Noonan syndrome: genes and variants

Genes linked to Noonan syndrome

• PTPN11: Tyrosine-protein phosphatase non-receptor type 11

  Its SHP2 phosphatase activity promotes RAS-MAPK signaling downstream of many receptor tyrosine kinases and cytokine receptors. Germline dysregulating variants cause Noonan-spectrum disorders, while somatic activating variants drive juvenile myelomonocytic leukemia and other cancers.

  44 disease-causing and 54 uncertain variants in PTPN11 are linked to Noonan syndrome.

• SOS1: Son of sevenless homolog 1

  It activates RAS by exchanging GDP for GTP downstream of receptor tyrosine kinases. Germline activating variants are a common cause of Noonan syndrome, while excessive SOS1-RAS signaling can contribute to cancer.

  30 disease-causing and 110 uncertain variants in SOS1 are linked to Noonan syndrome.

• RIT1: GTP-binding protein Rit1

  It transmits growth and stress signals through RAS-MAPK and related pathways and is important in cardiovascular and nervous-system development. Germline activating variants cause Noonan syndrome, often with a high frequency of hypertrophic cardiomyopathy.

  22 disease-causing and 113 uncertain variants in RIT1 are linked to Noonan syndrome.

• KRAS: GTPase KRas

  A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.

  16 disease-causing and 6 uncertain variants in KRAS are linked to Noonan syndrome.

• RAF1: RAF proto-oncogene serine/threonine-protein kinase

  It relays activated RAS signals to MEK and ERK and also participates in survival and developmental pathways. Germline activating variants cause Noonan syndrome and related RASopathies, while oncogenic activation contributes to selected cancers.

  14 disease-causing and 35 uncertain variants in RAF1 are linked to Noonan syndrome.

• BRAF: Serine/threonine-protein kinase B-raf

  It relays activated RAS signals through MEK and ERK to control proliferation, differentiation, and survival. Activating variants, especially V600E, drive melanoma and several other cancers and create sensitivity to pathway-directed therapies.

  11 disease-causing and 44 uncertain variants in BRAF are linked to Noonan syndrome.

• NRAS: GTPase NRas

  Its active GTP-bound state drives RAF-MEK-ERK and PI3K signaling downstream of growth-factor receptors. Somatic activating variants are common drivers of melanoma, leukemia, and other cancers, while germline activating variants can cause Noonan syndrome.

  9 disease-causing and 4 uncertain variants in NRAS are linked to Noonan syndrome.

• SOS2: Son of sevenless homolog 2

  It activates RAS by catalyzing GDP-GTP exchange downstream of growth-factor receptors. Germline activating variants cause Noonan syndrome, generally through increased RAS-MAPK signaling.

  8 disease-causing and 601 uncertain variants in SOS2 are linked to Noonan syndrome.

• MAPK1: Mitogen-activated protein kinase 1

  It converts upstream RAS-RAF-MEK signaling into phosphorylation of cytoplasmic and nuclear targets controlling proliferation, differentiation, and development. Germline dysregulating variants can cause neurodevelopmental RASopathy phenotypes, while pathway hyperactivation is common in cancer.

  4 disease-causing and 4 uncertain variants in MAPK1 are linked to Noonan syndrome.

• HRAS: GTPase HRas

  Its GTP-bound state activates RAF-MEK-ERK and other pathways downstream of growth-factor receptors. Somatic activating variants drive several cancers, while germline activating variants cause Costello syndrome.

  3 disease-causing and 0 uncertain variants in HRAS are linked to Noonan syndrome.

• MAP2K1: Dual specificity mitogen-activated protein kinase kinase 1

  It phosphorylates ERK1 and ERK2 downstream of RAF and thereby propagates RAS-MAPK growth and developmental signals. Activating somatic variants occur in several cancers, while germline activating variants can cause cardio-facio-cutaneous syndrome and related RASopathies.

  1 disease-causing and 4 uncertain variants in MAP2K1 are linked to Noonan syndrome.

• GJB2: Gap junction beta-2 protein

  Its connexin 26 channels support potassium and metabolite recycling within the cochlea and communication across epithelial gap junctions. Biallelic pathogenic variants are among the most common causes of congenital nonsyndromic hearing loss, while dominant variants can cause syndromic deafness with skin disease.

  1 disease-causing and 0 uncertain variants in GJB2 are linked to Noonan syndrome.

• PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

  Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.

  1 disease-causing and 0 uncertain variants in PIK3CA are linked to Noonan syndrome.

• MAP2K2: Dual specificity mitogen-activated protein kinase kinase 2

  It works with MEK1 to activate ERK signaling downstream of RAS and RAF. Germline activating variants can cause cardio-facio-cutaneous syndrome, while acquired activation can support oncogenic MAPK signaling and drug resistance.

  0 disease-causing and 3 uncertain variants in MAP2K2 are linked to Noonan syndrome.

• CBL: E3 ubiquitin-protein ligase CBL

  It limits receptor-tyrosine-kinase signaling by ubiquitinating activated receptors and promoting their internalization and degradation. Germline or somatic pathogenic variants can prolong RAS-MAPK signaling and cause Noonan-like developmental disease or myeloid malignancy.

  0 disease-causing and 2 uncertain variants in CBL are linked to Noonan syndrome.

• ARAF: Serine/threonine-protein kinase A-Raf

  It transmits RAS signals to the MEK-ERK pathway and participates in growth and developmental signaling. Activating germline or somatic variants can cause RASopathy phenotypes and have been identified as oncogenic drivers in selected tumors.

  0 disease-causing and 0 uncertain variants in ARAF are linked to Noonan syndrome.

• FGA: Fibrinogen alpha chain

  It contributes the alpha chains of fibrinogen, which thrombin converts into fibrin to form the structural mesh of blood clots. Pathogenic variants can cause afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, thrombosis, or certain hereditary amyloidoses.

  0 disease-causing and 0 uncertain variants in FGA are linked to Noonan syndrome.

• FGB: Fibrinogen beta chain

  It contributes the beta chains required for assembly and secretion of functional fibrinogen and subsequent fibrin-clot formation. Pathogenic variants can reduce fibrinogen quantity or alter clot properties, producing bleeding, thrombosis, or both.

  0 disease-causing and 0 uncertain variants in FGB are linked to Noonan syndrome.

• FGG: Fibrinogen gamma chain

  It contributes the gamma chains of fibrinogen and provides binding sites important for fibrin polymerization, platelet interactions, and clot stabilization. Pathogenic variants can cause quantitative or qualitative fibrinogen disorders and, in some alleles, hereditary renal amyloidosis.

  0 disease-causing and 0 uncertain variants in FGG are linked to Noonan syndrome.

• ITGA2B: Integrin alpha-IIb

  Together with ITGB3, it forms the major platelet fibrinogen receptor that becomes activated during platelet stimulation and drives aggregation. Biallelic loss-of-function variants cause Glanzmann thrombasthenia, a severe inherited platelet-aggregation disorder.

  0 disease-causing and 0 uncertain variants in ITGA2B are linked to Noonan syndrome.

• ITGB3: Integrin beta-3

  In platelets it pairs with ITGA2B to bind fibrinogen and mediate aggregation, while in other cells it forms integrins involved in matrix adhesion and signaling. Biallelic loss-of-function variants cause Glanzmann thrombasthenia.

  0 disease-causing and 0 uncertain variants in ITGB3 are linked to Noonan syndrome.

• MAPK3: Mitogen-activated protein kinase 3

  It works with ERK2 to transmit growth-factor and mitogen signals to transcriptional and cytoplasmic targets. Abnormal ERK activation is a hallmark of many RAS-MAPK-driven cancers and developmental syndromes.

  0 disease-causing and 0 uncertain variants in MAPK3 are linked to Noonan syndrome.

• SRC: Proto-oncogene tyrosine-protein kinase Src

  It integrates signals from growth-factor receptors, integrins, and other surface proteins to regulate proliferation, adhesion, migration, and survival. Persistent SRC-family signaling promotes invasion and therapy resistance in many cancers and remains an important therapeutic target.

  0 disease-causing and 0 uncertain variants in SRC are linked to Noonan syndrome.

• VCL: Vinculin

  It links integrins and cadherins to the actin cytoskeleton at focal adhesions and adherens junctions, transmitting mechanical force between cells and matrix. Pathogenic variants can cause dilated or hypertrophic cardiomyopathy and, in some cases, skeletal myopathy.

  0 disease-causing and 0 uncertain variants in VCL are linked to Noonan syndrome.

• VWF: von Willebrand factor

  It tethers platelets to damaged vessel walls and carries factor VIII in the circulation, linking primary hemostasis with coagulation. Quantitative or qualitative pathogenic variants cause von Willebrand disease, the most common inherited bleeding disorder.

  0 disease-causing and 0 uncertain variants in VWF are linked to Noonan syndrome.

Weakly linked (only a few uncertain records): CDC42.

Where Noonan syndrome variants cluster

• PTPN11 SH2 1 (positions 6–102): 18 of 44 disease-causing changes, 2.5× more than its size predicts.
• SOS2 DH (positions 198–388): 6 of 8 disease-causing changes, 5.2× more than its size predicts.
• BRAF Phorbol-ester/DAG-type (positions 234–280): 4 of 11 disease-causing changes, 5.9× more than its size predicts.
• KRAS Effector region (positions 32–40): 3 of 16 disease-causing changes, 3.9× more than its size predicts.
• BRAF Protein kinase (positions 457–717): 7 of 11 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Noonan syndrome

Showing 60 of 164.

Uncertain variants in Noonan syndrome that look disease-causing

Which prediction tools work for Noonan syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 91 out of 100
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaGenome (regulatory): 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 85 out of 100
• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 77 out of 100
• SIFT: 76 out of 100
• EVE: 75 out of 100
• DMS / MaveDB: 46 out of 100
• AlphaGenome (splicing): 39 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• RASopathy is also caused by PTPN11 variants; they fall in the same places as the Noonan syndrome variants (51 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by PTPN11 variants; they fall in the same places as the Noonan syndrome variants (29 disease-causing).
• LEOPARD syndrome 1 is also caused by PTPN11 variants; they fall partly in the same places as the Noonan syndrome variants (16 disease-causing).
• Metachondromatosis is also caused by PTPN11 variants; they fall in the same places as the Noonan syndrome variants (11 disease-causing).
• Monogenic short statue is also caused by PTPN11 variants; they fall in the same places as the Noonan syndrome variants (6 disease-causing).
• RASopathy is also caused by SOS1 variants; they fall partly in the same places as the Noonan syndrome variants (22 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by SOS1 variants; they fall in the same places as the Noonan syndrome variants (9 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by RIT1 variants; they fall mostly in different places as the Noonan syndrome variants (9 disease-causing).
• RASopathy is also caused by KRAS variants; they fall partly in the same places as the Noonan syndrome variants (23 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by KRAS variants; they fall partly in the same places as the Noonan syndrome variants (9 disease-causing).
• Autoimmune lymphoproliferative syndrome is also caused by KRAS variants; they fall mostly in different places as the Noonan syndrome variants (5 disease-causing).
• Non-small cell lung carcinoma is also caused by KRAS variants; they fall mostly in different places as the Noonan syndrome variants (5 disease-causing).
• Vascular malformation is also caused by KRAS variants; they fall mostly in different places as the Noonan syndrome variants (4 disease-causing).
• RASopathy is also caused by RAF1 variants; they fall partly in the same places as the Noonan syndrome variants (28 disease-causing).
• Dilated cardiomyopathy 1NN is also caused by RAF1 variants; they fall mostly in different places as the Noonan syndrome variants (5 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by RAF1 variants; they fall partly in the same places as the Noonan syndrome variants (4 disease-causing).
• RASopathy is also caused by BRAF variants; they fall partly in the same places as the Noonan syndrome variants (36 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall partly in the same places as the Noonan syndrome variants (26 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Noonan syndrome variants (17 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall in the same places as the Noonan syndrome variants (10 disease-causing).
• Non-small cell lung carcinoma is also caused by BRAF variants; they fall in the same places as the Noonan syndrome variants (9 disease-causing).

Diseases related to Noonan syndrome

• Hypertrophic cardiomyopathy, also linked to ARAF, BRAF, FGA, FGB and 12 more
• Costello syndrome, also linked to ARAF, BRAF, FGA, FGB and 11 more
• RASopathy, also linked to BRAF, CBL, HRAS, KRAS and 8 more
• Noonan syndrome and Noonan-related syndrome, also linked to BRAF, CBL, HRAS, KRAS and 8 more
• Cardiofaciocutaneous syndrome, also linked to BRAF, KRAS, MAP2K1, MAP2K2 and 1 more
• Cardio-facio-cutaneous syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Colorectal cancer, also linked to BRAF, KRAS, NRAS and PIK3CA
• Non-small cell lung carcinoma, also linked to BRAF, KRAS, MAP2K1 and PIK3CA
• Vascular malformation, also linked to BRAF, KRAS, MAP2K1 and NRAS
• Juvenile myelomonocytic leukemia, also linked to CBL, KRAS, NRAS and PTPN11
• Melanoma, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Acute myeloid leukemia, also linked to KRAS, NRAS and PTPN11

Frequently asked questions

Which genes are linked to Noonan syndrome?

In CATVariant, Noonan syndrome is linked to 25 analyzed proteins: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11), SOS1 (Son of sevenless homolog 1), RIT1 (GTP-binding protein Rit1), KRAS (GTPase KRas), RAF1 (RAF proto-oncogene serine/threonine-protein kinase), BRAF (Serine/threonine-protein kinase B-raf) and 19 more.

How many genetic variants are linked to Noonan syndrome?

1,358 variants: 164 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 980 are of uncertain significance or have conflicting reports.

Which uncertain variants in Noonan syndrome look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SOS1 M269V. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Noonan syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 111 disease-causing and 52 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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