NOTCH2

Chr 1AD

notch receptor 2

Also known as: AGS2, HJCYS, hN2

NCBI Gene: 4853ENSG00000134250UniProt: Q04721

This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

Primary Disease Associations & Inheritance

Alagille syndrome 2MIM #610205
AD
Hajdu-Cheney syndromeMIM #102500
AD
596
ClinVar variants
15
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— NOTCH2
🧬
Gene-Disease Validity (ClinGen)
Alagille syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 408 VUS of 596 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.12LOEUF
pLI 1.000
Z-score 8.83
OE 0.06 (0.03–0.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.50Z-score
OE missense 0.73 (0.69–0.77)
1000 obs / 1364.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.03–0.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.69–0.77)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 6 / 102.4Missense obs/exp: 1000 / 1364.0Syn Z: -0.44

ClinVar Variant Classifications

596 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic11
VUS408
Likely Benign161
Benign5
Conflicting7
4
Pathogenic
11
Likely Pathogenic
408
VUS
161
Likely Benign
5
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
3
0
4
Likely Pathogenic
9
1
1
0
11
VUS
5
370
25
8
408
Likely Benign
0
7
44
110
161
Benign
0
0
5
0
5
Conflicting
—7
Total1537878118596

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NOTCH2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NOTCH2-related Hajdu-Cheney syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersEyeSkeletal
G2P ↗

NOTCH2-related Alagille syndrome

strong
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
NOTCH RECEPTOR 2; NOTCH2
MIM #600275 · *

Alagille syndrome 2

MIM #610205

Molecular basis of disorder known

Autosomal dominant

Hajdu-Cheney syndrome

MIM #102500

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — NOTCH2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.
Schmitz R et al.·N Engl J Med
2018
Alagille Syndrome: A Focused Review on Clinical Features, Genetics, and Treatment.
Kohut TJ et al.·Semin Liver Dis
2021Review
Alagille Syndrome.
Mitchell E et al.·Clin Liver Dis
2018Review
Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report.
Lacy SE et al.·Blood
2020
High-risk MCL: recognition and treatment.
Jain P et al.·Blood
2025Review
Management of adults with Alagille syndrome.
Ayoub MD et al.·Hepatol Int
2023Review
Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma.
Shen R et al.·Signal Transduct Target Ther
2023
Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.
Nann D et al.·Blood Adv
2020
Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management.
Ayoub MD et al.·Clin Liver Dis
2022Review
Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management.
Jain P et al.·Am J Hematol
2019Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
ALKBH5 promotes ovarian cancer progression by activating Notch2 signaling.
Liu Y et al.·Biol Proced Online
2026
Notch2 is involved in regulating apical tissue repair following severe intrusive luxation.
He Y et al.·J Appl Oral Sci
2026
Fibroblast-Derived Microfibrillar-Associated Protein 5 Exerts Cardioprotective Effects After Myocardial Infarction by Activating the NOTCH2 Signaling in Cardiomyocytes.
Guo J et al.·J Am Heart Assoc
2026
Notch2, a Key Player in Chronic Lymphocytic Leukemia: Mechanism, Microenvironment Interactions, and Therapeutic Implications.
Miserendino R et al.·Cancers (Basel)
2026🔓 Open AccessFunctional
Correction: Development of a ferroptosis-related signature and identification of NOTCH2 as a novel prognostic biomarker in pancreatic cancer.
Zhang S et al.·Front Immunol
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
CADASIL

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study

RECRUITING
NCT05677880University of Wisconsin, MadisonStarted 2022-06-03
Study Procedures

External Resources

Links to major genomics databases and tools