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NF1

neurofibromin 1
16 disorders 9 untyped 2 risk factor 2 causative 1 susceptibility 1 no genetic record 1 somatic driver 17q11.2 gene with protein product
HGNC:7765MonarchNCBI Gene 4763ENSG00000196712UniProt P21359OMIM 613113
Normal function · from ai-gene-review (P21359, commit 79fe13b38970) · AI-generated, not KB evidence

Neurofibromin (NF1) is a large multidomain tumor suppressor protein of 2839 amino acids that functions as a negative regulator of the RAS-MAPK signaling pathway. The protein contains a central GTPase-activating protein (GAP) related domain (GRD, residues 1251-1482) that stimulates the intrinsic GTPase activity of RAS proteins, accelerating their conversion from active GTP-bound to inactive GDP-bound states. This Ras-GAP activity is the primary mechanism by which neurofibromin acts as a tumor suppressor. The protein also contains a SEC14/CRAL-TRIO lipid-binding domain (residues 1580-1738) that binds glycerophospholipids, particularly phosphatidylethanolamine and phosphatidylcholine with monounsaturated fatty acids, and an adjacent PH-like domain. Loss-of-function mutations cause neurofibromatosis type 1 (NF1), characterized by cafe-au-lait spots, neurofibromas, and increased cancer risk. Neurofibromin also regulates cAMP/PKA signaling in neurons and modulates cytoskeletal organization through effects on Rho/ROCK pathways.

NF1 is a RasGAP (Ras GTPase-activating protein) that stimulates the intrinsic GTPase activity of RAS proteins via its GRD domain (residues 1251-1482). The arginine finger at position R1276 is critical for catalysis. This is the primary molecular function and the basis for its tumor suppressor activity.
molecular function: GTPase activator activity · directly involved in: negative regulation of Ras protein signal transduction; negative regulation of MAPK cascade · locations: cytoplasm; plasma membrane
The SEC14/CRAL-TRIO domain (residues 1580-1738) binds glycerophospholipids, particularly phosphatidylethanolamine and phosphatidylcholine with monounsaturated fatty acids. This function was demonstrated by mass spectrometry and X-ray crystallography of lipid complexes.
molecular function: phosphatidylethanolamine binding · locations: cytoplasm
NF1 regulates Schwann cell development and myelination. It is most highly expressed in Schwann cells, and loss of NF1 in these cells leads to neurofibroma formation.
molecular function: GTPase activator activity · directly involved in: Schwann cell development; myelination in peripheral nervous system · locations: cytoplasm
NF1 is essential for brain development and cognitive function. It regulates cAMP/PKA signaling in neurons in addition to its RasGAP activity. Loss leads to cognitive deficits and learning difficulties.
molecular function: GTPase activator activity · directly involved in: brain development; regulation of long-term neuronal synaptic plasticity; cognition · locations: axon; dendrite
In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

DisorderRelationshipWhere the gene appears
Embryonal Rhabdomyosarcoma risk factor germline
Glomus Tumor susceptibility germline
mechanism: Constitutive Mitogenic Pathway Activation; NF1 Biallelic Inactivation
Neurofibromatosis causative
mechanism: Germline Tumor Suppressor Inactivation (First Hit); Neurofibromin Loss and RAS-MAPK Hyperactivation
subtype: NF1
scoped to subtype: NF1
Neurofibromatosis-Noonan Syndrome causative
mechanism: Neurofibromin RAS-GAP Loss
Ocular Melanoma somatic driver somatic
mechanism: UV-Associated BRAF/NRAS/NF1 Driver Activation
subtype: Conjunctival Melanoma
scoped to subtype: Conjunctival Melanoma
Pilocytic Astrocytoma risk factor germline and somatic
mechanism: Constitutive MAPK Cascade Activation
Congenital Renal Artery Stenosis untyped
Syndromic or nonsyndromic renovascular hypertension / midaortic syndrome risk gene
Cutaneous Melanoma untyped
Somatic loss of function
Glioblastoma, IDH-Wildtype untyped
Somatic Mutation
Juvenile Myelomonocytic Leukemia untyped
Germline predisposition with acquired biallelic inactivation
scoped to subtype: NF1-associated
Malignant Peripheral Nerve Sheath Tumor untyped
Germline predisposition with biallelic tumor-suppressor loss
somatic
mechanism: NF1 Biallelic Inactivation
Neurofibroma untyped
Germline predisposition with biallelic tumor-suppressor loss
mechanism: Biallelic NF1 Inactivation in Schwann Cell Lineage
Neurofibromatosis Type 1 untyped
Germline Loss-of-Function Mutations
mechanism: Malignant Peripheral Nerve Sheath Tumor Progression; NF1 Tumor Suppressor Loss
NF1 Microdeletion Syndrome untyped
Whole-gene deletion (contiguous gene deletion)
mechanism: Recurrent 17q11.2 Type-1 Contiguous Gene Deletion; Three-Dimensional Chromatin Reorganization (Position Effect)
Pheochromocytoma and Paraganglioma untyped
Germline Loss-of-Function Mutations
Legius Syndrome no genetic record
mechanism: Impaired Neurofibromin Recruitment to Activated RAS
ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen diseaseMOIClassificationdismech entry
neurofibromatosis type 1 MONDO:0018975 AD Definitive
2019-03-05
Mechanism modules · computed from kb/

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.