NOTCH2NLC

Chr 1AD

notch 2 N-terminal like C

Also known as: ETM6, NIID, OPDM3

NCBI Gene: 100996717 ENSG00000286219 UniProt: P0DPK4 OMIM: 618025

NOTCH2NLC encodes a human-specific protein that promotes neural progenitor proliferation and regulates Notch signaling during cerebral cortex development. Mutations cause autosomal dominant neuronal intranuclear inclusion disease, oculopharyngodistal myopathy 3, and hereditary essential tremor 6. These conditions primarily affect the nervous system and skeletal muscle, with neuronal intranuclear inclusion disease representing a particularly severe neurodegenerative disorder.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables Notch binding activity. Involved in cerebral cortex development and positive regulation of Notch signaling pathway. Located in extracellular region. Implicated in essential tremor 6; neuronal intranuclear inclusion disease; and oculopharyngodistal myopathy 3. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismAD3 OMIM phenotypes

Clinical Summary— NOTCH2NLC

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic of 1 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

gnomad: Error: Gene not found

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.4785th %ile

GOF

0.6639th %ile

LOF

0.4037th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThe haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 34675123 ↗

ClinVar Variant Classifications

1 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Pathogenic

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	—	—	—	—	1
Likely Pathogenic	—	—	—	—	0
VUS	—	—	—	—	0
Likely Benign	—	—	—	—	0
Benign	—	—	—	—	0
Total	—				1

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

4 pathogenic / likely-pathogenic (of 5) ClinVar copy-number / structural variants overlap NOTCH2NLC — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →