Non-small cell lung carcinoma: genes and variants

Genes linked to Non-small cell lung carcinoma

• 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.

  9 disease-causing and 1 uncertain variants in BRAF are linked to Non-small cell lung carcinoma.

• 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.

  5 disease-causing and 0 uncertain variants in KRAS are linked to Non-small cell lung carcinoma.

• 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 Non-small cell lung carcinoma.

• 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 0 uncertain variants in MAP2K1 are linked to Non-small cell lung carcinoma.

• ALK: ALK tyrosine kinase receptor

  Its kinase signaling influences neural development and cell growth, but constitutive activation can become strongly oncogenic. ALK fusions, activating mutations, or amplification drive anaplastic large-cell lymphoma, subsets of lung cancer, and neuroblastoma and can be targeted with ALK inhibitors.

  0 disease-causing and 0 uncertain variants in ALK are linked to Non-small cell lung carcinoma.

• CD274: Programmed cell death 1 ligand 1

  By engaging PD-1, it suppresses activated T cells by engaging PD-1 and thereby limits immune-mediated tissue damage. Many cancers exploit high PD-L1 expression to evade immune attack, making the PD-1/PD-L1 axis a central target of immune-checkpoint therapy.

  0 disease-causing and 0 uncertain variants in CD274 are linked to Non-small cell lung carcinoma.

• 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.

  0 disease-causing and 0 uncertain variants in CDKN2A are linked to Non-small cell lung carcinoma.

• 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 Non-small cell lung carcinoma.

• EGFR: Epidermal growth factor receptor

  A cell-surface receptor tyrosine kinase that responds to epidermal-growth-factor family ligands. Ligand binding activates phosphorylation cascades that regulate cell growth, survival, and differentiation, which is why EGFR changes are important in cancer biology.

  0 disease-causing and 0 uncertain variants in EGFR are linked to Non-small cell lung carcinoma.

• ERBB2: Receptor tyrosine-protein kinase erbB-2

  ERBB2, also called HER2, is a cell-surface receptor tyrosine kinase that works with other ERBB receptors to transmit growth signals. It helps organize signaling and cytoskeletal responses, and abnormal ERBB2 activity is a major feature of several cancers.

  0 disease-causing and 0 uncertain variants in ERBB2 are linked to Non-small cell lung carcinoma.

• ERBB3: Receptor tyrosine-protein kinase erbB-3

  It amplifies neuregulin and ERBB-family signaling primarily by heterodimerizing with catalytically active partners such as HER2 and strongly recruiting PI3K. Persistent signaling can promote tumor growth and resistance to targeted therapy.

  0 disease-causing and 0 uncertain variants in ERBB3 are linked to Non-small cell lung carcinoma.

• ERBB4: Receptor tyrosine-protein kinase erbB-4

  It transduces neuregulin and other EGF-family signals important for neural, cardiac, and mammary development. Altered signaling or somatic variants occur in several cancers and have also been studied in neurodevelopmental disease.

  0 disease-causing and 0 uncertain variants in ERBB4 are linked to Non-small cell lung carcinoma.

• FGFR1: Fibroblast growth factor receptor 1

  Its fibroblast-growth-factor signaling controls proliferation, differentiation, migration, and developmental patterning in many tissues. Germline pathogenic variants can cause hypogonadotropic hypogonadism or craniosynostosis syndromes, while fusions and other activating alterations drive selected cancers.

  0 disease-causing and 0 uncertain variants in FGFR1 are linked to Non-small cell lung carcinoma.

• FGFR4: Fibroblast growth factor receptor 4

  It transmits fibroblast-growth-factor signals involved in metabolism, tissue repair, development, and cell proliferation, with FGF19 as an important metabolic ligand. Aberrant signaling can support tumor growth, and activating alterations are therapeutic targets in selected cancers.

  0 disease-causing and 0 uncertain variants in FGFR4 are linked to Non-small cell lung carcinoma.

• KEAP1: Kelch-like ECH-associated protein 1

  It continuously targets NRF2 for degradation under basal conditions but releases this brake when reactive electrophiles or oxidative stress modify KEAP1. Somatic loss-of-function variants can lock tumors into a persistent antioxidant state that promotes survival and treatment resistance.

  0 disease-causing and 0 uncertain variants in KEAP1 are linked to Non-small cell lung carcinoma.

• MET: Hepatocyte growth factor receptor

  Hepatocyte-growth-factor signaling through this pathway promotes cell survival, proliferation, motility, and invasive growth during development and tissue repair. Exon 14 skipping, amplification, activating mutations, or fusions can drive cancer and create actionable therapeutic dependencies.

  0 disease-causing and 0 uncertain variants in MET are linked to Non-small cell lung carcinoma.

• NPM1: Nucleophosmin

  It coordinates ribosome biogenesis, nucleolar stress responses, centrosome regulation, and nucleocytoplasmic transport. Recurrent frameshift variants that mislocalize the protein to cytoplasm define one of the most common molecular subtypes of acute myeloid leukemia.

  0 disease-causing and 0 uncertain variants in NPM1 are linked to Non-small cell lung carcinoma.

• NTRK1: High affinity nerve growth factor receptor

  Nerve-growth-factor signaling through this pathway supports survival and differentiation of sensory and sympathetic neurons. Loss-of-function variants cause congenital insensitivity to pain with anhidrosis, whereas oncogenic NTRK1 fusions can drive diverse cancers.

  0 disease-causing and 0 uncertain variants in NTRK1 are linked to Non-small cell lung carcinoma.

• NTRK2: BDNF/NT-3 growth factors receptor

  BDNF and neurotrophin-4 signaling through this pathway promotes neuronal survival, synaptic plasticity, and circuit maturation. Rare germline variants can cause neurodevelopmental or metabolic phenotypes, while oncogenic NTRK2 fusions can drive diverse cancers.

  0 disease-causing and 0 uncertain variants in NTRK2 are linked to Non-small cell lung carcinoma.

• NTRK3: NT-3 growth factor receptor

  Neurotrophin-3 signaling through this pathway supports neuronal differentiation and survival. Constitutively active NTRK3 fusion kinases, most notably ETV6::NTRK3, drive several otherwise unrelated cancers and are highly actionable with TRK inhibitors.

  0 disease-causing and 0 uncertain variants in NTRK3 are linked to Non-small cell lung carcinoma.

• 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 Non-small cell lung carcinoma.

• PDGFRA: Platelet-derived growth factor receptor alpha

  PDGF signaling through this pathway promotes proliferation, survival, and migration of mesenchymal progenitors. Activating mutations or fusions drive gastrointestinal stromal tumors and selected hematologic and solid malignancies and can create kinase-inhibitor sensitivity.

  0 disease-causing and 0 uncertain variants in PDGFRA are linked to Non-small cell lung carcinoma.

• PDGFRB: Platelet-derived growth factor receptor beta

  Its signaling supports pericytes, vascular smooth-muscle cells, and other mesenchymal lineages during growth and tissue repair. Oncogenic fusions drive myeloid neoplasms, while germline activating or loss-of-function variants can cause developmental and vascular disorders.

  0 disease-causing and 0 uncertain variants in PDGFRB are linked to Non-small cell lung carcinoma.

• POLD1: DNA polymerase delta catalytic subunit

  It performs much of lagging-strand DNA synthesis and proofreads newly replicated DNA through its exonuclease activity. Germline proofreading-domain variants cause polymerase-proofreading-associated polyposis and cancer predisposition, while other variants can produce developmental progeroid syndromes.

  0 disease-causing and 0 uncertain variants in POLD1 are linked to Non-small cell lung carcinoma.

