NOTCH1

notch receptor 1

17 disorders 5 untyped 4 causative 3 somatic driver 2 susceptibility 2 unknown 1 no genetic record 9q34.3 gene with protein product

HGNC:7881 Monarch NCBI Gene 4851 ENSG00000148400 UniProt P46531 OMIM 190198

Previous symbols: TAN1.

Normal function · from ai-gene-review (P46531, commit 79fe13b38970) · AI-generated, not KB evidence

NOTCH1 is a type I transmembrane receptor that functions as a master regulator of cell-fate determination through juxtacrine signaling. Upon binding membrane-bound ligands (JAG1/2, DLL1/4) on neighboring cells, NOTCH1 undergoes sequential proteolytic cleavages by furin (S1 in Golgi), ADAM10/17 (S2 at plasma membrane), and gamma-secretase (S3/S4), releasing the Notch Intracellular Domain (NICD). NICD translocates to the nucleus where it forms a transcriptional activation complex with RBPJ and MAML coactivators to drive expression of target genes including HES and HEY family members. NOTCH1 plays essential roles in T-cell development, angiogenesis, neurogenesis, heart development, and somitogenesis. Mutations cause T-cell acute lymphoblastic leukemia (activating) and aortic valve disease/Adams-Oliver syndrome (loss-of-function).

NOTCH1 functions as a transmembrane signaling receptor at the plasma membrane, responding to membrane-bound DSL ligands (JAG1/2, DLL1/4) on neighboring cells to transduce cell-cell contact signals into transcriptional responses via regulated intramembrane proteolysis

molecular function: transmembrane signaling receptor activity · directly involved in: Notch signaling pathway; cell differentiation · locations: plasma membrane; cell surface

The cleaved NOTCH1 intracellular domain (NICD) functions as a transcriptional coactivator in the nucleus, displacing corepressors from RBPJ/CSL and recruiting MAML coactivators to form the CSL-NICD-MAML ternary transcription complex that activates target genes (HES1, HES5, HEY1, HEY2, HEYL)

molecular function: transcription coactivator activity · directly involved in: positive regulation of DNA-templated transcription; positive regulation of transcription of Notch receptor target · locations: nucleus · in complex: MAML1-RBP-Jkappa- ICN1 complex

NOTCH1 EGF-like domains bind calcium ions, which is essential for proper receptor folding, stability, and ligand interaction

molecular function: calcium ion binding · locations: plasma membrane

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.

Disorder	Relationship	Where the gene appears
Acute Lymphoblastic Leukemia	somatic driver somatic	mechanism: T-ALL NOTCH1 and T-Cell Transcriptional Activation scoped to subtype: T-ALL
Adams-Oliver Syndrome	causative germline	mechanism: NOTCH1 Haploinsufficiency; Reduced Canonical Notch Signaling subtype: AOS5 animal model: Mouse (Mus musculus) scoped to subtype: AOS5
Adenoid Cystic Carcinoma	somatic driver somatic	mechanism: NOTCH1 Pathway Hyperactivation
Aortic Valve Stenosis	causative	mechanism: NOTCH1 Loss of Function
Coarctation of the Aorta	susceptibility	mechanism: Left Ventricular Outflow Tract Developmental Program Disruption
Congenital Heart Disease	causative	mechanism: Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure scoped to subtype: LVOTO
Hypoplastic Left Heart Syndrome	susceptibility germline	mechanism: Genetic lesion affecting cardiac growth or valvulogenesis
Mixed Phenotype Acute Leukemia	somatic driver somatic	mechanism: Failure of Lineage Commitment scoped to subtype: MPAL T/myeloid NOS
Persistent Truncus Arteriosus	unknown de novo
Tetralogy of Fallot	causative germline
Vein of Galen malformation	unknown	mechanism: Dysregulated Endothelial Developmental Signaling
Esophageal Carcinoma	untyped Recurrent Somatic Mutation (ESCC)
Esophageal Squamous Cell Carcinoma	untyped Squamous Differentiation Pathway Alteration	mechanism: NOTCH Pathway Dysregulation
HPV-Negative Head and Neck Cancer	untyped Loss-of-Function Mutations	mechanism: NOTCH1 Inactivation
IDH-Mutant and 1p/19q-Codeleted Oligodendroglioma	untyped Somatic Mutation
Vulvar Carcinoma	untyped Somatic Mutation somatic	mechanism: HPV-Independent Somatic Driver Accumulation
Glomus Tumor	no genetic record somatic	mechanism: MIR143-NOTCH Gene Fusion

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 disease	MOI	Classification	dismech entry
NOTCH1-related AOS spectrum disorder MONDO:1060150	AD	Definitive 2025-03-07	no dismech entry

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