SEL1L

Summary

SEL1L (SEL1L adaptor subunit of SYVN1 ubiquitin ligase, HGNC:10717) is a protein-coding gene on chromosome 14q31, encoding Protein sel-1 homolog 1 (Q9UBV2). Plays a role in the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins.

The protein encoded by this gene is part of a protein complex required for the retrotranslocation or dislocation of misfolded proteins from the endoplasmic reticulum lumen to the cytosol, where they are degraded by the proteasome in a ubiquitin-dependent manner. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6400 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 105 total — 1 pathogenic
• Phenotypes (HPO): 74
• MANE Select transcript: NM_005065

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10717
Approved symbol	SEL1L
Name	SEL1L adaptor subunit of SYVN1 ubiquitin ligase
Location	14q31
Locus type	gene with protein product
Status	Approved
Aliases	IBD2, SEL1L1, Hrd3
Ensembl gene	ENSG00000071537
Ensembl biotype	protein_coding
OMIM	602329
Entrez	6400

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 3 retained_intron

ENST00000336735, ENST00000554293, ENST00000554744, ENST00000555824, ENST00000555923, ENST00000557372, ENST00000870905, ENST00000870906, ENST00000870907, ENST00000870908, ENST00000870909, ENST00000953128, ENST00000953129, ENST00000953130, ENST00000953131, ENST00000953132, ENST00000953133, ENST00000953134, ENST00000953135

RefSeq mRNA: 2 — MANE Select: NM_005065 NM_001244984, NM_005065

CCDS: CCDS58333, CCDS9876

Canonical transcript exons

ENST00000336735 — 21 exons

Exon	Start	End
ENSE00000659474	81492480	81492548
ENSE00000659478	81498413	81498494
ENSE00000659484	81506074	81506241
ENSE00000659486	81527701	81527738
ENSE00001158128	81479612	81479740
ENSE00001173673	81533675	81533853
ENSE00001201243	81487855	81487942
ENSE00001201251	81490388	81490465
ENSE00001271961	81489252	81489314
ENSE00001271990	81495081	81495137
ENSE00001272002	81497892	81498046
ENSE00001272066	81526733	81526964
ENSE00001272148	81484225	81484397
ENSE00001291157	81485672	81485746
ENSE00001310356	81486289	81486454
ENSE00001322142	81487390	81487538
ENSE00001389385	81471547	81477181
ENSE00003515222	81502721	81502883
ENSE00003517099	81504201	81504306
ENSE00003528077	81499459	81499518
ENSE00003599456	81499609	81499662

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.8349 / max 1052.5751, expressed in 1819 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144333	57.8349	1819

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.12	gold quality
pancreas	UBERON:0001264	97.74	gold quality
colonic epithelium	UBERON:0000397	96.84	gold quality
bone marrow cell	CL:0002092	96.74	gold quality
pericardium	UBERON:0002407	96.48	gold quality
decidua	UBERON:0002450	96.47	gold quality
cardia of stomach	UBERON:0001162	96.42	gold quality
pylorus	UBERON:0001166	95.95	gold quality
islet of Langerhans	UBERON:0000006	95.55	gold quality
jejunal mucosa	UBERON:0000399	95.54	gold quality
ileal mucosa	UBERON:0000331	95.53	gold quality
lower lobe of lung	UBERON:0008949	95.38	gold quality
superficial temporal artery	UBERON:0001614	95.32	gold quality
type B pancreatic cell	CL:0000169	95.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.28	gold quality
CA1 field of hippocampus	UBERON:0003881	95.18	gold quality
stromal cell of endometrium	CL:0002255	95.16	gold quality
subthalamic nucleus	UBERON:0001906	95.12	gold quality
medial globus pallidus	UBERON:0002477	95.10	gold quality
placenta	UBERON:0001987	95.07	gold quality
corpus epididymis	UBERON:0004359	95.04	gold quality
globus pallidus	UBERON:0001875	94.95	gold quality
duodenum	UBERON:0002114	94.88	gold quality
adrenal tissue	UBERON:0018303	94.87	gold quality
tibialis anterior	UBERON:0001385	94.79	gold quality
colonic mucosa	UBERON:0000317	94.77	gold quality
cauda epididymis	UBERON:0004360	94.77	gold quality
synovial joint	UBERON:0002217	94.70	gold quality
urethra	UBERON:0000057	94.64	gold quality
pons	UBERON:0000988	94.63	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	77.81
E-CURD-122	yes	46.46
E-ANND-3	yes	30.38
E-MTAB-8410	yes	25.20
E-CURD-46	yes	19.57
E-MTAB-10553	yes	8.95
E-CURD-11	no	652.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6

miRNA regulators (miRDB)

283 targeting SEL1L, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
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-4482-3P	99.98	72.50	3147

Literature-anchored findings (GeneRIF, showing 40)

• SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro. (PMID:11809711)
• Allele frequency of two intragenic microsatellite loci of SEL1L gene in Northern Italian population. (PMID:12030374)
• Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture. (PMID:12553058)
• Region within SEL1L between amino acid residues 659-794 contains a functionally relevant domain since a deletion mutant impairs SEL1L’s ability to suppress tumor cell growth. (PMID:14729273)
• SEL1L has a very complex structure consisting of 21 exons featuring several alternative transcripts encoding for putative protein isoforms. Its complexity ensures protein flexibility and specificity. (PMID:16331677)
• SEL1L alters the expression of mediators involved in the remodeling of the extracellular matrix by creating a microenvironment that is unfavorable to invasive growth. (PMID:16331889)
• A possible role of the novel polymorphism as independent susceptibility factor of Alzheimer’s dementia is shown (PMID:16412574)
• Overexpression of SEL1L protein is likely an early event during the pathogenesis of esophageal squamous cell carcinoma. (PMID:17822620)
• endoplasmic reticulum stress-induced HRD1 and SEL1 expressions are mediated by IRE1-XBP1- and ATF6-dependent pathways, respectively (PMID:17967421)
• OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD (PMID:18264092)
• These findings reveal a role for SEL1L and HRD1 in IgM quality control. (PMID:18314878)
• XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP (PMID:18502753)
• identified AUP1, UBXD8, UBC6e, and OS9 as functionally important components of this degradation complex formed by proteins that interact with SEL1L (PMID:18711132)
• knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6(G123D) and Cln6(M241T) polypeptides. (PMID:18811591)
• SEL1L-B and -C participate to novel molecular pathways that, in parallel with ERAD, contribute to the disposure of misfolded/unfolded or orphan proteins through degradation or secretion (PMID:19204006)
• Two new SEL1L variants are engaged in endosomal trafficking and secretion via vesicles, which could contribute to relieve ER stress in tumorigenic cells. (PMID:21359144)
• regulation of the stability and assembly of the HRD1-SEL1L complex is critical to optimize the degradation kinetics of ERAD substrates (PMID:21454652)
• the rs12435998 SNP in SEL1L gene plays a role in modifying age at diagnosis of PDA in Caucasian nonsmokers. (PMID:21656579)
• SEL1L expression is a potential colorectal cancer (CRC) tissue biomarker since its expression is significantly higher in adenoma cells with respect to normal mucosa; the levels of expression decrease in undifferentiated CRC cancers (PMID:22350780)
• ERdj5, by binding to Sel1L, triggers BiP-Cholera toxin interaction proximal to the Hrd1 complex; postulate this scenario enables the Hrd1-associated retrotranslocation machinery to capture the toxin efficiently once the toxin is released from BiP (PMID:23363602)
• Low expression of SEL1L is associated with pancreatic ductal adenocarcinoma. (PMID:23661430)
• ATF6 represents a novel type of ERAD-Lm substrate requiring SEL1L for degradation despite its transmembrane nature. (PMID:24043630)
• SEL1L down-modulation synergy enhances valporic acid cytotoxic effects by influencing glioma stem cells proliferation and self-renewal properties. (PMID:24311781)
• Data revealed close interaction of these two proteins in regulating the cross-talk between extracellular matrix and insulin signalling to create a favourable micro-environment for ss-cell development and function. (PMID:24324549)
• this is the first study reporting a significant association of the SEL1L SNP rs12435998 constitutive genetic variant with an improved overall survival in glioblastoma multiforme patients (PMID:25948789)
• The SEL1L critically regulates HRD1-mediated disposal of misfolded cargo through its short membrane spanning stretch. (PMID:26471130)
• Together, these results suggest that ER stress might comprise an important factor in GCD2 pathophysiology and that the effects of 4-PBA treatment might have important implications for the development of GCD2 therapeutics. (PMID:27373828)
• In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated endoplasmic reticulum stress, and delayed degradation which is dependent on SEL1L. (PMID:29371607)
• we found key statistical differences for the proteins SEL1, Notch3 and SOCS3 in the progression of uterine cervical cancer (PMID:29532409)
• Silencing of SEL1L during infection also stabilized an interaction of gO with the ER lectin OS-9, which likewise suggests that gO is an ER-associated degradation (ERAD) substrate. Taken together, our results identify an intriguing interaction of UL148 with the ERAD machinery and demonstrate that gO behaves as a constitutive ERAD substrate during infection. (PMID:29997207)
• SEL1L plays a major role in human malignant gliomas. (PMID:31111685)
• Sel1L-Hrd1 ER-associated degradation maintains beta cell identity via TGF-beta signaling. (PMID:32182217)
• Narrowing down the Common Cytogenetic Deletion 14q to a 5.6-Mb Critical Region in 1p/19q Codeletion Oligodendroglioma-Relapsed Patients Points to Two Potential Relapse-Related Genes: SEL1L and STON2. (PMID:32575107)
• SEL1L degradation intermediates stimulate cytosolic aggregation of polyglutamine-expanded protein. (PMID:33576152)
• Association between SYVN1 and SEL1 genetic polymorphisms and remission in rheumatoid arthritis patients treated with TNF-alpha inhibitors: a machine learning approach. (PMID:37119459)
• Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders. (PMID:37943610)
• Hypomorphic human SEL1L and HRD1 variants uncouple multilayered ER-associated degradation machinery. (PMID:38226624)
• Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover. (PMID:38378719)
• ER-associated degradation adapter Sel1L is required for CD8[+] T cell function and memory formation following acute viral infection. (PMID:38687642)
• Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. (PMID:39455574)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sel1l	ENSDARG00000004581
mus_musculus	Sel1l	ENSMUSG00000020964
rattus_norvegicus	Sel1l	ENSRNOG00000004464
drosophila_melanogaster	Hrd3	FBGN0028475
caenorhabditis_elegans		WBGENE00004759

Paralogs (4): DELE1 (ENSG00000081791), SEL1L3 (ENSG00000091490), SEL1L2 (ENSG00000101251), LRP2BP (ENSG00000109771)

Protein

Protein identifiers

Protein sel-1 homolog 1 — Q9UBV2 (reviewed: Q9UBV2)

Alternative names: Suppressor of lin-12-like protein 1

All UniProt accessions (2): Q9UBV2, G3V3B3

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Enhances SYVN1 stability. Plays a role in LPL maturation and secretion. Required for normal differentiation of the pancreas epithelium, and for normal exocrine function and survival of pancreatic cells. May play a role in Notch signaling.

Subunit / interactions. Homodimer and homooligomer. May form a complex with ERLEC1, HSPA5, OS9, and SYVN1. Interacts with FOXRED2 and EDEM1. Interacts with LPL. Interacts with LMF1; may stabilize the complex formed by LPL and LMF1 and thereby promote the export of LPL dimers. Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. SYNV1 assembles with SEL1L and FAM8A1 through its transmembrane domains, but interaction with its cytoplasmic domain is required to confer stability to FAM8A1 and enhance recruitment of HERPUD1. The interaction with SYNV1/HRD1 is direct. (Microbial infection) Interacts with human cytomegalovirus protein UL148.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Highly expressed in pancreas.

Post-translational modifications. N-glycosylated.

Disease relevance. Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies (NEDGSAF) [MIM:621067] A severe, autosomal recessive disorder with onset in infancy and characterized by developmental delay, absent speech, intellectual disability, short stature, microcephaly, facial dysmorphism, hypotonia, and/or ataxia. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia (NEDHGFA) [MIM:621068] A severe, autosomal recessive disorder with onset in early infancy and characterized by general developmental delay, intellectual disability, absent speech, severe axial hypotonia, short stature, and microcephaly. Patients exhibit agammaglobulinemia with no mature B cells, resulting in recurrent upper and lower respiratory infections and early death. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the sel-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBV2-1	1	yes
Q9UBV2-2	2

RefSeq proteins (2): NP_001231913, NP_005056* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000562	FN_type2_dom	Domain
IPR006597	Sel1-like	Repeat
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013806	Kringle-like	Homologous_superfamily
IPR036943	FN_type2_sf	Homologous_superfamily
IPR050767	Sel1_AlgK	Family

Pfam: PF00040, PF08238

UniProt features (88 total): helix 30, repeat 11, strand 11, region of interest 7, glycosylation site 5, sequence variant 5, compositionally biased region 3, turn 3, topological domain 2, disulfide bond 2, splice variant 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1, mutagenesis site 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8KET	ELECTRON MICROSCOPY	3.3
8KES	ELECTRON MICROSCOPY	3.5
8KEV	ELECTRON MICROSCOPY	3.5
9LWU	ELECTRON MICROSCOPY	3.5
9UAV	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBV2-F1	81.42	0.60

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 (1): 63

Disulfide bonds (2): 127–153, 141–168

Glycosylation sites (5): 195, 217, 272, 431, 608

Mutagenesis-validated functional residues (1):

Position	Phenotype
127	results in proteasome-mediated self-destruction of erad complex components and impaired degradation of erad substrates.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-1912420	Pre-NOTCH Processing in Golgi
R-HSA-382556	ABC-family protein mediated transport
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-901032	ER Quality Control Compartment (ERQC)
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5387390	Hh mutants abrogate ligand secretion
R-HSA-5619084	ABC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-597592	Post-translational protein modification
R-HSA-901042	Calnexin/calreticulin cycle

MSigDB gene sets: 445 (showing top): MYAATNNNNNNNGGC_UNKNOWN, REACTOME_SIGNALING_BY_NOTCH, GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GRUETZMANN_PANCREATIC_CANCER_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_308, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_PROTEIN_STABILIZATION, MODULE_301

GO Biological Process (8): triglyceride metabolic process (GO:0006641), Notch signaling pathway (GO:0007219), protein secretion (GO:0009306), retrograde protein transport, ER to cytosol (GO:0030970), ERAD pathway (GO:0036503), protein stabilization (GO:0050821), protein transport (GO:0015031), response to endoplasmic reticulum stress (GO:0034976)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): Hrd1p ubiquitin ligase complex (GO:0000836), Hrd1p ubiquitin ligase ERAD-L complex (GO:0000839), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Derlin-1 retrotranslocation complex (GO:0036513), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signal Transduction	2
Disease	2
Pre-NOTCH Expression and Processing	1
Transport of small molecules	1
Signaling by Hedgehog	1
Hh mutants abrogate ligand secretion	1
ABC transporter disorders	1
Calnexin/calreticulin cycle	1
Regulation of PD-L1(CD274) Post-translational modification	1
Signaling by NOTCH	1
Post-translational protein modification	1
Asparagine N-linked glycosylation	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disorders of transmembrane transporters	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acylglycerol metabolic process	1
cell surface receptor signaling pathway	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
regulation of protein stability	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
cellular response to stress	1
binding	1
ER ubiquitin ligase complex	1
Hrd1p ubiquitin ligase complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEL1L	SYVN1	Q86TM6	999
SEL1L	DERL1	Q9BUN8	996
SEL1L	OS9	Q13438	989
SEL1L	DERL2	Q9GZP9	981
SEL1L	UBE2J1	Q9Y385	977
SEL1L	FAF2	Q96CS3	966
SEL1L	ERLEC1	Q96DZ1	949
SEL1L	AUP1	Q9Y679	949
SEL1L	VCP	P55072	947
SEL1L	EDEM1	Q92611	940
SEL1L	DNAJC10	Q8IXB1	924
SEL1L	CANX	P27824	904
SEL1L	HSPA5	P11021	898
SEL1L	DERL3	Q96Q80	886
SEL1L	SELENOS	Q9BQE4	873

IntAct

197 interactions, top by confidence:

A	B	Type	Score
SEL1L	OS9	psi-mi:“MI:0914”(association)	0.860
SEL1L	OS9	psi-mi:“MI:0915”(physical association)	0.860
SYVN1	FAM8A1	psi-mi:“MI:0914”(association)	0.790
FAM8A1	SYVN1	psi-mi:“MI:0914”(association)	0.790
FOXRED2	SEL1L	psi-mi:“MI:0915”(physical association)	0.780
SEL1L	FOXRED2	psi-mi:“MI:0915”(physical association)	0.780
SYVN1	SEL1L	psi-mi:“MI:0914”(association)	0.770
SEL1L	SYVN1	psi-mi:“MI:0914”(association)	0.770
SYVN1	SEL1L	psi-mi:“MI:0915”(physical association)	0.770
AUP1	UBE2G2	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RXYLT1	FKTN	psi-mi:“MI:0914”(association)	0.710
SYVN1	OS9	psi-mi:“MI:0914”(association)	0.690
OS9	SYVN1	psi-mi:“MI:0914”(association)	0.690
USP15	SYVN1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (297): OS9 (Affinity Capture-MS), SYVN1 (Affinity Capture-MS), SYVN1 (Affinity Capture-Western), SEL1L (Affinity Capture-Western), SEL1L (Affinity Capture-Western), SEL1L (Affinity Capture-Western), ITGB4 (Affinity Capture-Western), SEL1L (Affinity Capture-MS), SEL1L (Affinity Capture-MS), SEL1L (Affinity Capture-MS), SEL1L (Affinity Capture-MS), SEL1L (Affinity Capture-MS), SEL1L (Affinity Capture-MS), OS9 (Affinity Capture-MS), UBE2J1 (Affinity Capture-MS)

ESM2 similar proteins: A7E2Z9, B0S5G3, E2RQ08, F1QR43, F1R520, O18756, O43556, O43909, O70258, O94923, O94985, P04843, P49256, P49257, P59481, P79282, Q09328, Q0V989, Q12907, Q24322, Q28F39, Q29S03, Q2HJD1, Q4R4T0, Q4R5B1, Q4V872, Q5R7F5, Q5RAP2, Q5RCF0, Q5RFB6, Q62902, Q6NVP8, Q6YAT4, Q70JA7, Q76KF0, Q8NFY4, Q8VDA1, Q91YQ5, Q9D0F3, Q9DBH5

Diamond homologs: O13875, Q3V172, Q5TEA6, Q5XI05, Q80Z70, Q9C6B6, Q9ESM7, Q9LM25, Q9UBV2, Q9Z2G6, A4KX75, D0EM77, D3ZTE0, G5EBU3, G5EGM1, O04529, O18733, O23507, O35548, O44836, O54732, O55761, O60449, O75900, O88272, O88676, O97507, P00748, P02751, P04937, P07589, P08169, P08253, P09237, P11276, P11717, P11722, P14780, P22757, P22897

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 207 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	5	14.7×	2e-03
Defective CFTR causes cystic fibrosis	9	13.7×	1e-05
Hh mutants are degraded by ERAD	7	11.8×	3e-04
Hedgehog ligand biogenesis	8	11.8×	1e-04
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	8	10.8×	2e-04
ABC-family protein mediated transport	9	7.6×	4e-04
SLC-mediated transmembrane transport	12	4.9×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
retrograde protein transport, ER to cytosol	11	60.2×	2e-15
ERAD pathway	18	18.0×	3e-15
endoplasmic reticulum unfolded protein response	8	13.1×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	79
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3602004	M528R	Pathogenic

SpliceAI

3169 predictions. Top by Δscore:

Variant	Effect	Δscore
14:81479604:CCA:C	donor_gain	1.0000
14:81479607:CTTA:C	donor_loss	1.0000
14:81479610:A:AC	donor_gain	1.0000
14:81479610:ACGT:A	donor_loss	1.0000
14:81479611:C:CA	donor_gain	1.0000
14:81479611:CG:C	donor_gain	1.0000
14:81479611:CGT:C	donor_gain	1.0000
14:81479611:CGTT:C	donor_gain	1.0000
14:81479611:CGTTT:C	donor_gain	1.0000
14:81479736:ATATC:A	acceptor_gain	1.0000
14:81479737:TATC:T	acceptor_gain	1.0000
14:81479739:TC:T	acceptor_gain	1.0000
14:81479740:CC:C	acceptor_gain	1.0000
14:81479740:CCTA:C	acceptor_loss	1.0000
14:81479741:C:CC	acceptor_gain	1.0000
14:81479746:A:AC	acceptor_gain	1.0000
14:81479749:C:CT	acceptor_gain	1.0000
14:81479750:A:T	acceptor_gain	1.0000
14:81479752:G:C	acceptor_gain	1.0000
14:81482835:T:A	donor_gain	1.0000
14:81484220:CTCA:C	donor_loss	1.0000
14:81484221:TCA:T	donor_loss	1.0000
14:81484222:CA:C	donor_loss	1.0000
14:81484223:A:C	donor_loss	1.0000
14:81484224:C:CT	donor_loss	1.0000
14:81484399:T:C	acceptor_gain	1.0000
14:81485668:TTACC:T	donor_loss	1.0000
14:81485669:TA:T	donor_loss	1.0000
14:81485670:A:AC	donor_gain	1.0000
14:81485670:AC:A	donor_gain	1.0000

AlphaMissense

5217 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:81477090:C:T	G756E	1.000
14:81477102:G:T	A752E	1.000
14:81477128:C:A	W743C	1.000
14:81477128:C:G	W743C	1.000
14:81477130:A:G	W743R	1.000
14:81477130:A:T	W743R	1.000
14:81479704:C:G	A695P	1.000
14:81479707:C:G	A694P	1.000
14:81479721:C:G	R689P	1.000
14:81479722:G:T	R689S	1.000
14:81479723:T:A	K688N	1.000
14:81479723:T:G	K688N	1.000
14:81479727:G:A	A687V	1.000
14:81479727:G:T	A687E	1.000
14:81479728:C:G	A687P	1.000
14:81479730:A:G	L686P	1.000
14:81479739:T:A	D683V	1.000
14:81479739:T:C	D683G	1.000
14:81479739:T:G	D683A	1.000
14:81479740:C:G	D683H	1.000
14:81484235:C:T	G679D	1.000
14:81484236:C:G	G679R	1.000
14:81484241:C:A	G677V	1.000
14:81484241:C:T	G677E	1.000
14:81484242:C:G	G677R	1.000
14:81484242:C:T	G677R	1.000
14:81484251:G:C	H674D	1.000
14:81484259:C:A	G671V	1.000
14:81484259:C:T	G671E	1.000
14:81484260:C:G	G671R	1.000

dbSNP variants (sampled 300 via entrez): RS1000098970 (14:81472925 A>G), RS1000194004 (14:81486894 G>A), RS1000373395 (14:81493637 C>G), RS1000377235 (14:81532920 T>C), RS1000379786 (14:81519158 A>G), RS1000389101 (14:81509862 G>A), RS1000411585 (14:81478273 A>C), RS1000412537 (14:81518911 T>TA), RS1000519510 (14:81495809 C>T), RS1000534438 (14:81525330 C>A), RS1000534710 (14:81473175 T>C), RS1000642752 (14:81487184 T>C), RS1000809848 (14:81507681 C>A), RS1000832882 (14:81533225 T>A,C), RS1000901878 (14:81482831 A>G)

Disease associations

OMIM: gene MIM:602329 | disease phenotypes: MIM:621067

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal recessive

Mondo (2): neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies (MONDO:0976130), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000049	Shawl scrotum
HP:0000054	Micropenis
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000400	Macrotia
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000778	Hypoplasia of the thymus
HP:0000817	Reduced eye contact
HP:0000821	Hypothyroidism
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001348	Brisk reflexes

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002312_9	Periodontal disease-related phenotype (Socransky)	7.000000e-06
GCST002936_14	Cadmium levels	9.000000e-06
GCST003542_76	Night sleep phenotypes	4.000000e-06
GCST005580_108	Intraocular pressure	1.000000e-08
GCST010989_64	Body size at age 10	3.000000e-10
GCST90002388_138	Lymphocyte count	3.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004587	lymphocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	increases expression, affects expression, decreases expression	3
Cyclosporine	increases expression	3
bisphenol A	increases expression	2
Nickel	increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
lasiocarpine	decreases expression	1
deoxynivalenol	decreases expression	1
lead acetate	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc protoporphyrin	affects cotreatment, decreases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
NCS 382	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
thifluzamide	increases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
enzalutamide	affects expression	1
NSC 689534	affects binding, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	affects expression	1
Air Pollutants	increases abundance, affects expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0UW	Ubigene Hep G2 SEL1L KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice