DLK2

Chr 6

delta like non-canonical Notch ligand 2

Also known as: DLK-2, EGFL9

NCBI Gene: 65989ENSG00000171462UniProt: Q6UY11

Predicted to enable Notch binding activity. Involved in negative regulation of Notch signaling pathway. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

65
ClinVar variants
9
Pathogenic / LP
0.78
pLI score
0
Active trials
Clinical Summary— DLK2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 51 VUS of 65 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.46LOEUF
pLI 0.779
Z-score 2.94
OE 0.15 (0.06–0.46)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.93Z-score
OE missense 0.66 (0.58–0.75)
164 obs / 249.7 exp
Tolerant

Mild missense constraint

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.0.15 (0.06–0.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.58–0.75)
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.0.85
0≤1.21.6
LoF obs/exp: 2 / 13.7Missense obs/exp: 164 / 249.7Syn Z: 1.12

ClinVar Variant Classifications

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
VUS51
Likely Benign4
Conflicting1
9
Pathogenic
51
VUS
4
Likely Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
0
0
0
VUS
0
49
2
0
51
Likely Benign
0
2
0
2
4
Benign
0
0
0
0
0
Conflicting
—1
Total05111265

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

View in ClinVar →

Protein Context — Lollipop Plot

DLK2 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.
Sánchez-Solana B et al.·Biochim Biophys Acta
2011
Delta-Like Homolog 2 Facilitates Malignancy of Hepatocellular Carcinoma via Activating EGFR/PKM2 Signaling Pathway.
Liu X et al.·Mol Carcinog
2025
Comprehensive analysis and validation of TP73 as a biomarker for calcium oxalate nephrolithiasis using machine learning and in vivo and in vitro experiments.
Zhou Z et al.·Urolithiasis
2024
Polygenic associations of neurodevelopmental genes in suicide attempt.
Sokolowski M et al.·Mol Psychiatry
2016
NanoString-based breast cancer risk prediction for women with sclerosing adenosis.
Winham SJ et al.·Breast Cancer Res Treat
2017
Abnormal expression pattern of Notch receptors, ligands, and downstream effectors in the dorsolateral prefrontal cortex and amygdala of suicidal victims.
Monsalve EM et al.·Mol Neurobiol
2014
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
DLK1 and DLK2, two non-canonical ligands of NOTCH receptors, differentially modulate the osteogenic differentiation of mesenchymal C3H10T1/2 cells.
Rodríguez-Cano MM et al.·Biol Res
2024🔓 Open Access
Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation.
Chen X et al.·Cell Death Dis
2023🔓 Open Access
Crystal structure of Arabidopsis DWARF14-LIKE2 (DLK2) reveals a distinct substrate binding pocket architecture.
Bürger M et al.·Plant Direct
2022🔓 Open Access
DLK2 Acts as a Potential Prognostic Biomarker for Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis.
Lee MG et al.·Genes (Basel)
2022🔓 Open Access
Different Expression Levels of DLK2 Inhibit NOTCH Signaling and Inversely Modulate MDA-MB-231 Breast Cancer Tumor Growth In Vivo.
Naranjo AI et al.·Int J Mol Sci
2022🔓 Open Access
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