DLL1

Chr 6AD

delta like canonical Notch ligand 1

Also known as: DELTA1, DL1, Delta, NEDBAS

NCBI Gene: 28514 ENSG00000198719 UniProt: O00548 OMIM: 606582

This gene encodes a transmembrane ligand protein that binds to NOTCH receptors and regulates cell fate decisions during embryonic development, particularly in brain development where it controls neuronal differentiation and maintains neural stem cell quiescence. Mutations cause neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.095), reflecting its critical role in development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.101 OMIM phenotype

Clinical Summary— DLL1

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DLL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.10LOEUF

pLI 1.000

Z-score 5.20

OE 0.00 (0.00–0.10)

Highly constrained

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

Missense Constraint

1.82Z-score

OE missense 0.76 (0.69–0.83)

335 obs / 442.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.10)

0≤0.351.4

Missense OE0.76 (0.69–0.83)

0≤0.61.4

Synonymous OE1.23

0≤1.21.6

LoF obs/exp: 0 / 31.5Missense obs/exp: 335 / 442.5Syn Z: -2.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateDLL1-related neurodevelopmental disorder with nonspecific brain abnormalities, with or without seizuresLOFAD

0.3693th %ile

GOF

0.5268th %ile

LOF

0.71top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.10

Literature Evidence

LOFHaploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders.PMID:31353024

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

DLL1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — DLL1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Acute Myeloid Leukemia

Chimeric Antigen Receptor T-cells for The Treatment of AML Expressing CLL-1 Antigen

ACTIVE NOT RECRUITING

NCT04219163Phase PHASE1Baylor College of MedicineStarted 2020-07-09

CLL-1.CAR T cells

LymphomaLymphoma, B-CellImmune System Diseases

Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma

ACTIVE NOT RECRUITING

NCT03696784Phase PHASE1UNC Lineberger Comprehensive Cancer CenterStarted 2019-03-12

iC9-CAR19 T cellsBendamustineFludarabine

Hematologic Malignancy

Safety/PK Study of Gene Modified Donor T Cell Infusion in Children With Recurrent Hem Malignancies After Allo Transplant

ACTIVE NOT RECRUITING

NCT03459170Phase PHASE1Bellicum PharmaceuticalsStarted 2018-02-01

BPX-501 T cellsrimiducid

EGFR Gene MutationGlioblastomaMGMT-Unmethylated Glioblastoma

Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13Ralpha2 CAR (E-SYNC) T Cells

RECRUITING

NCT06186401Phase PHASE1Hideho Okada, MD, PhDStarted 2024-04-30

E-SYNC T CellsCyclophosphamide (non-investigational)Fludarabine (non-investigational)

Liver Cell CarcinomaSolid TumorWilms Tumor

Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in Autologous T Cells for Solid Tumors

ACTIVE NOT RECRUITING

NCT05103631Phase PHASE1Baylor College of MedicineStarted 2021-06-17

CATCH T cells

Relapsed/Refractory Small Cell Lung Cancer

This Study is an Open-lable, Early Study to Evaluate the Safety, Feasibility, Cytokinetics, and Preliminary Efficacy of GC511B in DLL3+ Relapsed/Refractory Small Cell Lung Cancer.

RECRUITING

NCT07249879Phase PHASE1Cancer Institute and Hospital, Chinese Academy of Medical SciencesStarted 2026-03-03

GC511B CAR-T Cell Injection

Liver CancerRhabdomyosarcomaMalignant Rhabdoid Tumor

Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors

ACTIVE NOT RECRUITING

NCT04377932Phase PHASE1Baylor College of MedicineStarted 2021-08-08

AGAR T cells

Brain TumorCancer

A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

RECRUITING

NCT05588141Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2023-05-16