Melanoma: genes and variants

Genes linked to Melanoma

• 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.

  2 disease-causing and 1 uncertain variants in BRAF are linked to Melanoma.

• CDKN2A: Tumor suppressor ARF

  The ARF product of CDKN2A is a tumor-suppressor protein that binds MDM2 and helps preserve p53 activity. By promoting cell-cycle arrest and apoptosis, it provides an important barrier to uncontrolled cell growth from within the nucleolus.

  1 disease-causing and 0 uncertain variants in CDKN2A are linked to Melanoma.

• ARID2: AT-rich interactive domain-containing protein 2

  It contributes DNA targeting and regulatory specificity to PBAF chromatin-remodeling complexes. Somatic loss-of-function alterations occur in melanoma, liver cancer, and other tumors, while germline variants can cause a Coffin-Siris-spectrum neurodevelopmental disorder.

  0 disease-causing and 0 uncertain variants in ARID2 are linked to Melanoma.

• CTLA4: Cytotoxic T-lymphocyte protein 4

  It restrains T-cell activation by competing with CD28 for CD80 and CD86 and by delivering inhibitory signals after immune activation. Haploinsufficiency causes immune dysregulation with autoimmunity and lymphoproliferation, while therapeutic blockade enhances antitumor immunity.

  0 disease-causing and 0 uncertain variants in CTLA4 are linked to Melanoma.

• IFNAR1: Interferon alpha/beta receptor 1

  Together with IFNAR2, it detects type I interferons and activates JAK-STAT antiviral and immunoregulatory programs. Loss-of-function can impair antiviral defense, while excessive pathway activation contributes to interferon-driven inflammatory disease.

  0 disease-causing and 0 uncertain variants in IFNAR1 are linked to Melanoma.

• IFNAR2: Interferon alpha/beta receptor 2

  It provides the high-affinity ligand-binding component of the type I interferon receptor complex and triggers antiviral JAK-STAT signaling with IFNAR1. Biallelic loss-of-function variants can predispose to severe viral infections, including critical COVID-19 in some individuals.

  0 disease-causing and 0 uncertain variants in IFNAR2 are linked to Melanoma.

• IRF4: Interferon regulatory factor 4

  It controls differentiation and function of B cells, plasma cells, T cells, and other immune lineages in a context-dependent manner. Germline variants can cause immunodeficiency, while rearrangements or abnormal expression drive several lymphoid malignancies.

  0 disease-causing and 0 uncertain variants in IRF4 are linked to Melanoma.

• LAG3: Lymphocyte activation gene 3 protein

  It restrains activated and chronically stimulated T cells and contributes to immune tolerance and T-cell exhaustion. Its coexpression with other inhibitory receptors in tumors makes LAG-3 an established immune-checkpoint target in cancer therapy.

  0 disease-causing and 0 uncertain variants in LAG3 are linked to Melanoma.

• 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.

  0 disease-causing and 0 uncertain variants in MAP2K1 are linked to Melanoma.

• 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 0 uncertain variants in MAP2K2 are linked to Melanoma.

• MITF: Microphthalmia-associated transcription factor

  0 disease-causing and 0 uncertain variants in MITF are linked to Melanoma.

• NF1: Neurofibromin

  It accelerates conversion of active RAS-GTP to inactive RAS-GDP and therefore restrains RAS-MAPK signaling. Loss-of-function variants cause neurofibromatosis type 1 with neurofibromas, pigmentary features, learning difficulties, and increased tumor risk.

  0 disease-causing and 0 uncertain variants in NF1 are linked to Melanoma.

• 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.

  0 disease-causing and 0 uncertain variants in NRAS are linked to Melanoma.

• PDCD1: Programmed cell death protein 1

  PDCD1 is an inhibitory receptor on activated T cells that binds PD-L1 and PD-L2. Its signaling helps maintain immune tolerance by restraining T-cell activation, making the protein important in autoimmunity and cancer immunotherapy.

  0 disease-causing and 0 uncertain variants in PDCD1 are linked to Melanoma.

• PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

  A lipid and protein phosphatase that removes phosphate groups from signaling molecules, especially PIP3. By opposing the PI3K-AKT pathway, it limits cell growth and survival signals, and PTEN variants are associated with Cowden syndrome and multiple cancers.

  0 disease-causing and 0 uncertain variants in PTEN are linked to Melanoma.

• RAC1: Ras-related C3 botulinum toxin substrate 1

  It acts as a molecular switch controlling actin remodeling, cell migration, membrane trafficking, reactive-oxygen production, and developmental signaling. De novo activating or loss-of-function variants can cause neurodevelopmental syndromes with abnormal brain growth and craniofacial features.

  0 disease-causing and 0 uncertain variants in RAC1 are linked to Melanoma.

Weakly linked (only a few uncertain records): CDK12 and DNMT3A.

Known disease-causing variants in Melanoma

Same protein, different disease

• RASopathy is also caused by BRAF variants; they fall mostly in different places as the Melanoma variants (36 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Melanoma variants (26 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Melanoma variants (17 disease-causing).
• Noonan syndrome is also caused by BRAF variants; they fall mostly in different places as the Melanoma variants (11 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall mostly in different places as the Melanoma variants (10 disease-causing).
• Familial melanoma is also caused by CDKN2A variants; they fall mostly in different places as the Melanoma variants (15 disease-causing).
• Melanoma-pancreatic cancer syndrome is also caused by CDKN2A variants; they fall mostly in different places as the Melanoma variants (11 disease-causing).
• Melanoma, cutaneous malignant, susceptibility to, 8 is also caused by CDKN2A variants; they fall mostly in different places as the Melanoma variants (6 disease-causing).
• Melanoma and neural system tumor syndrome is also caused by CDKN2A variants; they fall mostly in different places as the Melanoma variants (5 disease-causing).

Diseases related to Melanoma

• Non-small cell lung carcinoma, also linked to BRAF, CDKN2A, CTLA4, MAP2K1 and 1 more
• Hypertrophic cardiomyopathy, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• RASopathy, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Noonan syndrome, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Noonan syndrome and Noonan-related syndrome, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Cardiofaciocutaneous syndrome, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Costello syndrome, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Hepatocellular carcinoma, also linked to ARID2, BRAF, CDKN2A and CTLA4
• Neurofibromatosis, also linked to MAP2K1, MAP2K2 and NF1
• Cardio-facio-cutaneous syndrome, also linked to BRAF, MAP2K1 and MAP2K2
• Melanoma, cutaneous malignant, susceptibility to, 8, also linked to BRAF, CDKN2A and MITF
• Vascular malformation, also linked to BRAF, MAP2K1 and NRAS

Frequently asked questions

Which genes are linked to Melanoma?

In CATVariant, Melanoma is linked to 16 analyzed proteins: BRAF (Serine/threonine-protein kinase B-raf), CDKN2A (Tumor suppressor ARF), ARID2 (AT-rich interactive domain-containing protein 2), CTLA4 (Cytotoxic T-lymphocyte protein 4), IFNAR1 (Interferon alpha/beta receptor 1), IFNAR2 (Interferon alpha/beta receptor 2) and 10 more.

How many genetic variants are linked to Melanoma?

6 variants: 3 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1 are of uncertain significance or have conflicting reports.

Which uncertain variants in Melanoma look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

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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