Neurofibromatosis: genes and variants

Genes linked to Neurofibromatosis

• 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.

  51 disease-causing and 854 uncertain variants in NF1 are linked to Neurofibromatosis.

• NF2: Merlin

  Its merlin product links membrane and cytoskeletal signaling to contact-dependent growth control. Germline loss-of-function variants cause NF2-related schwannomatosis with vestibular schwannomas, meningiomas, and other nervous-system tumors.

  6 disease-causing and 611 uncertain variants in NF2 are linked to Neurofibromatosis.

• 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 Neurofibromatosis.

• 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 Neurofibromatosis.

Weakly linked (only a few uncertain records): ARID1B and NOTCH1.

Where Neurofibromatosis variants cluster

• NF1 Ras-GAP (positions 1251–1482): 8 of 51 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Neurofibromatosis

Uncertain variants in Neurofibromatosis that look disease-causing

Which prediction tools work for Neurofibromatosis

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

• MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 88 out of 100
• SIFT: 83 out of 100
• MutPred2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 76 out of 100
• PolyPhen-2: 75 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 73 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Neurofibromatosis

• Melanoma, also linked to MAP2K1, MAP2K2 and NF1
• Hypertrophic cardiomyopathy, also linked to MAP2K1 and MAP2K2
• RASopathy, also linked to MAP2K1 and MAP2K2
• Noonan syndrome, also linked to MAP2K1 and MAP2K2
• Noonan syndrome and Noonan-related syndrome, also linked to MAP2K1 and MAP2K2
• Cardiofaciocutaneous syndrome, also linked to MAP2K1 and MAP2K2
• Cardio-facio-cutaneous syndrome, also linked to MAP2K1 and MAP2K2
• Costello syndrome, also linked to MAP2K1 and MAP2K2
• Non-small cell lung carcinoma, also linked to MAP2K1
• Vascular malformation, also linked to MAP2K1
• Juvenile myelomonocytic leukemia, also linked to NF1
• Male infertility with azoospermia or oligozoospermia due to single gene mutation, also linked to MAP2K1

Frequently asked questions

Which genes are linked to Neurofibromatosis?

In CATVariant, Neurofibromatosis is linked to 4 analyzed proteins: NF1 (Neurofibromin), NF2 (Merlin), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1) and MAP2K2 (Dual specificity mitogen-activated protein kinase kinase 2).

How many genetic variants are linked to Neurofibromatosis?

1,598 variants: 57 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,467 are of uncertain significance or have conflicting reports.

Which uncertain variants in Neurofibromatosis look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NF1 G1277D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Neurofibromatosis?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 25 disease-causing and 81 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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