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; nucleoplasm; and plasma membrane. Implicated in essential tremor 6; neuronal intranuclear inclusion disease; and oculopharyngodistal myopathy 3. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neuronal intranuclear inclusion diseaseMIM #603472

Oculopharyngodistal myopathy 3MIM #619473

Tremor, hereditary essential, 6MIM #618866

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neuronal intranuclear inclusion disease; Oculopharyngodistal myopathy 3 (+1); no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

—

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

gnomad: Error: Gene not found

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in NOTCH2NLC?

gnomAD v4 · ~652k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 320

76 rare PASS variants

Rare truncating (LoF)

1 in 260

48 rare PASS variants

Rare synonymous (reference)

1 in 220

29 rare PASS variants

Rare missense and truncating variants are carried at similar rates in NOTCH2NLC; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~521k	1 in 480	1 in 190
South Asian	~38k	1 in 580	1 in 270
Remaining (unassigned)	~27k	1 in 490	1 in 260
European (Finnish)	~26k	1 in 540	1 in 280
Admixed American	~21k	1 in 370	1 in 350
African / African American	~20k	1 in 250	1 in 430
East Asian	~19k	1 in 230	≈ 1 in 5,500
Ashkenazi Jewish	~11k	1 in 1,600	1 in 730
Middle Eastern	~2,495	1 in 270	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 0 of 5 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 5 poorly covered; exon 1 marginal. Genomes: 0 of 5 (exons 1, 2, 3, 4, 5 below).? see exons ↓