DERL1

Summary

DERL1 (derlin 1, HGNC:28454) is a protein-coding gene on chromosome 8q24.13, encoding Derlin-1 (Q9BUN8). Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins.

The protein encoded by this gene is a member of the derlin family. Members of this family participate in the ER-associated degradation response and retrotranslocate misfolded or unfolded proteins from the ER lumen to the cytosol for proteasomal degradation. This protein recognizes substrate in the ER and works in a complex to retrotranslocate it across the ER membrane into the cytosol. This protein may select cystic fibrosis transmembrane conductance regulator protein (CFTR) for degradation as well as unfolded proteins in Alzheimer’s disease. Alternative splicing results in multiple transcript variants that encode different protein isoforms.

Source: NCBI Gene 79139 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 50 total
• Druggable target: yes
• MANE Select transcript: NM_024295

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28454
Approved symbol	DERL1
Name	derlin 1
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Aliases	MGC3067, PRO2577, FLJ13784, DER1, DER-1, derlin-1
Ensembl gene	ENSG00000136986
Ensembl biotype	protein_coding
OMIM	608813
Entrez	79139

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000259512, ENST00000405944, ENST00000419562, ENST00000519018, ENST00000523036, ENST00000524119, ENST00000887845, ENST00000887846, ENST00000887847, ENST00000887848, ENST00000940121, ENST00000940122, ENST00000940123

RefSeq mRNA: 4 — MANE Select: NM_024295 NM_001134671, NM_001330601, NM_001363963, NM_024295

CCDS: CCDS47915, CCDS6337, CCDS83319

Canonical transcript exons

ENST00000259512 — 8 exons

Exon	Start	End
ENSE00001090782	123019195	123019305
ENSE00001252562	123013170	123015585
ENSE00001744457	123030605	123030716
ENSE00002100614	123041970	123042302
ENSE00003463068	123021447	123021499
ENSE00003525192	123023713	123023739
ENSE00003575205	123024986	123025050
ENSE00003665103	123022684	123022779

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.5965 / max 243.9257, expressed in 1827 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94702	56.1419	1826
94703	4.0361	1679
94704	1.1583	649
94701	0.9249	487
94700	0.6203	304
94699	0.6112	72
94698	0.1037	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.11	gold quality
stromal cell of endometrium	CL:0002255	96.82	gold quality
islet of Langerhans	UBERON:0000006	96.82	gold quality
tendon of biceps brachii	UBERON:0008188	95.84	gold quality
germinal epithelium of ovary	UBERON:0001304	95.39	gold quality
epithelium of nasopharynx	UBERON:0001951	95.20	gold quality
nasopharynx	UBERON:0001728	95.18	gold quality
gastrocnemius	UBERON:0001388	95.00	gold quality
sperm	CL:0000019	94.99	gold quality
palpebral conjunctiva	UBERON:0001812	94.84	gold quality
muscle of leg	UBERON:0001383	94.73	gold quality
tibia	UBERON:0000979	94.60	gold quality
superficial temporal artery	UBERON:0001614	94.54	gold quality
vermiform appendix	UBERON:0001154	94.50	gold quality
jejunal mucosa	UBERON:0000399	94.40	gold quality
decidua	UBERON:0002450	94.31	gold quality
caecum	UBERON:0001153	94.23	gold quality
lymph node	UBERON:0000029	94.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.09	gold quality
rectum	UBERON:0001052	94.08	gold quality
right adrenal gland cortex	UBERON:0035827	94.05	gold quality
tendon	UBERON:0000043	94.01	gold quality
eye	UBERON:0000970	94.01	gold quality
right adrenal gland	UBERON:0001233	94.00	gold quality
cervix squamous epithelium	UBERON:0006922	93.98	silver quality
oocyte	CL:0000023	93.92	gold quality
cartilage tissue	UBERON:0002418	93.91	gold quality
left adrenal gland	UBERON:0001234	93.90	gold quality
bone marrow	UBERON:0002371	93.89	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.86	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	46.44
E-HCAD-1	yes	44.02
E-CURD-122	yes	37.76
E-ANND-3	yes	22.24
E-GEOD-110499	no	585.82
E-CURD-112	no	2.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

118 targeting DERL1, 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-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776

Literature-anchored findings (GeneRIF, showing 38)

• Derlin-1 is an important factor for the extraction of certain aberrantly folded proteins from the mammalian ER (PMID:15215855)
• Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor (PMID:15215856)
• Derlin-1 interacts with the N-terminal domain of PNGase via its cytosolic C-terminus. PNGase distributed in two populations; ER-associated and free in the cytosol, which suggests the deglycosylation process can proceed at either site (PMID:16055502)
• Derlin-1 is part of a retrotranslocation channel that is associated with both the polyubiquitination and p97-ATPase machineries at the endoplasmic reticulum membrane. (PMID:16186510)
• Derlin-1 recognizes misfolded, nonubiquitylated CFTR to initiate its dislocation and degradation early in the course of CFTR biogenesis, perhaps by detecting structural instability within the first transmembrane domain (PMID:16954204)
• The pool of active Derlin-1 in the ER membrane can be modulated in response to ER stress. (PMID:17453418)
• SVIP is an endogenous inhibitor of ERAD that acts through regulating the assembly of the gp78-p97/VCP-Derlin1 complex. (PMID:17872946)
• DERL1-containing protein mediates the endoplasmic reticulum-associated degradation of V2 vasopressin receptors. (PMID:18048502)
• These findings indicate that Derlin-1 facilitates the retro-translocation of Cholera toxin. (PMID:18094046)
• derlin-1 overexpression in breast cancer, together with its function in relieving ER stress-induced apoptosis, suggests that regulation of the ER stress response pathway may be critical in the development and progression of breast cancer. (PMID:18205950)
• KCa3.1 and KCa2.3 are translocated out of the endoplasmic reticulum associated with Derlin-1. (PMID:18227067)
• Overexpression of DERL1 is associated with neoplasms (PMID:18927294)
• Derlin-1 did not modify KCNQ1 expression level, and no interaction between endogenous KCNQ1 and Derlin-1 could be detected. (PMID:19114714)
• Derlin-1 is a negative regulator for both glycosylated and non-glycosylated BCRP expression and provide a novel posttranslational regulatory mechanism of BCRP by Derlin-1. (PMID:21184741)
• These results indicate that ApoB after lipidation is dislocated from the ER lumen to the LD surface for proteasomal degradation and that Derlin-1 and UBXD8 are engaged in the predislocation and postdislocation steps, respectively. (PMID:22238364)
• Derlin-1 expression levels may affect glucose-stimulated insulin secretion by altering surface expression of K(ATP) channels. (PMID:22311976)
• Upregulation of derlin-1 may be associated with endoplasmic reticulum stress in neuronal cells in Alzheimer’s disease. (PMID:22627700)
• Derlin-1 is overexpressed in non-small cell lung cancer and promotes invasion by EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9. (PMID:23306155)
• Cav-1 may be a cofactor in the interaction of Derlin-1 and N-glycosylated COX-2 and may facilitate Derlin-1- and p97 complex-mediated COX-2 ubiquitination, retrotranslocation, and degradation. (PMID:24089527)
• TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. (PMID:25030448)
• Results showed that Derlin-1 is overexpressed in colon cancer and promotes proliferation of colon cancer cells. (PMID:26173415)
• data suggest that miR-181d is a tumor suppressor in ESCC inversely regulating its downstream target gene of DERL1. (PMID:27572270)
• insights into the interactions between other SHP-containing proteins and p97N (PMID:27714797)
• Derlin-1 was overexpressed in bladder cancer and was associated with the malignancy of bladder cancer. (PMID:27977784)
• The derlin-1 pathway therefore may represent a significant early checkpoint in the recognition and degradation of ENaC in mammalian cells. (PMID:28137758)
• Derlin-1 is overexpressed in bladder cancer and promotes malignant phenotype through ERK/MMP-2/9 and PI3K/AKT signaling pathway. (PMID:28178653)
• ChIP assays were used to ascertain the correlations between HNF1beta and Derlin-1 in the miR-217/HNF1beta/Derlin-1 pathway in glioma cells (PMID:28219405)
• Overexpression of Derlin-1 is Associated with Non-small Cell Lung Cancer. (PMID:29530993)
• association of the degradation factor HRD1 with the translocon and the rerouting factor Derlin-1 may be necessary for the smooth and effective clearance of ERpQC substrates (PMID:29743537)
• These findings for the first time revealed that miR-598, as a tumor suppressor, negatively regulate DERL1 and Epithelial-Mesenchymal Transition to suppress the invasion and migration in Non-Small Cell Lung Cancer (NSCLC), thereby putatively serving as a novel therapeutic target for NSCLC clinical treatment. (PMID:29768262)
• Derlin-1 exhibits oncogenic activities and indicates an unfavorable prognosis in breast cancer. (PMID:31670413)
• Derlin-1 functions as a growth promoter in breast cancer. (PMID:31721721)
• The cryo-EM structure of an ERAD protein channel formed by tetrameric human Derlin-1. (PMID:33658201)
• Derlin-1, as a Potential Early Predictive Biomarker for Nonresponse to Infliximab Treatment in Rheumatoid Arthritis, Is Related to Autophagy. (PMID:35046954)
• Circular RNA circTTBK2 facilitates non-small-cell lung cancer malignancy through the miR-873-5p/TEAD1/DERL1 axis. (PMID:35916080)
• Regulation of Derlin-1-mediated degradation of NADPH oxidase partner p22(phox) by thiol modification. (PMID:36122532)
• Derlin-1 ameliorates nonalcoholic hepatic steatosis by promoting ubiquitylation and degradation of FABP1. (PMID:37499886)
• Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis. (PMID:38522486)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	derl1	ENSDARG00000021905
mus_musculus	Derl1	ENSMUSG00000022365
rattus_norvegicus	Derl1	ENSRNOG00000005551
drosophila_melanogaster	Der-1	FBGN0267972
caenorhabditis_elegans	cup-2	WBGENE00000843

Paralogs (2): DERL2 (ENSG00000072849), DERL3 (ENSG00000099958)

Protein

Protein identifiers

Derlin-1 — Q9BUN8 (reviewed: Q9BUN8)

Alternative names: Degradation in endoplasmic reticulum protein 1, Der1-like protein 1

All UniProt accessions (3): B4E1G1, E5RGY0, Q9BUN8

UniProt curated annotations — full annotation on UniProt →

Function. Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. Forms homotetramers which encircle a large channel traversing the endoplasmic reticulum (ER) membrane. This allows the retrotranslocation of misfolded proteins from the ER into the cytosol where they are ubiquitinated and degraded by the proteasome. The channel has a lateral gate within the membrane which provides direct access to membrane proteins with no need to reenter the ER lumen first. May mediate the interaction between VCP and the misfolded protein. Also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway. (Microbial infection) In case of infection by cytomegaloviruses, it plays a central role in the export from the ER and subsequent degradation of MHC class I heavy chains via its interaction with US11 viral protein, which recognizes and associates with MHC class I heavy chains. Also participates in the degradation process of misfolded cytomegalovirus US2 protein.

Subunit / interactions. Homotetramer. The four subunits of the tetramer are arranged in a twofold symmetry. Forms heterooligomers with DERL2 and DERL3; binding to DERL3 is poorer than that between DERL2 and DERL3. Interacts (via SHP-box motif) with VCP. Interacts with AMFR, SELENOS, SEL1L, SELENOK and SYVN1, as well as with SEL1L-SYVN1 and VCP-SELENOS protein complexes; this interaction is weaker than that observed between DERL2 and these complexes. Interacts with NGLY1 and YOD1. Does not bind to EDEM1. Interacts with DNAJB9. Interacts with RNF103. Interacts with HM13. Interacts with XBP1 isoform 1 (via luminal/ectodomain domain); the interaction obviates the need for ectodomain shedding prior HM13/SPP-mediated XBP1 isoform 1 cleavage. Interacts with the signal recognition particle/SRP and the SRP receptor; in the process of endoplasmic reticulum stress-induced pre-emptive quality control. May interact with UBXN6. Interacts with ZFAND2B; probably through VCP. Interacts with CCDC47. Interacts with C18orf32. May interact with TRAM1. Forms a complex with SVIP and VCP/p97. (Microbial infection) Interacts with the cytomegalovirus US11 protein.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous.

Similarity. Belongs to the derlin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BUN8-1	1	yes
Q9BUN8-2	2

RefSeq proteins (4): NP_001128143, NP_001317530, NP_001350892, NP_077271* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007599	DER1	Family
IPR035952	Rhomboid-like_sf	Homologous_superfamily

Pfam: PF04511

Enzyme classification (BRENDA):

• EC 3.4.21.105 — rhomboid protease (BRENDA: 42 organisms, 229 substrates, 68 inhibitors, 19 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BODIPY FL CASEIN	0.0007–0.0029	12
FL-CASEIN	0.0018–0.0065	3
TATA	0.0076–0.119	3
CYPET-TATA-YPET	0.0039	1

UniProt features (32 total): mutagenesis site 8, topological domain 7, transmembrane region 6, modified residue 4, initiator methionine 1, chain 1, region of interest 1, short sequence motif 1, splice variant 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5GLF	X-RAY DIFFRACTION	2.25
9LLK	ELECTRON MICROSCOPY	3.55
7Y53	ELECTRON MICROSCOPY	3.61
7Y4W	ELECTRON MICROSCOPY	3.67
7CZB	ELECTRON MICROSCOPY	3.8
7Y59	ELECTRON MICROSCOPY	4.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BUN8-F1	80.76	0.40

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): 2, 201, 202, 226

Mutagenesis-validated functional residues (8):

Position	Phenotype
70	impaired erad substrate degradation.
73	impaired erad substrate degradation.
164	impaired erad substrate degradation.
165	impaired erad substrate degradation.
180	reduces interaction with and proteolysis of xbp1 isoform 1.
243–245	significantly reduced binding to vcp.
247	significantly reduced binding to vcp.
248	significantly reduced binding to vcp.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-382556	ABC-family protein mediated transport
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)

MSigDB gene sets: 221 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_PROTEIN_DESTABILIZATION, ONKEN_UVEAL_MELANOMA_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, LANDIS_ERBB2_BREAST_TUMORS_65_DN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (14): response to unfolded protein (GO:0006986), endoplasmic reticulum unfolded protein response (GO:0030968), retrograde protein transport, ER to cytosol (GO:0030970), positive regulation of protein ubiquitination (GO:0031398), protein destabilization (GO:0031648), ERAD pathway (GO:0036503), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), establishment of protein localization (GO:0045184), cellular response to misfolded protein (GO:0071218), response to stress (GO:0006950), proteasomal protein catabolic process (GO:0010498), protein transport (GO:0015031), cellular response to stress (GO:0033554), cellular response to unfolded protein (GO:0034620)

GO Molecular Function (10): protease binding (GO:0002020), signal recognition particle binding (GO:0005047), ubiquitin protein ligase binding (GO:0031625), signaling receptor activity (GO:0038023), MHC class I protein binding (GO:0042288), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), ATPase binding (GO:0051117), ubiquitin-specific protease binding (GO:1990381), protein binding (GO:0005515)

GO Cellular Component (8): early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), Derlin-1-VIMP complex (GO:0036502), Derlin-1 retrotranslocation complex (GO:0036513), endoplasmic reticulum quality control compartment (GO:0044322)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Transport of small molecules	1
Asparagine N-linked glycosylation	1
ABC transporter disorders	1
Protein ubiquitination	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to endoplasmic reticulum stress	2
proteasomal protein catabolic process	2
cellular response to topologically incorrect protein	2
enzyme binding	2
binding	2
endosome	2
cellular anatomical structure	2
endoplasmic reticulum membrane	2
membrane protein complex	2
endoplasmic reticulum protein-containing complex	2
response to topologically incorrect protein	1
cellular response to unfolded protein	1
intracellular signal transduction	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of protein stability	1
response to chemical	1
ubiquitin-dependent protein catabolic process	1
establishment of localization	1
response to misfolded protein	1
response to stimulus	1
protein catabolic process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
response to stress	1
cellular response to stimulus	1
response to unfolded protein	1
ribonucleoprotein complex binding	1
ubiquitin-like protein ligase binding	1
molecular transducer activity	1
MHC protein binding	1
protein binding	1
protease binding	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

1872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DERL1	SEL1L	Q9UBV2	996
DERL1	SYVN1	Q86TM6	986
DERL1	UFD1	Q92890	894
DERL1	RNF5	Q99942	893
DERL1	SEC61A1	P38378	849
DERL1	MARCHF6	O60337	833
DERL1	UBE2J1	Q9Y385	829
DERL1	OS9	Q13438	814
DERL1	VCP	P55072	813
DERL1	ERLEC1	Q96DZ1	809
DERL1	NPLOC4	Q8TAT6	803
DERL1	EDEM1	Q92611	798
DERL1	AMFR	P26442	795
DERL1	STUB1	Q9UNE7	680
DERL1	SELENOS	Q9BQE4	669

IntAct

134 interactions, top by confidence:

A	B	Type	Score
RNF5	CFTR	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	DERL1	psi-mi:“MI:0915”(physical association)	0.690
DERL1	CFTR	psi-mi:“MI:0914”(association)	0.690
SELENOS	Vcp	psi-mi:“MI:0914”(association)	0.610
DERL1	TCF25	psi-mi:“MI:0915”(physical association)	0.560
LNX1	DERL1	psi-mi:“MI:0915”(physical association)	0.560
KASH5	DERL1	psi-mi:“MI:0915”(physical association)	0.560
	DERL1	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	DERL1	psi-mi:“MI:0915”(physical association)	0.560
DERL1	SLC7A8	psi-mi:“MI:0915”(physical association)	0.560
DERL1	UBE2J1	psi-mi:“MI:0915”(physical association)	0.560
AQP6	DERL1	psi-mi:“MI:0915”(physical association)	0.560
RETREG3	DERL1	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	DERL1	psi-mi:“MI:0915”(physical association)	0.560
DERL1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	DERL1	psi-mi:“MI:0915”(physical association)	0.560
TEX44	DERL1	psi-mi:“MI:0915”(physical association)	0.560
DERL1	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
GAD2	DERL1	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	DERL1	psi-mi:“MI:0915”(physical association)	0.560
DERL1	REEP4	psi-mi:“MI:0915”(physical association)	0.560
SLC7A14	DERL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (600): DERL1 (Affinity Capture-Western), XBP1 (Affinity Capture-Western), DERL1 (Two-hybrid), ESYT2 (Affinity Capture-MS), HMOX1 (Affinity Capture-MS), EPHX1 (Affinity Capture-MS), POR (Affinity Capture-MS), YIF1B (Affinity Capture-MS), RTN4 (Affinity Capture-MS), SEC22B (Affinity Capture-MS), ARL6IP5 (Affinity Capture-MS), VCP (Affinity Capture-MS), PGRMC2 (Affinity Capture-MS), FAF2 (Affinity Capture-MS), ESYT1 (Affinity Capture-MS)

ESM2 similar proteins: G5EEP3, O13883, O14364, O42826, O74926, O94448, O94458, P34356, P38307, P87155, Q03530, Q06397, Q08929, Q09758, Q0P5E4, Q10254, Q12239, Q21997, Q4G2J3, Q4G2J4, Q4G2J5, Q4G2J6, Q54IC9, Q54NN1, Q5ACU3, Q5R9W3, Q5RC74, Q6CK18, Q6CR06, Q6FSG0, Q6FWN4, Q6IUY1, Q71SS4, Q851X7, Q8BNI4, Q8RXQ2, Q8VZ96, Q93561, Q96Q80, Q99J56

Diamond homologs: O94458, Q06397, Q0P5E4, Q21997, Q4G2J3, Q4G2J4, Q4G2J5, Q4G2J6, Q54NN1, Q5R9W3, Q5RC74, Q71SS4, Q851X7, Q8BNI4, Q8VZ96, Q8VZU9, Q93561, Q96Q80, Q99J56, Q9BUN8, Q9D8K3, Q9GZP9, Q9VQ57, Q9ZS88, Q54IC9, Q9Y7Y0

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SELENOS	“up-regulates activity”	DERL1	binding
VCP	“up-regulates activity”	DERL1	binding
SOD1	“down-regulates activity”	DERL1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	9	19.2×	8e-07
fat cell differentiation	6	12.8×	3e-03
cellular response to oxidative stress	6	10.9×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1219 predictions. Top by Δscore:

Variant	Effect	Δscore
8:123030722:C:CT	acceptor_gain	1.0000
8:123019193:A:AC	donor_gain	0.9900
8:123019194:C:CC	donor_gain	0.9900
8:123021445:A:AC	donor_gain	0.9900
8:123021446:C:CC	donor_gain	0.9900
8:123022780:C:CC	acceptor_gain	0.9900
8:123024985:C:CT	donor_gain	0.9900
8:123041906:CG:C	donor_gain	0.9900
8:123041965:AGTAC:A	donor_loss	0.9900
8:123041966:GTA:G	donor_loss	0.9900
8:123041967:TACCT:T	donor_loss	0.9900
8:123041968:A:T	donor_loss	0.9900
8:123019224:T:TA	donor_gain	0.9800
8:123021445:ACGAG:A	donor_gain	0.9800
8:123021446:CGAG:C	donor_gain	0.9800
8:123021446:CGAGC:C	donor_gain	0.9800
8:123041912:G:C	donor_gain	0.9800
8:123023746:T:C	acceptor_gain	0.9700
8:123023746:T:TC	acceptor_gain	0.9700
8:123030678:C:T	acceptor_gain	0.9700
8:123030722:C:T	acceptor_gain	0.9700
8:123041911:AGCCG:A	donor_gain	0.9700
8:123041992:T:TA	donor_gain	0.9600
8:123030598:AACAT:A	donor_loss	0.9500
8:123030599:ACAT:A	donor_loss	0.9500
8:123030600:CATA:C	donor_loss	0.9500
8:123030601:ATAC:A	donor_loss	0.9500
8:123030602:TA:T	donor_loss	0.9500
8:123030603:A:AT	donor_loss	0.9500
8:123030604:C:CT	donor_loss	0.9500

AlphaMissense

1624 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:123019273:C:T	G180E	0.999
8:123019274:C:G	G180R	0.999
8:123019274:C:T	G180R	0.999
8:123019285:C:A	G176V	0.999
8:123019285:C:T	G176E	0.999
8:123019286:C:G	G176R	0.999
8:123019286:C:T	G176R	0.999
8:123021484:A:G	W157R	0.999
8:123021484:A:T	W157R	0.999
8:123022688:A:G	F150S	0.999
8:123022740:A:G	W133R	0.999
8:123022740:A:T	W133R	0.999
8:123025043:A:C	F91L	0.999
8:123025043:A:T	F91L	0.999
8:123025045:A:G	F91L	0.999
8:123030622:G:A	S83F	0.999
8:123030622:G:T	S83Y	0.999
8:123030713:A:G	W53R	0.999
8:123030713:A:T	W53R	0.999
8:123019273:C:A	G180V	0.998
8:123021471:C:T	G161E	0.998
8:123021472:C:G	G161R	0.998
8:123021472:C:T	G161R	0.998
8:123021489:A:G	L155S	0.998
8:123022697:C:T	G147E	0.998
8:123022705:A:C	F144L	0.998
8:123022705:A:T	F144L	0.998
8:123022706:A:G	F144S	0.998
8:123022707:A:G	F144L	0.998
8:123023733:C:G	G113R	0.998

dbSNP variants (sampled 300 via entrez): RS1000171640 (8:123033750 A>G), RS1000260979 (8:123041616 T>A), RS1000376132 (8:123024231 T>A,C), RS1000430911 (8:123030432 A>T), RS1000486364 (8:123030878 C>A,G), RS1000630024 (8:123042905 C>G), RS1000694993 (8:123041910 T>A), RS1000815724 (8:123023982 A>C), RS1000848275 (8:123023563 A>G), RS1001127720 (8:123029842 T>C), RS1001135165 (8:123037048 T>TAC), RS1001219237 (8:123030064 T>A,C), RS1001291086 (8:123025498 T>C), RS1001384472 (8:123030931 T>C), RS1001391393 (8:123023510 A>G)

Disease associations

OMIM: gene MIM:608813 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1559	Metabolite levels	5.000000e-06
GCST90002396_438	Mean reticulocyte volume	5.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009776	ornithine measurement
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067266 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
bisphenol A	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
pyrimidin-2-one beta-ribofuranoside	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Benzo(a)pyrene	affects methylation	1
Carcinogens	decreases expression	1
Curcumin	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Isoniazid	increases expression	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Mutagens	decreases expression	1
Smoke	decreases expression	1
Oleic Acid	affects cotreatment, affects expression	1
Palmitic Acid	affects cotreatment, affects expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651273	Binding	Binding affinity to human DERL1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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