G, p.Asn308Ser) in seven affected individuals, demonstrating complete co-segregation.Structural modeling demonstrated that this mutation disrupts hydrogen bonding within the PTP domain, triggering conformational changes that destabilize SHP-2 autoinhibition. Phosphoproteomics showed that the phosphorylation level was significantly up-regulated after the mutation, and the differentially phosphorylated sites were mainly involved in multiple cross-talking pathways, which synergistically affected the activity of multiple signaling pathways, leading to the abnormalities of the broader signaling network. Functional validation in HEK293T cells confirmed RAS-MAPK pathway hyperactivation. The present study demonstrated that the PTPN11 c.923A>G (p.Asn308Ser) mutation is the responsible causative mutation in this NS family line with characteristic facies and short stature phenotype, mechanistically linking structural domain perturbations and multi-pathway phosphorylation imbalances.