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

DLL1 is a human homolog of the Notch Delta ligand and is a member of the delta/serrate/jagged family. It plays a role in mediating cell fate decisions during hematopoiesis. It may play a role in cell-to-cell communication. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizuresMIM #618709

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.10

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

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 OE?0.00 (0.00–0.10)

0≤0.351.4

Missense OE?0.76 (0.69–0.83)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

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

Background carrier burden — how many people carry a rare variant somewhere in DLL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 42

899 rare PASS variants

Rare truncating (LoF)

1 in 10,000

27 rare PASS variants

Rare synonymous (reference)

1 in 43

501 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DLL1. 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)	~556k	1 in 76	1 in 39,000
South Asian	~43k	1 in 49	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 43	≈ 1 in 15,000
European (Finnish)	~27k	1 in 150	1 in 910
Admixed American	~22k	1 in 53	none seen
African / African American	~21k	1 in 60	≈ 1 in 10,000
East Asian	~20k	1 in 65	none seen
Ashkenazi Jewish	~13k	1 in 280	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 61	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): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