• POLE: DNA polymerase epsilon catalytic subunit A

  It performs leading-strand DNA synthesis and proofreads newly incorporated bases during replication. Germline exonuclease-domain variants cause polymerase-proofreading-associated polyposis, while somatic proofreading defects create ultramutated tumors with distinctive mutation signatures.

  0 disease-causing and 0 uncertain variants in POLE are linked to Non-small cell lung carcinoma.

• RB1: Retinoblastoma-associated protein

  It restrains E2F-dependent transcription and prevents inappropriate G1-to-S cell-cycle progression until proliferative signals are appropriate. Loss of function is a fundamental cancer-driving event, while germline pathogenic variants cause hereditary retinoblastoma and increase risk of additional tumors.

  0 disease-causing and 0 uncertain variants in RB1 are linked to Non-small cell lung carcinoma.

• RBM10: RNA-binding protein 10

  It regulates alternative pre-mRNA splicing and influences expression of proteins controlling cell growth, apoptosis, and differentiation. Loss-of-function variants cause TARP syndrome, while somatic inactivation is recurrent in lung adenocarcinoma and other cancers.

  0 disease-causing and 0 uncertain variants in RBM10 are linked to Non-small cell lung carcinoma.

• RET: Proto-oncogene tyrosine-protein kinase receptor Ret

  Its activation by GDNF-family ligands guides development of the enteric nervous system, kidney, and other tissues. Activating variants cause multiple endocrine neoplasia type 2 and can drive cancer, whereas loss-of-function variants are an important cause of Hirschsprung disease.

  0 disease-causing and 0 uncertain variants in RET are linked to Non-small cell lung carcinoma.

• ROS1: Proto-oncogene tyrosine-protein kinase ROS

  Its normal physiologic signaling remains incompletely defined, but chromosomal rearrangement can place its kinase domain under constitutive control. ROS1 fusion kinases are actionable oncogenic drivers in non-small-cell lung cancer and several other tumors.

  0 disease-causing and 0 uncertain variants in ROS1 are linked to Non-small cell lung carcinoma.

• SMARCA4: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4

  Its ATPase activity drives nucleosome remodeling in BAF-family complexes and thereby controls access to regulatory DNA. Germline pathogenic variants cause Coffin-Siris syndrome or rhabdoid-tumor predisposition, while somatic loss defines several aggressive cancers.

  0 disease-causing and 0 uncertain variants in SMARCA4 are linked to Non-small cell lung carcinoma.

• STK11: Serine/threonine-protein kinase STK11

  It activates AMPK-family kinases to coordinate cellular energy sensing, polarity, and growth restraint. Germline loss-of-function variants cause Peutz-Jeghers syndrome and its associated cancer predisposition, while somatic loss is common in lung and other cancers.

  0 disease-causing and 0 uncertain variants in STK11 are linked to Non-small cell lung carcinoma.

• TOP1: DNA topoisomerase 1

  It relieves torsional strain in DNA by creating and resealing transient single-strand breaks during replication and transcription. Trapping of the cleavage intermediate is the mechanism exploited by topoisomerase I inhibitors such as irinotecan and topotecan in cancer therapy.

  0 disease-causing and 0 uncertain variants in TOP1 are linked to Non-small cell lung carcinoma.

• TUBA1A: Tubulin alpha-1A chain

  An alpha-tubulin chain that pairs with beta-tubulin to build microtubules. Microtubules provide tracks for transport and help shape dividing and migrating cells, making TUBA1A especially important for fetal brain development.

  0 disease-causing and 0 uncertain variants in TUBA1A are linked to Non-small cell lung carcinoma.

• TUBB2B: Tubulin beta-2B chain

  It contributes to neuronal microtubules needed for progenitor division, neuronal migration, axon development, and cortical organization. Heterozygous pathogenic variants cause tubulinopathy with polymicrogyria, cortical dysplasia, developmental delay, and sometimes epilepsy.

  0 disease-causing and 0 uncertain variants in TUBB2B are linked to Non-small cell lung carcinoma.

• TUBB3: Tubulin beta-3 chain

  It forms neuronal microtubules required for axon growth, guidance, and intracellular transport. Heterozygous pathogenic variants can cause congenital fibrosis of the extraocular muscles type 3 and broader tubulinopathy phenotypes with brain and cranial-nerve abnormalities.

  0 disease-causing and 0 uncertain variants in TUBB3 are linked to Non-small cell lung carcinoma.

Where Non-small cell lung carcinoma variants cluster

• BRAF Protein kinase (positions 457–717): 9 of 9 disease-causing changes, 2.9× more than its size predicts.

Known disease-causing variants in Non-small cell lung carcinoma

Which prediction tools work for Non-small cell lung carcinoma

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

• AlphaMissense: 99 out of 100
• CATVariant: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 81 out of 100
• PolyPhen-2: 78 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• RASopathy is also caused by BRAF variants; they fall partly in the same places as the Non-small cell lung carcinoma variants (36 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (26 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (17 disease-causing).
• Noonan syndrome is also caused by BRAF variants; they fall partly in the same places as the Non-small cell lung carcinoma variants (11 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by BRAF variants; they fall partly in the same places as the Non-small cell lung carcinoma variants (10 disease-causing).
• RASopathy is also caused by KRAS variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (23 disease-causing).
• Noonan syndrome is also caused by KRAS variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (16 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by KRAS variants; they fall partly in the same places as the Non-small cell lung carcinoma variants (9 disease-causing).
• Autoimmune lymphoproliferative syndrome is also caused by KRAS variants; they fall partly in the same places as the Non-small cell lung carcinoma variants (5 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by KRAS variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (4 disease-causing).
• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (30 disease-causing).
• Cowden syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (23 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (4 disease-causing).
• RASopathy is also caused by MAP2K1 variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (14 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by MAP2K1 variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (14 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by MAP2K1 variants; they fall mostly in different places as the Non-small cell lung carcinoma variants (6 disease-causing).

Diseases related to Non-small cell lung carcinoma

• Colorectal cancer, also linked to BRAF, EGFR, ERBB2, FGFR1 and 9 more
• Ovarian cancer, also linked to ALK, ERBB2, NTRK1, PDGFRA and 7 more
• Lung adenocarcinoma, also linked to BRAF, CDKN2A, EGFR, ERBB2 and 7 more
• Hepatocellular carcinoma, also linked to BRAF, CD274, CDKN2A, CTLA4 and 5 more
• Lung cancer, also linked to ALK, BRAF, CD274, EGFR and 4 more
• Renal cell carcinoma, also linked to BRAF, CTLA4, FGFR1, MET and 4 more
• Acute myeloid leukemia, also linked to KRAS, NPM1, PDGFRA, PDGFRB and 2 more
• Gastric cancer, also linked to ERBB2, KRAS, PDCD1, PIK3CA and 1 more
• Malignant tumor of urinary bladder, also linked to ERBB2, ERBB3, KRAS, PIK3CA and 1 more
• Melanoma, also linked to BRAF, CDKN2A, CTLA4, MAP2K1 and 1 more
• Cervical cancer, also linked to PDCD1, TOP1, TUBA1A, TUBB2B and 1 more
• Noonan syndrome, also linked to BRAF, KRAS, MAP2K1 and PIK3CA

Frequently asked questions

Which genes are linked to Non-small cell lung carcinoma?

In CATVariant, Non-small cell lung carcinoma is linked to 35 analyzed proteins: BRAF (Serine/threonine-protein kinase B-raf), KRAS (GTPase KRas), PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1), ALK (ALK tyrosine kinase receptor), CD274 (Programmed cell death 1 ligand 1) and 29 more.

How many genetic variants are linked to Non-small cell lung carcinoma?

18 variants: 16 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 Non-small cell lung carcinoma look disease-causing?

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

Which variant effect predictor works best for Non-small cell lung carcinoma?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 13 disease-causing and 157 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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