DLL3

Summary

DLL3 (delta like canonical Notch ligand 3, HGNC:2909) is a protein-coding gene on chromosome 19q13.2, encoding Delta-like protein 3 (Q9NYJ7). Inhibits primary neurogenesis.

This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. Mutations in this gene cause autosomal recessive spondylocostal dysostosis 1. Two transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 10683 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylocostal dysostosis 1, autosomal recessive (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 685 total — 32 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 54
• Druggable target: yes
• MANE Select transcript: NM_203486

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2909
Approved symbol	DLL3
Name	delta like canonical Notch ligand 3
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	SCDO1
Ensembl gene	ENSG00000090932
Ensembl biotype	protein_coding
OMIM	602768
Entrez	10683

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000205143, ENST00000356433, ENST00000596614, ENST00000600437, ENST00000600579, ENST00000913807

RefSeq mRNA: 2 — MANE Select: NM_203486 NM_016941, NM_203486

CCDS: CCDS12537, CCDS12538

Canonical transcript exons

ENST00000356433 — 9 exons

Exon	Start	End
ENSE00000706129	39505229	39505451
ENSE00000706130	39507039	39507618
ENSE00001400420	39508252	39508469
ENSE00001414694	39507830	39507914
ENSE00003461060	39500615	39500672
ENSE00003471994	39504071	39504288
ENSE00003523169	39499192	39499473
ENSE00003602581	39502815	39503057
ENSE00003684342	39498947	39499043

Expression profiles

Bgee: expression breadth broad, 62 present calls, max score 88.77.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7156 / max 469.9338, expressed in 351 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175782	3.2738	331
175781	0.4418	193

Top tissues by expression

240 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	88.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.65	gold quality
cortical plate	UBERON:0005343	82.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.47	gold quality
ventricular zone	UBERON:0003053	77.49	gold quality
nucleus accumbens	UBERON:0001882	75.91	gold quality
amygdala	UBERON:0001876	75.12	gold quality
embryo	UBERON:0000922	74.72	gold quality
anterior cingulate cortex	UBERON:0009835	73.98	gold quality
cingulate cortex	UBERON:0003027	73.87	gold quality
prefrontal cortex	UBERON:0000451	72.37	gold quality
hypothalamus	UBERON:0001898	71.43	gold quality
putamen	UBERON:0001874	71.31	gold quality
caudate nucleus	UBERON:0001873	70.50	gold quality
right frontal lobe	UBERON:0002810	70.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	69.61	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.01	gold quality
neocortex	UBERON:0001950	67.85	gold quality
pancreatic ductal cell	CL:0002079	67.77	silver quality
telencephalon	UBERON:0001893	66.53	gold quality
frontal cortex	UBERON:0001870	66.49	gold quality
frontal lobe	UBERON:0016525	66.49	gold quality
forebrain	UBERON:0001890	66.34	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.20	gold quality
cerebral cortex	UBERON:0000956	65.59	gold quality
oocyte	CL:0000023	64.83	silver quality
brain	UBERON:0000955	64.73	gold quality
Ammon’s horn	UBERON:0001954	63.97	gold quality
spinal cord	UBERON:0002240	63.83	gold quality
substantia nigra	UBERON:0002038	63.17	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1179.75
E-MTAB-11121	yes	815.33
E-MTAB-9435	yes	747.58
E-GEOD-93593	yes	699.01
E-MTAB-9388	yes	336.92
E-ANND-3	no	1.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, NEUROG2

miRNA regulators (miRDB)

40 targeting DLL3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-361-3P	99.19	66.45	1381

Literature-anchored findings (GeneRIF, showing 29)

• We suggest that the three human DLL3 mutations associated with spondylocostal dysplasia are also functionally equivalent to the Dll3(neo) null allele in mice. (PMID:11923214)
• mutations in DLL3 cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis (PMID:12746394)
• no novel or previously described mutations are present in our cohort, indicating that DLL3 mutations may not be a major cause of congenital scoliosis. (PMID:15717203)
• The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity (PMID:18676613)
• DLL3 was silenced by methylation in human human hepatocellular carcinoma and it negatively regulates the growth of human hepatocellular carcinoma cells. (PMID:23337976)
• Both global haplotype and individual haplotype analyses showed that the haplotypes of SNP1/SNP2/SNP3/SNP4/SNP5 did not correlate with the disease (P >0.05). Together, these data suggest that genetic variants of the DLL3 gene are not associated with CS in the Chinese Han population. (PMID:27472720)
• The Dll3 was rarely detectable in the para-carcinoma tissues, but positive in 82.1% of non-small cell cancer tissues. (PMID:28007595)
• our results indicated epidermal growth factor-like domain multiple 7 protein participates in growth hormone-secreting pituitary adenoma proliferation and invasion regulation via Notch2/DLL3 signaling pathway. These findings raised the possibility that epidermal growth factor-like domain multiple 7 protein might serve as a useful biomarker to assess growth hormone-secreting pituitary adenoma invasion and prognosis (PMID:28705113)
• these results reveal that DLL3 is expressed in tumor specimens from most patients with small cell lung cancer (PMID:29290251)
• Results indicated that DLL3 expression was silenced in hepatocellular carcinoma (HCC) cells by DNA methylation and was more readily affected by histone acetylation than histone methylation (H3K9me2 or H3K27me3). (PMID:29512761)
• DLL3 expression is silenced during hepatocarcinogenesis in association with HBV infection via an epigenetic mechanism (PMID:29555949)
• Overexpression of DLL3 mRNA and protein is common in small-cell bladder cancer (SCBC) and correlates with shorter overall survival . A DLL3-targeted antibody-drug conjugate demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC. (PMID:30327311)
• DLL3 is selectively and homogeneously expressed in IDH-mutant gliomas and can be targeted with Rova-T in patient-derived IDH-mutant glioma tumorspheres. (PMID:30397180)
• The DLL3 expression could be a potential and novel tumor marker for early diagnosis and an independent predictor of poor survival for patients with endometrial cancer (PMID:30572444)
• Results showed that DLL3 downregulation attenuated small cell lung cancer (SCLC)-cell proliferation, migration and invasion in a process involving the attenuation of Snail activation. In addition, DLL3 overexpression promoted subcutaneous tumor growth in the mouse models. (PMID:30874360)
• DLL3 is preferentially expressed in castration-resistant neuroendocrine prostate cancer and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer. (PMID:30894499)
• LIN28B and miR-518d-5p could regulate DLL3-mediated cell proliferation and migration. (PMID:31079917)
• Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in Small cell lung cancer (SCLC) and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. [review] (PMID:31215500)
• Results showed that DLL3 localized in normal neuroendocrine cells. Considerable upregulation of DLL3 was found in gastrointestinal neuroendocrine carcinoma cell lines. Its silencing caused significant growth inhibition and induction of intrinsic apoptosis. This study suggests that DLL3, expressed in neuroendocrine cells of the gastrointestinal tract, has a pivotal role in gastrointestinal neuroendocrine carcinoma. (PMID:31369178)
• DLL3 expression is reliably quantifiable by pathologists and is highly expressed in the majority of SCLC and a subset of carcinoid tumors, making it an attractive target for anti-DLL3 treatment. (PMID:31447005)
• DLL3 is expressed at high frequency (74%) in stage IV pulmonary large cell neuroendocrine carcinoma and is a potential therapy target. (PMID:31678831)
• A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer. (PMID:32554516)
• DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC. (PMID:32691982)
• TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection. (PMID:33031101)
• Diagnostic and Predictive Role of DLL3 Expression in Gastroenteropancreatic Neuroendocrine Neoplasms. (PMID:33409812)
• Delta-like canonical Notch ligand 3 as a potential therapeutic target in malignancies: A brief overview. (PMID:34107132)
• Investigation of Candidate Genes and Pathways in Basal/TNBC Patients by Integrated Analysis. (PMID:34184566)
• ASCL1 and DLL3 expressions and their clinicopathological implications in surgically resected pure small cell lung cancer: A study of 247 cases from the National Cancer Center of China. (PMID:34931456)
• DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms. (PMID:35983951)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dll3	ENSMUSG00000003436
rattus_norvegicus	Dll3	ENSRNOG00000019338
caenorhabditis_elegans		WBGENE00000168
caenorhabditis_elegans		WBGENE00012018
caenorhabditis_elegans		WBGENE00013480
caenorhabditis_elegans		WBGENE00013486
caenorhabditis_elegans		WBGENE00013487
caenorhabditis_elegans		WBGENE00018906
caenorhabditis_elegans		WBGENE00019901
caenorhabditis_elegans		WBGENE00022858

Paralogs (8): CD93 (ENSG00000125810), FBLN7 (ENSG00000144152), WIF1 (ENSG00000156076), CRELD1 (ENSG00000163703), DLK2 (ENSG00000171462), CD248 (ENSG00000174807), CLEC14A (ENSG00000176435), CRELD2 (ENSG00000184164)

Protein

Protein identifiers

Delta-like protein 3 — Q9NYJ7 (reviewed: Q9NYJ7)

Alternative names: Drosophila Delta homolog 3

All UniProt accessions (2): Q9NYJ7, M0R177

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits primary neurogenesis. May be required to divert neurons along a specific differentiation pathway. Plays a role in the formation of somite boundaries during segmentation of the paraxial mesoderm.

Subunit / interactions. Can bind and activate Notch-1 or another Notch receptor.

Subcellular location. Membrane.

Post-translational modifications. Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation.

Disease relevance. Spondylocostal dysostosis 1, autosomal recessive (SCDO1) [MIM:277300] A condition of variable severity associated with vertebral and rib segmentation defects. The main skeletal malformations include fusion of vertebrae, hemivertebrae, fusion of certain ribs, and other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of the malformation and leads to a dwarf-like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections resulting in life-threatening complications in the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The DSL domain is required for binding to the Notch receptor.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYJ7-1	1	yes
Q9NYJ7-2	2

RefSeq proteins (2): NP_058637, NP_982353* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011651	Notch_ligand_N	Domain
IPR013032	EGF-like_CS	Conserved_site
IPR051022

Pfam: PF00008, PF07657, PF12661

UniProt features (40 total): disulfide bond 18, domain 7, sequence variant 5, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYJ7-F1	65.42	0.07

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (18): 220–231, 224–237, 239–248, 278–289, 283–298, 300–309, 316–327, 321–339, 341–350, 357–368, 362–377, 379–388, 395–406, 400–415, 417–426, 433–444, 438–453, 455–464

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9824272	Somitogenesis

MSigDB gene sets: 269 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GCANCTGNY_MYOD_Q6, AP4_Q6, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, GOBP_SOMITOGENESIS

GO Biological Process (11): skeletal system development (GO:0001501), somitogenesis (GO:0001756), Notch signaling pathway (GO:0007219), compartment pattern specification (GO:0007386), cell differentiation (GO:0030154), negative regulation of Notch signaling pathway (GO:0045746), paraxial mesoderm development (GO:0048339), negative regulation of neurogenesis (GO:0050768), multicellular organism development (GO:0007275), tissue development (GO:0009888), developmental process (GO:0032502)

GO Molecular Function (2): Notch binding (GO:0005112), calcium ion binding (GO:0005509)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gastrulation	1
Formation of paraxial mesoderm	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anterior/posterior pattern specification	2
anatomical structure development	2
system development	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
cell surface receptor signaling pathway	1
cellular developmental process	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
mesoderm development	1
mesenchyme development	1
negative regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
negative regulation of nervous system development	1
multicellular organismal process	1
biological_process	1
signaling receptor binding	1
metal ion binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLL3	NOTCH2	Q04721	988
DLL3	NOTCH4	Q99466	988
DLL3	NOTCH1	P46531	987
DLL3	NOTCH3	Q9UM47	982
DLL3	SRRT	Q9BXP5	867
DLL3	MESP2	Q0VG99	857
DLL3	LFNG	Q8NES3	843
DLL3	EGF	P01133	757
DLL3	RBPJ	Q06330	727
DLL3	HES5	Q5TA89	719
DLL3	GNLY	P09325	698
DLL3	MAML1	Q92585	680
DLL3	HEY1	Q9Y5J3	677
DLL3	MAML2	Q8IZL2	676
DLL3	ASCL1	P50553	669

IntAct

15 interactions, top by confidence:

A	B	Type	Score
DLL3	TUBB8	psi-mi:“MI:0914”(association)	0.350
DLL3	FBXW7	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	DLL3	psi-mi:“MI:2364”(proximity)	0.270
SPOP	DLL3	psi-mi:“MI:2364”(proximity)	0.270
DLL3	SPOP	psi-mi:“MI:2364”(proximity)	0.270
DLL3	EGFR	psi-mi:“MI:2364”(proximity)	0.270
DLL3	PTEN	psi-mi:“MI:2364”(proximity)	0.270
DLL3	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
DLL3	TP53	psi-mi:“MI:2364”(proximity)	0.270
DLL3	AKT1	psi-mi:“MI:2364”(proximity)	0.270
DLL3	BRAF	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (7): XYLT2 (Affinity Capture-MS), CGRRF1 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), MYADM (Affinity Capture-MS), HSPA1A (Affinity Capture-MS), PDP1 (Affinity Capture-MS), DLL3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GUA5, A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A0JNN8, A2A699, A2ARS0, A2VDX9, A5A769, A5PJP1, A6NGB7, A8MVW0, C9JTQ0, O43541, O70218, O70220, P04488, P06764, P07646, P0DPE3, P17542, P22091, P82976, P98162, Q08101, Q08102, Q1HCM0, Q5BLP8, Q5T230, Q6F5E0, Q6QNY0, Q703F0, Q80WY3, Q867D0, Q8K025, Q8TAT2, Q8TD94, Q8WY41, Q8WZ71

Diamond homologs: A2ASQ1, A2ASS6, A3KN33, A8DYP0, B4F785, O00468, O35474, O43854, O55005, O88516, O89026, O94779, P00740, P25304, P29294, P35590, Q05793, Q06561, Q16787, Q4LDE5, Q4VBE4, Q5R7K9, Q5RBN1, Q63HQ2, Q7TPD3, Q8N9C0, Q8TER0, Q8WZ42, Q95ND7, Q96MS0, Q9HCK4, Q9NYJ7, Q9NYQ8, Q9Y2H6, Q9Y6N7, Q9Z2I4, A2CG49, G5EBF1, O01761, O60229

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MIB1	“up-regulates activity”	DLL3	ubiquitination
DLL3	“up-regulates activity”	NOTCH1	binding
DLL3	“up-regulates activity”	PP2B	binding
DLL3	“up-regulates activity”	NOTCH	binding
LFNG	up-regulates	DLL3	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

685 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	15
Uncertain significance	234
Likely benign	324
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074987	NM_203486.3(DLL3):c.637G>T (p.Glu213Ter)	Pathogenic
1332772	NM_203486.3(DLL3):c.871-1G>A	Pathogenic
1457773	NM_203486.3(DLL3):c.530_531del (p.Arg177fs)	Pathogenic
1705307	NM_203486.3(DLL3):c.1339_1340insT (p.His447fs)	Pathogenic
2098741	NM_203486.3(DLL3):c.596_608dup (p.Leu204fs)	Pathogenic
2098742	NM_203486.3(DLL3):c.882del (p.Arg294fs)	Pathogenic
2701337	NM_203486.3(DLL3):c.201del (p.Leu68fs)	Pathogenic
2709025	NM_203486.3(DLL3):c.347G>A (p.Trp116Ter)	Pathogenic
2736891	NM_203486.3(DLL3):c.602_614dup (p.Pro206fs)	Pathogenic
2756605	NM_203486.3(DLL3):c.1394_1395del (p.Glu465fs)	Pathogenic
2769821	NM_203486.3(DLL3):c.1157dup (p.Arg387fs)	Pathogenic
2848381	NM_203486.3(DLL3):c.1282G>T (p.Glu428Ter)	Pathogenic
2864342	NM_203486.3(DLL3):c.558del (p.Cys187fs)	Pathogenic
2865637	NM_203486.3(DLL3):c.785del (p.Gly262fs)	Pathogenic
2919568	NM_203486.3(DLL3):c.211G>T (p.Glu71Ter)	Pathogenic
2958779	NM_203486.3(DLL3):c.325C>T (p.Gln109Ter)	Pathogenic
2976430	NM_203486.3(DLL3):c.1472_1473delinsGA (p.Tyr491Ter)	Pathogenic
3002344	NM_203486.3(DLL3):c.373G>T (p.Glu125Ter)	Pathogenic
3020631	NM_203486.3(DLL3):c.1078C>T (p.Gln360Ter)	Pathogenic
3242702	NC_000019.9:g.(?39989615)(39998653_?)del	Pathogenic
3242703	NC_000019.9:g.(?39989615)(39991332_?)del	Pathogenic
3617733	NM_203486.3(DLL3):c.1392_1393del (p.Cys464_Glu465delinsTer)	Pathogenic
3642051	NM_203486.3(DLL3):c.805G>T (p.Gly269Ter)	Pathogenic
3663911	NM_203486.3(DLL3):c.639dup (p.Cys214fs)	Pathogenic
3669097	NM_203486.3(DLL3):c.1165_1196del (p.Glu389fs)	Pathogenic
391971	NM_203486.3(DLL3):c.661C>T (p.Arg221Ter)	Pathogenic
4617415	NM_203486.3(DLL3):c.1365_1381del (p.Cys455fs)	Pathogenic
632311	NM_203486.3(DLL3):c.395del (p.Gly132fs)	Pathogenic
6831	NM_203486.3(DLL3):c.1291_1307dup (p.Pro437fs)	Pathogenic
6832	NM_203486.3(DLL3):c.618del (p.Cys207fs)	Pathogenic

SpliceAI

1315 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39499470:GCCT:G	donor_gain	1.0000
19:39499474:G:GG	donor_gain	1.0000
19:39500590:T:G	acceptor_gain	1.0000
19:39500672:GGTG:G	donor_loss	1.0000
19:39500673:GTGA:G	donor_loss	1.0000
19:39500674:T:A	donor_loss	1.0000
19:39507825:CACA:C	acceptor_loss	1.0000
19:39507827:C:G	acceptor_gain	1.0000
19:39507828:A:AG	acceptor_gain	1.0000
19:39507829:G:GG	acceptor_gain	1.0000
19:39507829:GCTC:G	acceptor_gain	1.0000
19:39507874:GGATT:G	donor_gain	1.0000
19:39507875:G:T	donor_gain	1.0000
19:39507875:GATT:G	donor_gain	1.0000
19:39507912:G:GT	donor_gain	1.0000
19:39499469:GGCCT:G	donor_gain	0.9900
19:39499470:GCCTG:G	donor_gain	0.9900
19:39500589:A:AG	acceptor_gain	0.9900
19:39500605:A:AG	acceptor_gain	0.9900
19:39500606:C:G	acceptor_gain	0.9900
19:39500609:A:AG	acceptor_gain	0.9900
19:39500610:A:G	acceptor_gain	0.9900
19:39500611:CCAG:C	acceptor_loss	0.9900
19:39500612:CA:C	acceptor_loss	0.9900
19:39500614:G:GT	acceptor_gain	0.9900
19:39500614:GGGC:G	acceptor_gain	0.9900
19:39500614:GGGCA:G	acceptor_gain	0.9900
19:39500669:GGAG:G	donor_gain	0.9900
19:39500670:GAG:G	donor_gain	0.9900
19:39500670:GAGG:G	donor_gain	0.9900

AlphaMissense

3734 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39505392:T:G	F345C	0.999
19:39505391:T:C	F345L	0.998
19:39505393:C:A	F345L	0.998
19:39505393:C:G	F345L	0.998
19:39505397:G:T	G347C	0.998
19:39505406:T:A	C350S	0.998
19:39505407:G:A	C350Y	0.998
19:39505407:G:C	C350S	0.998
19:39505268:T:C	F304L	0.997
19:39505270:C:A	F304L	0.997
19:39505270:C:G	F304L	0.997
19:39505407:G:T	C350F	0.997
19:39505408:T:G	C350W	0.997
19:39505269:T:G	F304C	0.996
19:39505283:T:A	C309S	0.996
19:39505284:G:C	C309S	0.996
19:39505337:T:A	C327S	0.996
19:39505338:G:C	C327S	0.996
19:39505374:G:A	C339Y	0.996
19:39507206:T:C	F421L	0.996
19:39507208:C:A	F421L	0.996
19:39507208:C:G	F421L	0.996
19:39504147:G:C	W243C	0.995
19:39504147:G:T	W243C	0.995
19:39505320:G:A	C321Y	0.995
19:39505321:C:G	C321W	0.995
19:39505284:G:T	C309F	0.994
19:39505319:T:A	C321S	0.994
19:39505320:G:C	C321S	0.994
19:39505338:G:A	C327Y	0.994

dbSNP variants (sampled 300 via entrez): RS1000063112 (19:39503673 C>T), RS1000248109 (19:39498576 A>G), RS1000417251 (19:39498857 C>T), RS1000528691 (19:39500088 C>G,T), RS1000598515 (19:39498836 C>A,G,T), RS1001047983 (19:39503343 T>C), RS1001161913 (19:39508115 C>G), RS1002024535 (19:39507061 C>A,T), RS1002072157 (19:39506619 A>G), RS1002538626 (19:39502501 G>T), RS1002559420 (19:39503770 C>T), RS1002974572 (19:39500401 G>C), RS1003699055 (19:39508745 A>T), RS1003751343 (19:39508531 G>A,T), RS1004319514 (19:39506522 T>A)

Disease associations

OMIM: gene MIM:602768 | disease phenotypes: MIM:277300

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylocostal dysostosis 1, autosomal recessive	Definitive	Autosomal recessive
autosomal recessive spondylocostal dysostosis	Supportive	Autosomal recessive

Mondo (3): spondylocostal dysostosis 1, autosomal recessive (MONDO:0020692), syndactyly (MONDO:0021002), autosomal recessive spondylocostal dysostosis (MONDO:0010180)

Orphanet (1): Autosomal recessive spondylocostal dysostosis (Orphanet:2311)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000069	Abnormality of the ureter
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000476	Cystic hygroma
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000902	Rib fusion
HP:0001249	Intellectual disability
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001537	Umbilical hernia
HP:0001538	Protuberant abdomen
HP:0002093	Respiratory insufficiency
HP:0002205	Recurrent respiratory infections
HP:0002435	Meningocele
HP:0002650	Scoliosis
HP:0002751	Kyphoscoliosis
HP:0002808	Kyphosis

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D013576	Syndactyly	C05.116.099.370.894.819; C05.660.585.800; C05.660.906.819; C16.131.621.585.800; C16.131.621.906.819
C535781	Spondylocostal dysostosis, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630888 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression	2
FR900359	increases phosphorylation	1
bisphenol A	affects methylation	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
clothianidin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	increases expression	1
jinfukang	increases expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects expression	1
Copper	increases expression, affects cotreatment	1
Estradiol	affects expression	1
Hydrogen Peroxide	affects expression	1
Lead	affects expression	1
N-Nitrosopyrrolidine	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 3 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8EP	Abcam HCT 116 DLL3 KO	Cancer cell line	Male
CVCL_B9GY	Abcam A-549 DLL3 KO	Cancer cell line	Male
CVCL_D2EU	Abcam MCF-7 DLL3 KO	Cancer cell line	Female
CVCL_D7NS	Ubigene A-549 DLL3 KO	Cancer cell line	Male
CVCL_D9DG	Ubigene HEK293 DLL3 KO	Transformed cell line	Female
CVCL_E0BT	Ubigene HeLa DLL3 KO	Cancer cell line	Female
CVCL_E4J7	Genomeditech HEK-293 H_DLL3	Transformed cell line	Female
CVCL_E8SN	SHP-77 DLL3 KO clone 2B1	Cancer cell line	Male
CVCL_E8SP	SHP-77 DLL3 KO clone 2C3	Cancer cell line	Male
CVCL_UE38	293T human DLL3	Transformed cell line	Female

Clinical trials (associated diseases)

4 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT03107546	Not specified	COMPLETED	Comparison of Scar Formation in Syndactyly Release Surgery With Full Thickness Skin Graft Versus Skin Graft Substitute
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT07596862	Not specified	COMPLETED	Remote Assesment of Functional Sequelae in Patients Operated for Congenital Syndactyly