NOTCH4

Chr 6

notch receptor 4

NCBI Gene: 4855ENSG00000204301UniProt: Q99466

Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. May regulate branching morphogenesis in the developing vascular system (By similarity)

334
ClinVar variants
5
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NOTCH4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 222 VUS of 334 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.74LOEUF
pLI 0.000
Z-score 3.56
OE 0.59 (0.47–0.74)
Tolerant

Typical tolerance to LoF variation

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.
2.14Z-score
OE missense 0.82 (0.78–0.87)
937 obs / 1139.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.59 (0.47–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.78–0.87)
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.0.82
0≤1.21.6
LoF obs/exp: 51 / 86.7Missense obs/exp: 937 / 1139.9Syn Z: 3.02

ClinVar Variant Classifications

334 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic1
VUS222
Likely Benign23
Benign83
Conflicting1
4
Pathogenic
1
Likely Pathogenic
222
VUS
23
Likely Benign
83
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
1
0
1
VUS
0
214
8
0
222
Likely Benign
0
11
3
9
23
Benign
0
10
52
21
83
Conflicting
—1
Total02356830334

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

View in ClinVar →

Protein Context — Lollipop Plot

NOTCH4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
NOTCH RECEPTOR 4; NOTCH4
MIM #164951 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.
Yu Chen H et al.·Eur Heart J
2023Meta-analysis
Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling.
Liu M et al.·Nat Commun
2017
Regulatory T-cells in asthma.
Harb H et al.·Curr Opin Allergy Clin Immunol
2023Review
Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene.
Zhang Y et al.·J Med Genet
2021Meta-analysis
Precision medicine for human cancers with Notch signaling dysregulation (Review).
Katoh M et al.·Int J Mol Med
2020Review
A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia.
Wang Z et al.·Am J Med Genet B Neuropsychiatr Genet
2006Review
Notch signaling and targeted therapy in non-small cell lung cancer.
Sun J et al.·Cancer Lett
2024Review
Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.
Grosche S et al.·Nat Commun
2021Meta-analysis
A re-review of the association between the NOTCH4 locus and schizophrenia.
Shayevitz C et al.·Am J Med Genet B Neuropsychiatr Genet
2012Review
Immunology of Giant Cell Arteritis.
Weyand CM et al.·Circ Res
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools