DNER

Summary

DNER (delta/notch like EGF repeat containing, HGNC:24456) is a protein-coding gene on chromosome 2q36.3, encoding Delta and Notch-like epidermal growth factor-related receptor (Q8NFT8). Activator of the NOTCH1 pathway.

Predicted to enable Notch binding activity. Involved in central nervous system development. Located in dendrite; early endosome; and plasma membrane.

Source: NCBI Gene 92737 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 153 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 26 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.21 (intermediate), LOEUF 0.56 (moderately constrained)
• MANE Select transcript: NM_139072
• Notable: 153 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24456
Approved symbol	DNER
Name	delta/notch like EGF repeat containing
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	UNQ26, bet
Ensembl gene	ENSG00000187957
Ensembl biotype	protein_coding
OMIM	607299
Entrez	92737

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000341772

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1

ENST00000341772, ENST00000482831, ENST00000898994, ENST00000898995, ENST00000898996, ENST00000898997, ENST00000898998, ENST00000898999, ENST00000899000, ENST00000965600, ENST00000965601, ENST00000965602, ENST00000965603, ENST00000965604, ENST00001110658, ENST00001111685, ENST00001145396

RefSeq mRNA: 1 — MANE Select: NM_139072 NM_139072

CCDS: CCDS33390

Canonical transcript exons

ENST00000341772 — 13 exons

Exon	Start	End
ENSE00001369002	229588394	229588488
ENSE00001369600	229512783	229512936
ENSE00001370453	229714148	229714555
ENSE00001370514	229418108	229418230
ENSE00001379900	229447316	229447540
ENSE00001380033	229477140	229477253
ENSE00001381270	229546947	229547092
ENSE00001384187	229591580	229591888
ENSE00001390233	229357629	229358651
ENSE00001391125	229366873	229367119
ENSE00001505005	229388265	229388396
ENSE00001505006	229407232	229407345
ENSE00003609520	229585858	229586024

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 99.34.

FANTOM5 (CAGE): breadth broad, TPM avg 12.2313 / max 553.9189, expressed in 730 samples.

Highest expression (Bgee): lateral nuclear group of thalamus, cerebellar vermis, substantia nigra pars reticulata, substantia nigra pars compacta, dorsal plus ventral thalamus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DNER is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 26 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 29 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	2.3e-26	-0.30	2:229445094:G:C
Heart Atrial Appendage	eqtl	3.2e-25	-0.42	2:229656625:T:C
Nerve Tibial	eqtl	1.0e-23	-0.42	2:229445094:G:C
Artery Aorta	eqtl	1.3e-14	-0.29	2:229408975:A:C
Skin Not Sun Exposed Suprapubic	eqtl	2.3e-09	-0.17	2:229445094:G:C
Brain Putamen basal ganglia	eqtl	1.0e-06	-0.22	2:229667481:ATCCT:A
Brain Caudate basal ganglia	eqtl	5.2e-06	-0.23	2:229667481:ATCCT:A
Artery Aorta	sqtl	7.0e-06	-0.96	2:229410211:C:T
Cells Cultured fibroblasts	eqtl	4.4e-05	-0.15	2:229445094:G:C
Artery Tibial	eqtl	5.3e-04	+0.20	2:229413263:G:A
Muscle Skeletal	eqtl	9.1e-04	+0.18	2:229410903:C:T
Brain Hypothalamus	eqtl	1.5e-03	+0.18	2:229660017:G:A
Adipose Subcutaneous	eqtl	1.7e-03	+0.15	2:229339115:G:A
Brain Hippocampus	eqtl	2.0e-03	-0.21	2:229667481:ATCCT:A
Brain Frontal Cortex BA9	eqtl	3.5e-03	-0.33	2:229712618:G:A
Esophagus Gastroesophageal Junction	eqtl	3.8e-03	-0.24	2:229410974:C:A
Brain Anterior cingulate cortex BA24	eqtl	4.1e-03	-0.25	2:229659115:C:T
Pituitary	eqtl	4.3e-03	-0.19	2:229713881:A:G
Esophagus Muscularis	eqtl	5.0e-03	+0.18	2:229413480:G:A
Colon Sigmoid	sqtl	5.5e-03	-2.34	2:229312260:T:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
34420	11.4439	590
34417	0.4359	187
34419	0.1995	94
34418	0.1521	84

Top tissues by expression

showing 100 of 250 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.34	gold quality
cerebellar vermis	UBERON:0004720	99.32	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.21	gold quality
substantia nigra pars compacta	UBERON:0001965	99.12	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.98	gold quality
parotid gland	UBERON:0001831	98.86	gold quality
subthalamic nucleus	UBERON:0001906	98.73	gold quality
lateral globus pallidus	UBERON:0002476	98.69	gold quality
inferior vagus X ganglion	UBERON:0005363	98.47	gold quality
superior vestibular nucleus	UBERON:0007227	98.44	gold quality
globus pallidus	UBERON:0001875	98.40	gold quality
medulla oblongata	UBERON:0001896	98.39	gold quality
medial globus pallidus	UBERON:0002477	98.30	gold quality
ventral tegmental area	UBERON:0002691	98.20	gold quality
midbrain	UBERON:0001891	98.07	gold quality
substantia nigra	UBERON:0002038	98.03	gold quality
pons	UBERON:0000988	97.94	gold quality
hypothalamus	UBERON:0001898	97.94	gold quality
ventricular zone	UBERON:0003053	97.42	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.36	gold quality
spinal cord	UBERON:0002240	97.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.16	gold quality
postcentral gyrus	UBERON:0002581	97.13	gold quality
parietal lobe	UBERON:0001872	96.68	gold quality
amygdala	UBERON:0001876	96.55	gold quality
prefrontal cortex	UBERON:0000451	96.35	gold quality
Ammon’s horn	UBERON:0001954	96.35	gold quality
corpus callosum	UBERON:0002336	96.24	gold quality
right adrenal gland cortex	UBERON:0035827	96.11	gold quality
ganglionic eminence	UBERON:0004023	95.90	gold quality
right adrenal gland	UBERON:0001233	95.82	gold quality
temporal lobe	UBERON:0001871	95.79	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.73	gold quality
superior frontal gyrus	UBERON:0002661	95.68	gold quality
endothelial cell	CL:0000115	95.66	gold quality
left adrenal gland	UBERON:0001234	95.46	gold quality
adrenal cortex	UBERON:0001235	95.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.20	gold quality
caudate nucleus	UBERON:0001873	95.16	gold quality
cerebral cortex	UBERON:0000956	95.15	gold quality
anterior cingulate cortex	UBERON:0009835	95.13	gold quality
left adrenal gland cortex	UBERON:0035825	95.07	gold quality
entorhinal cortex	UBERON:0002728	95.03	gold quality
brain	UBERON:0000955	94.87	gold quality
putamen	UBERON:0001874	94.86	gold quality
forebrain	UBERON:0001890	94.81	gold quality
neocortex	UBERON:0001950	94.78	gold quality
cortical plate	UBERON:0005343	94.76	gold quality
frontal cortex	UBERON:0001870	94.69	gold quality
adrenal tissue	UBERON:0018303	94.02	gold quality
occipital lobe	UBERON:0002021	93.94	gold quality
nucleus accumbens	UBERON:0001882	93.90	gold quality
dorsal root ganglion	UBERON:0000044	93.74	gold quality
cerebellum	UBERON:0002037	93.61	gold quality
adrenal gland	UBERON:0002369	93.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.30	gold quality
cerebellar cortex	UBERON:0002129	93.27	gold quality
cerebellar hemisphere	UBERON:0002245	93.10	gold quality
primary visual cortex	UBERON:0002436	93.10	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.57	gold quality
right frontal lobe	UBERON:0002810	91.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.91	gold quality
adenohypophysis	UBERON:0002196	89.05	gold quality
adult organism	UBERON:0007023	89.03	gold quality
pituitary gland	UBERON:0000007	88.62	gold quality
middle temporal gyrus	UBERON:0002771	87.00	gold quality
upper leg skin	UBERON:0004262	86.68	gold quality
bronchial epithelial cell	CL:0002328	86.06	gold quality
bronchus	UBERON:0002185	84.82	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.81	gold quality
trigeminal ganglion	UBERON:0001675	83.18	gold quality
metanephros	UBERON:0000081	82.25	gold quality
epithelium of nasopharynx	UBERON:0001951	81.65	gold quality
upper arm skin	UBERON:0004263	81.42	gold quality
cardiac atrium	UBERON:0002081	81.41	gold quality
islet of Langerhans	UBERON:0000006	81.25	gold quality
right atrium auricular region	UBERON:0006631	81.11	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.90	gold quality
decidua	UBERON:0002450	78.82	gold quality
adult mammalian kidney	UBERON:0000082	78.75	gold quality
body of stomach	UBERON:0001161	78.22	gold quality
kidney	UBERON:0002113	77.11	gold quality
skin of hip	UBERON:0001554	76.99	gold quality
skin of leg	UBERON:0001511	76.66	gold quality
kidney epithelium	UBERON:0004819	76.32	silver quality
stomach	UBERON:0000945	75.16	gold quality
zone of skin	UBERON:0000014	75.11	gold quality
amniotic fluid	UBERON:0000173	74.27	gold quality
metanephros cortex	UBERON:0010533	73.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.92	gold quality
left uterine tube	UBERON:0001303	72.63	gold quality
nasal cavity mucosa	UBERON:0001826	72.61	gold quality
skin of abdomen	UBERON:0001416	72.27	gold quality
mucosa of paranasal sinus	UBERON:0005030	72.05	gold quality
cortex of kidney	UBERON:0001225	71.72	gold quality
mucosa of stomach	UBERON:0001199	71.10	gold quality
caput epididymis	UBERON:0004358	69.87	gold quality
ascending aorta	UBERON:0001496	69.72	gold quality
thoracic aorta	UBERON:0001515	69.69	gold quality
fundus of stomach	UBERON:0001160	69.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	1654.80
E-HCAD-5	yes	15.76
E-HCAD-10	yes	12.81
E-GEOD-137537	yes	6.07
E-ANND-3	yes	5.56

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 73 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	276.9
Locus coeruleus	tissue	168.8
Thalamus	tissue	137.1
Midbrain	tissue	121.4
Superior colliculi	tissue	110.9
Pons	tissue	110.6
Nucleus accumbens	tissue	110.6
Frontal cortex	tissue	108.3
Spinal cord	tissue	106.9
Hippocampus	tissue	106.0	low
Medulla oblongata	tissue	99.9
Substantia nigra	tissue	88.1
Postcentral gyrus	tissue	82.9
Hypothalamus	tissue	74.7
Cerebellum	tissue	70.2	high
Periaqueductal gray	tissue	68.2
Caudate putamen	tissue	67.6
Olfactory bulb	tissue	67.0
Corpus callosum	tissue	63.2
Hippocampal formation	tissue	58.4
Retina	tissue	56.1
Adrenal gland	tissue	53.9	medium
Amygdala	tissue	53.6
Septum	tissue	53.5
Cerebral cortex	tissue	50.9	medium
Motor cortex	tissue	50.9
Prefrontal cortex	tissue	50.2
Temporal cortex	tissue	48.7
Somatosensory cortex	tissue	48.5
Ventral forebrain	tissue	47.4
Insular cortex	tissue	45.6
Retrosplenial and cingulate cortex	tissue	44.8
Retrosplenial cortex	tissue	43.8
Occipital cortex	tissue	41.6
Entorhinal cortex	tissue	40.9
Salivary gland	tissue	40.8	not detected
Putamen	tissue	31.0
Pituitary gland	tissue	28.1
Basal ganglia	tissue	25.0	medium
Kidney	tissue	10.4	not detected
Stomach 1	tissue	10.1	not detected
Parathyroid gland	tissue	8.3	not detected
Heart muscle	tissue	7.6	not detected
Epididymis	tissue	5.3	not detected
Fallopian tube	tissue	3.3	not detected
Breast	tissue	2.2	not detected
Prostate	tissue	1.8	not detected
Colon	tissue	1.2	low
Appendix	tissue	1.2	not detected
Cervix	tissue	1.1	not detected
Rectum	tissue	1.1	not detected
Smooth muscle	tissue	1.1	low
Tonsil	tissue	1.1	not detected
Testis	tissue	1.0	not detected
Vagina	tissue	1.0	not detected
Endometrium 1	tissue	1.0	not detected
Lung	tissue	0.9	not detected
Pancreas	tissue	0.8	not detected
Small intestine	tissue	0.8	low
Adipose tissue	tissue	0.5	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Ventral posteromedial thalamic nucleus (282.2), Anterior thalamic nucleus, ventral (267.4), Cerebellar nuclei (266.6), Pulvinar (265.8), Lateral geniculate body (261.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, NEUROG3, NKX6-1, PDX1

miRNA regulators (miRDB)

Targeting DNER by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 80 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-1303	99.65	69.77	1662

Functional genomics

gnomAD constraint: pLI 0.21, LOEUF 0.561, missense Z 0.373 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000341772 — one region, missense o/e 0.94.

Literature-anchored findings (GeneRIF, showing 23)

• expression in developing and mature central nervous system (PMID:11950833)
• The inhibition of DNER protein resulted in an increase in adipocyte maturation, partly via a reduction of cell proliferation through elevation of CCAAT-Enhancer-Binding Protein-delta expression. (PMID:20070733)
• Our data suggest that clathrin-independent endocytosis is critical for the polarized targeting of somatodendritic proteins(DNER). (PMID:20367751)
• These studies implicate DNER as a susceptibility gene for T2DM in American Indians. (PMID:24101674)
• DNER rs1861612 C to T change and variant T genotype may contribute to T2DM in a Chinese Han population (PMID:25300688)
• we review and discuss the structural biology of BET family BDs and their applications in major diseases. (PMID:27240990)
• is not a Notch ligand (PMID:27622512)
• Collectively, our study identified an unexpected transcriptional repression function of the BET bromodomain and a novel mechanism for TAZ upregulation. (PMID:27717711)
• our findings show that targeting BET proteins for degradation represents an effective therapeutic strategy for Triple-negative breast cancers (TNBC)treatment (PMID:28209615)
• quantum dot-based immunofluorescent imaging and quantitative analytical system (QD-IIQAS) is an easy and accurate method for assessing DNER and the DNER expression was an independent prognostic factor in prostate cancer. (PMID:29843212)
• Taken together, DNER could promote proliferation, migration, and invasion of HCC cells by regulating the activation of PI3K/AKT pathway. (PMID:30235011)
• Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces apoptosis of triple-negative breast cancer (TNBC) by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes. (PMID:31000582)
• DNER is a novel protein induced in COPD patients and 6months CS-exposed mice that regulates IFNgamma secretion via non-canonical Notch in pro-inflammatory recruited macrophages. (PMID:31060902)
• PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis. (PMID:31653826)
• These findings are important for all SIRT1 and BET inhibitor-related research, and they show that different BET inhibitors might have important individual effects (PMID:32165310)
• Epigenetic targeting of Waldenstrom macroglobulinemia cells with BET inhibitors synergizes with BCL2 or histone deacetylase inhibition. (PMID:33356554)
• Development of an intracellular quantitative assay to measure compound binding kinetics. (PMID:34520747)
• Repressing MYC by targeting BET synergizes with selective inhibition of PI3Kalpha against B cell lymphoma. (PMID:34688842)
• mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer. (PMID:36883564)
• Role of Delta/Notch-like EGF-related receptor in blood glucose homeostasis. (PMID:37223028)
• Delta/Notch-like Epidermal Growth Factor-Related Receptor (DNER), a Potential Prognostic Marker of Gastric Cancer Regulates Cell Survival and Cell Cycle Progression. (PMID:37373228)
• BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer. (PMID:38216082)
• Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy. (PMID:38588830)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	dner	ENSDARG00000061031
mus_musculus	Dner	ENSMUSG00000036766
rattus_norvegicus	Dner	ENSRNOG00000016640
drosophila_melanogaster	Delta	FBGN0000463
drosophila_melanogaster	Ser	FBGN0004197
caenorhabditis_elegans	F25D7.5	WBGENE00009114
caenorhabditis_elegans	F55H12.3	WBGENE00010134
caenorhabditis_elegans		WBGENE00013498

Paralogs (5): JAG1 (ENSG00000101384), DLL4 (ENSG00000128917), JAG2 (ENSG00000184916), DLL1 (ENSG00000198719), NOTCH4 (ENSG00000204301)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2152889) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cerebellum development	1
abnormal cerebellar foliation	1
abnormal cerebellum external granule cell layer morphology	1
abnormal CNS glial cell morphology	1
abnormal lens morphology	1
cataract	1
abnormal retina morphology	1
impaired coordination	1
ectopic Bergmann glia cells	1
abnormal excitatory postsynaptic currents	1
abnormal Purkinje cell innervation	1
increased circulating aspartate transaminase level	1
decreased excitatory postsynaptic current amplitude	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R6R1	93.7%	Diamond
Bos taurus	A4FV93	92.7%	Diamond
Macaca fascicularis	A0A2K5V015	92.0%	Diamond
Sus scrofa	B2LW77	89.8%	Diamond
Oryctolagus cuniculus	P57999	61.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PID1	protein-coding	55022
TRIP12	protein-coding	9320
LINC01807	ncRNA	101928765
FBXO36	protein-coding	130888
SLC16A14	protein-coding	151473

Protein

Protein identifiers

Delta and Notch-like epidermal growth factor-related receptor — Q8NFT8 (reviewed: Q8NFT8)

All UniProt accessions (1): Q8NFT8

UniProt curated annotations — full annotation on UniProt →

Function. Activator of the NOTCH1 pathway. May mediate neuron-glia interaction during astrocytogenesis.

Subunit / interactions. Interacts with AP1G1. Interacts with NOTCH1.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in brain, spinal cord and adrenal gland.

RefSeq proteins (1): NP_620711* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013032	EGF-like_CS	Conserved_site
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR045769	DNER_C	Domain
IPR051022

Pfam: PF00008, PF12661, PF19330

UniProt features (54 total): disulfide bond 29, domain 11, modified residue 4, region of interest 2, topological domain 2, glycosylation site 2, signal peptide 1, chain 1, transmembrane region 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFT8-F1	70.51	0.12

Human Protein Atlas

Protein class: Predicted membrane proteins, Cancer-related genes, Mutated cancer genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

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

Post-translational modifications (4)

Type	Positions
Phosphoserine	685, 722
Phosphotyrosine	711, 721

Disulfide bonds (29)

Type	Positions
Disulfide bond	48–59, 53–80, 82–91, 98–108, 103–121, 123–132, 319–336, 338–347, 353–364, 358–378, 380–389, 396–407, 401–416, 418–427, 434–445, 439–454, 456–465, 472–482, 477–491, 493–502, 509–520, 514–529, 531–540, 547–558, 552–567, 569–578, 585–596, 590–605, 607–616

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	223, 564

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus	electronic
R-HSA-162582	Signal Transduction	—
R-HSA-157118	Signaling by NOTCH	—
R-HSA-1980143	Signaling by NOTCH1	—

MSigDB gene sets: 186 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_SIGNALING_BY_NOTCH, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, GOBP_NOTCH_RECEPTOR_PROCESSING, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP, GOBP_CELL_JUNCTION_ORGANIZATION, MODULE_205

GO Biological Process (6): neuron migration (GO:0001764), endocytosis (GO:0006897), Notch signaling pathway (GO:0007219), synapse assembly (GO:0007416), central nervous system development (GO:0007417), nervous system development (GO:0007399)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), Notch binding (GO:0005112), calcium ion binding (GO:0005509), clathrin binding (GO:0030276), protein binding (GO:0005515)

GO Cellular Component (4): early endosome (GO:0005769), plasma membrane (GO:0005886), dendrite (GO:0030425), neuronal cell body (GO:0043025)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Signaling by NOTCH1	1
Signal Transduction	1
Signaling by NOTCH	1

GO top-level categories

23 GO namespaces:

Category	Terms
nervous system development	2
system development	2
animal gross anatomical part developmental process	2
cell migration	1
generation of neurons	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
cell surface receptor signaling pathway	1
cell junction assembly	1
synapse organization	1
signaling receptor activity	1
signaling receptor binding	1
metal ion binding	1
protein binding	1
binding	1
endosome	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
somatodendritic compartment	1
cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 15 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
central nervous system development	BP	expression pattern
dendrite	CC	direct assay
early endosome	CC	direct assay
plasma membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 732 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNER	ZIC4	Q8N9L1	835
DNER	AMPH	P49418	812
DNER	LGI1	O95970	759
DNER	BIN1	O00499	746
DNER	IGLON5	A6NGN9	736
DNER	PNMA2	Q9UL42	736
DNER	DPYSL5	Q9BPU6	716
DNER	DTX1	Q86Y01	706
DNER	DPP10	Q8N608	704
DNER	DPP6	P42658	702
DNER	RCVRN	P35243	700
DNER	CNTNAP2	Q9UHC6	678
DNER	RBPJ	Q06330	676
DNER	ARHGAP26	Q9UNA1	666
DNER	HOMER3	Q9NSC5	654

IntAct

Human interaction partners of DNER in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
PDLIM7	physical association	0.560	3
PSEN1	association	0.350	1
RSPH1	physical association	0.000	1
ZNF24	physical association	0.000	1

BioGRID (6 interactions; top human partners by supporting records): NUDT21 (Affinity Capture-RNA), PDLIM7 (Two-hybrid), RSPH1 (Two-hybrid), TGOLN2 (Proximity Label-MS), TRIM25 (Affinity Capture-RNA)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
DNER	up-regulates	NOTCH1	binding

Disease & clinical

Genetic variants

Variant evidence for DNER: 153 ClinVar records (1 pathogenic / likely pathogenic); 11 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	122
Likely benign	7
Benign	10

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
441824	GRCh37/hg19 2q36.3-37.1(chr2:230491213-231404389)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore DNER’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 1,751):

Position(s)	Effect	Δscore	Sites
2:229358652	acceptor_loss	1.0000	2
2:229366880	donor_gain	1.0000
2:229447541–229447542	acceptor_loss	1.0000	3
2:229477138–229477139	donor_loss	1.0000	5
2:229477254–229477255	acceptor_loss	1.0000	6
2:229512815	donor_gain	1.0000
2:229546945–229546946	donor_loss	1.0000	4
2:229547093–229547094	acceptor_loss	1.0000	2
2:229585856–229585857	donor_loss	1.0000	5
2:229588392–229588393	donor_loss	1.0000	4

AlphaMissense

1,511 missense substitutions predicted likely pathogenic (of 4,853 scored), across 356 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F650	8	0.919	0.985
F284	8	0.915	0.988
F281	8	0.911	0.993
D736	8	0.884	0.960
C596	7	0.995	0.998
C616	7	0.995	0.998
C493	7	0.994	0.997
C502	7	0.994	0.998
C514	7	0.994	0.997
C540	7	0.994	0.998
C509	7	0.993	0.998
C520	7	0.993	0.997
C482	7	0.992	0.996
C585	7	0.992	0.998
C590	7	0.992	0.996
C529	7	0.991	0.997
C531	7	0.991	0.997
C605	7	0.991	0.995
C607	7	0.991	0.996
C491	7	0.990	0.997

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	unfavorable	5.73e-06
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	7.18e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000342

Disease associations

OMIM: gene MIM:607299 | disease phenotypes:

GWAS associations

11 associations:

Study	Trait	p-value
GCST005830_52	Hand grip strength	4e-13
GCST012490_338	Femur bone mineral density x serum urate levels interaction	2e-12
GCST012490_248	Femur bone mineral density x serum urate levels interaction	2e-11
GCST001784_44	Pulmonary function (smoking interaction)	5e-11
GCST001784_16	Pulmonary function (smoking interaction)	3e-9
GCST006585_136	Blood protein levels	2e-8
GCST002224_1	Type 2 diabetes	7e-8
GCST012484_8	Cerebral amyloid angiopathy x APOEe4 status interaction in Alzheimer’s disease	2e-6
GCST012483_4	Cerebral amyloid angiopathy in APOEe4 non-carrier Alzheimer’s disease	6e-6
GCST009391_1898	Metabolite levels	8e-6
GCST010151_14	Carotid intima media thickness x smoking interaction	8e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0006941	grip strength measurement
EFO:0010508	malate measurement
EFO:0006527	smoking status measurement
EFO:0007659	APOE carrier status
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291567 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4303293	IC50	92 nM
(S)-JQ1 (1)	IC50	103 nM

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.85	IC50	142.3	nM	CHEMBL4303293
6.71	IC50	196	nM	CHEMBL4303293
6.51	IC50	310	nM	CHEMBL4303293
6.34	IC50	458.1	nM	CHEMBL4303293
6.30	IC50	500	nM	CHEMBL1957266
6.19	IC50	646.7	nM	CHEMBL4303293
5.16	IC50	6919	nM	CHEMBL4303293

PubChem BioAssay actives

7 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide	2196757: Inhibition of BET in bortezomib Resistant human RPMI-8226 cells assessed as reduction of cell growth incubated for 72 hrs by CellTiter 96 aqueous one solution cell proliferation assay	ic50	0.1423	uM
tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	1924151: Inhibition of BET (unknown origin)	ic50	0.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression	8
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
domiphen	affects response to substance	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression, increases expression	1
3,4-dichloroaniline	increases expression	1
o,p’-DDT	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	decreases expression	1
cupric chloride	increases expression	1
hydroquinone	decreases expression	1
1-nitropyrene	increases expression	1
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone	affects response to substance	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5227235	Binding	Inhibition of BET (unknown origin)	Small-Molecule Drug Discovery in Triple Negative Breast Cancer: Current Situation and Future Directions. — *J Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DNER across ~30M SureChEMBL compounds — explore on Sugi Predict.