ERLIN2

Summary

ERLIN2 (ER lipid raft associated 2, HGNC:1356) is a protein-coding gene on chromosome 8p11.23, encoding Erlin-2 (O94905). Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1.

This gene encodes a member of the SPFH domain-containing family of lipid raft-associated proteins. The encoded protein is localized to lipid rafts of the endoplasmic reticulum and plays a critical role in inositol 1,4,5-trisphosphate (IP3) signaling by mediating ER-associated degradation of activated IP3 receptors. Mutations in this gene are a cause of spastic paraplegia-18 (SPG18). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 11160 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 18 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 229 total — 20 pathogenic, 12 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈5% of expected missense variation)
• Expression (HPA): Low tissue specificity — highest in choroid plexus, thyroid gland, parathyroid gland
• GTEx eGene: eQTL in 19 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 75
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 0.70 (unconstrained)
• MANE Select transcript: NM_007175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1356
Approved symbol	ERLIN2
Name	ER lipid raft associated 2
Location	8p11.23
Locus type	gene with protein product
Status	Approved
Aliases	NET32, Erlin-2
Ensembl gene	ENSG00000147475
Ensembl biotype	protein_coding
OMIM	611605
Entrez	11160

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 23 protein_coding, 5 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000519638

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3, TSL 3: 3, TSL 4: 1, TSL 5: 1

ENST00000519638, ENST00000335171, ENST00000518526, ENST00000518586, ENST00000519872, ENST00000521644, ENST00000521993, ENST00000523107, ENST00000523887, ENST00000647813, ENST00000648919, ENST00000861237, ENST00000861238, ENST00000861239, ENST00000861240, ENST00000861241, ENST00000861242, ENST00000861243, ENST00000861244, ENST00000963383, ENST00000963384, ENST00000983343, ENST00000983344, ENST00001020833, ENST00001020834, ENST00001067998, ENST00001067999, ENST00001068000, ENST00001126614, ENST00001126615, ENST00001126616

RefSeq mRNA: 5 — MANE Select: NM_007175 NM_001003790, NM_001003791, NM_001362878, NM_001362880, NM_007175

CCDS: CCDS34879, CCDS6095

Canonical transcript exons

ENST00000519638 — 12 exons

Exon	Start	End
ENSE00001027993	37751626	37751715
ENSE00001027994	37753450	37753529
ENSE00001027997	37749794	37749852
ENSE00001683883	37750395	37750486
ENSE00002139307	37753915	37758422
ENSE00003516997	37737908	37738029
ENSE00003521630	37741772	37741818
ENSE00003614770	37744571	37744696
ENSE00003622241	37740365	37740446
ENSE00003654515	37744355	37744416
ENSE00003655817	37749559	37749632
ENSE00003836324	37736634	37736678

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 96.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.6078 / max 302.5516, expressed in 1817 samples.

Highest expression (Bgee): choroid plexus epithelium, renal medulla, calcaneal tendon, islet of Langerhans, parotid gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ERLIN2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 21 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	8.1e-09	-0.55	8:37735588:C:T
Esophagus Mucosa	eqtl	2.4e-08	+0.70	8:37736607:C:A
Artery Aorta	eqtl	1.9e-06	-0.66	8:37735588:C:T
Adipose Subcutaneous	eqtl	6.3e-06	-0.56	8:37735588:C:T
Nerve Tibial	eqtl	2.0e-04	-0.38	8:37735588:C:T
Pancreas	eqtl	2.0e-04	-0.60	8:37735588:C:T
Colon Transverse	eqtl	5.0e-04	-0.37	8:37735588:C:T
Skin Sun Exposed Lower leg	eqtl	1.6e-03	-0.48	8:37694154:C:T
Esophagus Muscularis	eqtl	2.0e-03	-0.36	8:37735588:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.2e-03	-0.45	8:37735588:C:T
Artery Tibial	eqtl	4.3e-03	-0.37	8:37735588:C:T
Adipose Visceral Omentum	eqtl	6.0e-03	-0.43	8:37735588:C:T
Whole Blood	eqtl	7.3e-03	+0.21	8:37760432:A:G
Adrenal Gland	eqtl	8.0e-03	-0.46	8:37196862:T:C
Cells Cultured fibroblasts	eqtl	8.0e-03	-0.36	8:38162005:C:T
Nerve Tibial	sqtl	1.5e-02	+0.36	8:38566605:T:C
Ovary	eqtl	1.9e-02	-0.23	8:38600002:G:T
Lung	eqtl	2.2e-02	-0.31	8:37735588:C:T
Spleen	eqtl	3.2e-02	+0.44	8:37804320:TC:T
Esophagus Muscularis	sqtl	3.3e-02	+0.67	8:38349601:C:T

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
88444	16.7108	1790
88443	3.4937	1545
88445	2.5028	1338
88447	1.0209	476
88442	0.9156	654
88446	0.5174	289
88448	0.2384	87
88449	0.2083	100

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	96.91	gold quality
renal medulla	UBERON:0000362	93.27	gold quality
calcaneal tendon	UBERON:0003701	93.22	gold quality
islet of Langerhans	UBERON:0000006	93.05	gold quality
parotid gland	UBERON:0001831	92.48	gold quality
germinal epithelium of ovary	UBERON:0001304	92.41	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.38	gold quality
bronchial epithelial cell	CL:0002328	92.20	gold quality
adrenal tissue	UBERON:0018303	91.84	gold quality
nephron tubule	UBERON:0001231	91.63	gold quality
caput epididymis	UBERON:0004358	91.41	gold quality
stromal cell of endometrium	CL:0002255	91.39	gold quality
corpus epididymis	UBERON:0004359	91.34	gold quality
rectum	UBERON:0001052	91.19	gold quality
renal glomerulus	UBERON:0000074	91.06	gold quality
metanephric glomerulus	UBERON:0004736	90.97	gold quality
parietal pleura	UBERON:0002400	90.92	gold quality
mammary duct	UBERON:0001765	90.88	gold quality
pigmented layer of retina	UBERON:0001782	90.66	gold quality
seminal vesicle	UBERON:0000998	90.61	gold quality
pancreas	UBERON:0001264	90.45	gold quality
cranial nerve II	UBERON:0000941	90.40	gold quality
body of pancreas	UBERON:0001150	90.14	gold quality
epithelium of bronchus	UBERON:0002031	90.14	gold quality
epithelium of mammary gland	UBERON:0003244	90.04	gold quality
bronchus	UBERON:0002185	89.95	gold quality
pleura	UBERON:0000977	89.65	gold quality
tibia	UBERON:0000979	89.48	gold quality
cortex of kidney	UBERON:0001225	89.45	gold quality
thoracic mammary gland	UBERON:0005200	89.37	gold quality
mammary gland	UBERON:0001911	89.34	gold quality
gall bladder	UBERON:0002110	89.31	gold quality
ventricular zone	UBERON:0003053	89.21	gold quality
liver	UBERON:0002107	88.75	gold quality
decidua	UBERON:0002450	88.70	gold quality
palpebral conjunctiva	UBERON:0001812	88.67	gold quality
endometrium	UBERON:0001295	88.59	gold quality
skin of hip	UBERON:0001554	88.50	gold quality
hair follicle	UBERON:0002073	88.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.41	gold quality
endothelial cell	CL:0000115	88.40	gold quality
monocyte	CL:0000576	88.39	gold quality
sural nerve	UBERON:0015488	88.24	gold quality
mononuclear cell	CL:0000842	87.94	gold quality
thyroid gland	UBERON:0002046	87.68	gold quality
leukocyte	CL:0000738	87.61	gold quality
ovary	UBERON:0000992	87.60	gold quality
cauda epididymis	UBERON:0004360	87.54	gold quality
visceral pleura	UBERON:0002401	87.43	gold quality
kidney	UBERON:0002113	87.33	gold quality
saliva-secreting gland	UBERON:0001044	87.22	gold quality
left lobe of thyroid gland	UBERON:0001120	87.16	gold quality
left ovary	UBERON:0002119	87.14	gold quality
right lobe of thyroid gland	UBERON:0001119	87.12	gold quality
right uterine tube	UBERON:0001302	87.10	gold quality
right lobe of liver	UBERON:0001114	87.03	gold quality
esophagus squamous epithelium	UBERON:0006920	86.96	gold quality
popliteal artery	UBERON:0002250	86.74	gold quality
tibial artery	UBERON:0007610	86.74	gold quality
corpus callosum	UBERON:0002336	86.56	gold quality
adult mammalian kidney	UBERON:0000082	86.55	gold quality
descending thoracic aorta	UBERON:0002345	86.54	gold quality
blood vessel layer	UBERON:0004797	86.51	gold quality
right coronary artery	UBERON:0001625	86.50	gold quality
duodenum	UBERON:0002114	86.43	gold quality
right ovary	UBERON:0002118	86.43	gold quality
nasal cavity mucosa	UBERON:0001826	86.34	gold quality
right adrenal gland	UBERON:0001233	86.28	gold quality
urinary bladder	UBERON:0001255	86.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.21	gold quality
aorta	UBERON:0000947	86.17	gold quality
minor salivary gland	UBERON:0001830	86.15	gold quality
right adrenal gland cortex	UBERON:0035827	86.14	gold quality
colonic mucosa	UBERON:0000317	86.13	gold quality
uterus	UBERON:0000995	86.13	gold quality
female reproductive system	UBERON:0000474	86.12	gold quality
stomach	UBERON:0000945	86.11	gold quality
adrenal gland	UBERON:0002369	85.93	gold quality
metanephros	UBERON:0000081	85.85	gold quality
body of stomach	UBERON:0001161	85.83	gold quality
kidney epithelium	UBERON:0004819	85.81	gold quality
left adrenal gland	UBERON:0001234	85.66	gold quality
synovial joint	UBERON:0002217	85.61	gold quality
transverse colon	UBERON:0001157	85.59	gold quality
coronary artery	UBERON:0001621	85.56	gold quality
left coronary artery	UBERON:0001626	85.53	gold quality
mouth mucosa	UBERON:0003729	85.52	gold quality
thoracic aorta	UBERON:0001515	85.44	gold quality
ganglionic eminence	UBERON:0004023	85.43	gold quality
body of uterus	UBERON:0009853	85.43	gold quality
smooth muscle tissue	UBERON:0001135	85.38	gold quality
tendon	UBERON:0000043	85.33	gold quality
ascending aorta	UBERON:0001496	85.31	gold quality
epithelium of esophagus	UBERON:0001976	85.27	gold quality
left adrenal gland cortex	UBERON:0035825	85.25	gold quality
vermiform appendix	UBERON:0001154	85.21	gold quality
adipose tissue	UBERON:0001013	85.18	gold quality
endocervix	UBERON:0000458	85.16	gold quality
tonsil	UBERON:0002372	85.15	gold quality
colonic epithelium	UBERON:0000397	85.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.80
E-MTAB-7606	no	526.19

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	49.4
Thyroid gland	tissue	43.5	high
Parathyroid gland	tissue	38.9	medium
Liver	tissue	38.1	high
Kidney	tissue	37.7	high
Epididymis	tissue	30.5	high
Caudate putamen	tissue	28.5
Fallopian tube	tissue	28.3	high
Salivary gland	tissue	27.7	medium
Ovary	tissue	27.5	medium
Frontal cortex	tissue	25.3
Pancreas	tissue	24.7	medium
Prostate	tissue	23.9	medium
Stomach 1	tissue	23.5	high
Breast	tissue	23.4	high
Rectum	tissue	23.4	medium
Colon	tissue	22.7	medium
Seminal vesicle	tissue	22.4	medium
Small intestine	tissue	22.2	medium
Hippocampus	tissue	21.0	high
Nucleus accumbens	tissue	20.5
Spinal cord	tissue	20.4
Retina	tissue	20.0
Placenta	tissue	19.9	high
Endometrium 1	tissue	19.8	medium
Locus coeruleus	tissue	19.5
Adipose tissue	tissue	19.0	medium
Medulla oblongata	tissue	19.0
Cervix	tissue	18.8	low
Thalamus	tissue	18.7
Substantia nigra	tissue	18.6
Midbrain	tissue	18.5
Gallbladder	tissue	18.5	high
Periaqueductal gray	tissue	18.5
Pons	tissue	18.4
Smooth muscle	tissue	18.2	medium
Hypothalamus	tissue	18.2
Superior colliculi	tissue	18.2
Skeletal muscle	tissue	17.7	low
Hippocampal formation	tissue	17.1
Amygdala	tissue	16.9
Esophagus	tissue	16.8	medium
Duodenum	tissue	16.7	medium
Adrenal gland	tissue	16.7	medium
Heart muscle	tissue	16.6	not detected
Testis	tissue	15.9	high
Urinary bladder	tissue	15.7	medium
Septum	tissue	15.6
Cerebral cortex	tissue	15.5	high
Motor cortex	tissue	15.5
Postcentral gyrus	tissue	15.5
Somatosensory cortex	tissue	15.2
Entorhinal cortex	tissue	15.1
Prefrontal cortex	tissue	15.0
Corpus callosum	tissue	15.0
Temporal cortex	tissue	14.9
Putamen	tissue	14.8
Insular cortex	tissue	14.7
Cerebellum	tissue	14.6	high
Lung	tissue	14.6	high

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Periaquaductal grey, lateral (31.4), Area postrema (30.3), Cervical spinal cord, central gray (30.1), Corpus callosum, genu (white matter) (30.1), Periaquaductal grey, dorsal (29.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ERLIN2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 186 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
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-150-5P	99.99	66.69	1976
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-15A-5P	99.90	72.80	2787

Functional genomics

gnomAD constraint: pLI 0.01, LOEUF 0.703, missense Z 3.31 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000519638 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈5% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
8:37,737,923–37,744,612	93 / 139.0	0.67	no
8:37,744,613–37,744,659	1 / 18.9	0.05	yes (p 3.9e-05)
8:37,744,660–37,754,112	153 / 256.4	0.60	no

Literature-anchored findings (GeneRIF, showing 25)

• Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. (PMID:16835267)
• SPFH2 as a key endoplasmic reticulum associated degradation pathway component and suggest that it may act as a substrate recognition factor. (PMID:17502376)
• Results suggest that this novel SPFH1/2 complex is a recognition factor that targets IP(3)Rs and perhaps other substrates for ERAD. (PMID:19240031)
• m3 receptor-expressing HeLa cells are a valuable system for studying IP(3) receptor ERAD, and suggest that the SPFH1/2 complex is a factor that selectively mediates the ERAD of activated IP(3) receptors. (PMID:19751772)
• The gene encodes endoplasmic reticulum (ER) lipid raft-associated protein 2 that mediates the ER-associated degradation of activated inositol 1,4,5-trisphosphate receptors and other substrates. (PMID:21330303)
• study describes an extended consanguineous Saudi family in which hereditary spastic paraplegia is linked to SPG18, an autosomal recessive locus, and show it is associated with a nullimorphic deletion of ERLIN2 (PMID:21796390)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• ERLIN2 may confer a selective growth advantage for breast cancer cells by facilitating a cytoprotective response to various cellular stresses associated with oncogenesis. (PMID:22681620)
• a novel role for ERLIN2 in supporting cancer cell growth by promoting the activation of the key lipogenic regulator SREBP1c and the production of cytosolic lipid droplets. (PMID:22690709)
• a novel brain gamma-secretase associated protein , erlin-2, that resides in detergent resistant membranes and affects amyloid beta-peptide production. (PMID:22771797)
• ERLIN2 was found to be responsible for causing hereditary spastic paraplegia in a Saudi family. (PMID:23085305)
• ERLIN2 loss on cell growth may advance understanding of the mechanism behind motor neuron degeneration in primary lateral sclerosis (PMID:23109145)
• Erlin-2 and the related erlin-1 were found to negatively regulate cholesterol and fatty acid biosynthesis in cultured cell models when the proteins were depleted by RNAi. The proteins also selectively bound cholesterol. (PMID:24217618)
• Here we show that the multimeric ER proteins erlins-1 and -2 are additional sterol regulatory element binding protein regulators. (PMID:24217618)
• Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18 (PMID:27824013)
• Here we suggest that ERLIN1 variants, previously shown in juvenile hereditary spastic paraplegia cases, may also be the cause of a slowly progressive early-onset Amyotrophic lateral sclerosis (ALS) , starting with upper motor neuron features and developing into classical ALS with the addition of lower motor neuron dysfunction. (PMID:29453415)
• Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. (PMID:29528531)
• An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18). (PMID:32094424)
• Expansion of the genetic landscape of ERLIN2-related disorders. (PMID:32147972)
• Molecular and Immune Characteristics for Lung Adenocarcinoma Patients With ERLIN2 Overexpression. (PMID:33424830)
• Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection. (PMID:37683630)
• A novel autosomal dominant ERLIN2 variant activates endoplasmic reticulum stress in a Chinese HSP family. (PMID:37752894)
• KCNN1 promotes proliferation and metastasis of breast cancer via ERLIN2-mediated stabilization and K63-dependent ubiquitination of Cyclin B1. (PMID:37831636)
• Novel ERLIN2 variant expands the phenotype of Spastic Paraplegia 18. (PMID:38159148)
• The erlin1/erlin2 complex binds to and stabilizes phosphatidylinositol 3-phosphate and regulates autophagy. (PMID:39018973)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	erlin2	ENSDARG00000086523
mus_musculus	Erlin2	ENSMUSG00000031483
rattus_norvegicus	Erlin2	ENSRNOG00000013763
caenorhabditis_elegans		WBGENE00016592

Paralogs (1): ERLIN1 (ENSG00000107566)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2387215) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased circulating amylase level	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	Q5R7C5	100.0%	Diamond
Bos taurus	Q1RMU4	97.6%	Diamond
Xenopus laevis	Q5XH03	93.1%	Diamond
Xenopus tropicalis	Q28J34	90.2%	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
ZNF703	protein-coding	80139
PLPBP	protein-coding	11212
ADGRA2	protein-coding	25960
BRF2	protein-coding	55290
RAB11FIP1	protein-coding	80223

Protein

Protein identifiers

Erlin-2 — O94905 (reviewed: O94905)

Alternative names: Endoplasmic reticulum lipid raft-associated protein 2, Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2

All UniProt accessions (4): O94905, A0A384ME54, E5RHW4, E5RJ09

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1. Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex. Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex.

Subunit / interactions. Forms a heteromeric complex with ERLIN1. In complex with ERLIN1, interacts with RNF170. Interacts with activated ITPR1, independently of the degree of ITPR1 polyubiquitination. Interacts with SCAP, INSIG1, SREBF1 and SREBF2 under cholesterol sufficiency conditions; indicative for an association with the SCAP-SREBP-INSIG complex. Probably part of an AMFR/gp78 and INSIG1-containing ubiquitin ligase complex involved in ERAD of HMGCR. Interacts with TMUB1; TMUB1 bridges the association with AMFR. Interacts with SYVN1 and RNF139. Interacts with TMEM259. Interacts with TMEM41B.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Deubiquitinated by USP25; leading to stabilization.

Disease relevance. Spastic paraplegia 18B, autosomal recessive (SPG18B) [MIM:611225] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG18B is a severe form with onset in early childhood. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 18A, autosomal dominant (SPG18A) [MIM:620512] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG18A is a pure form. Age at onset of symptoms varies considerably from childhood to adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the band 7/mec-2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O94905-1	1	yes
O94905-2	2
O94905-3	3

RefSeq proteins (5): NP_001003790, NP_001003791, NP_001349807, NP_001349809, NP_009106* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001107	Band_7	Domain
IPR033294	Erlin1/2	Family
IPR036013	Band_7/SPFH_dom_sf	Homologous_superfamily

Pfam: PF01145

UniProt features (18 total): sequence variant 5, splice variant 4, topological domain 2, chain 1, mutagenesis site 1, sequence conflict 1, transmembrane region 1, region of interest 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
9WFF	Cryo-EM structure of the human Erlin2 oligomer	ELECTRON MICROSCOPY	2.12
9VVJ	Cryo-EM structure of the erlin1/2 complex purified using DDM and GDN	ELECTRON MICROSCOPY	2.6
9VVG	Cryo-EM structure of the erlin1/2 complex purified using GDN and CHS	ELECTRON MICROSCOPY	2.7
9O9U	The Erlin1/2 complex	ELECTRON MICROSCOPY	3
9WE7	Cryo-EM structure of RNF170-Erlin1-Erlin2	ELECTRON MICROSCOPY	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94905-F1	85.35	0.70

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Accessory Factors Involved in Transport, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum

Antibody reliability (HPA): IH supported · IF supported

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)

Type	Positions
N6-acetyllysine	267

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	106

Mutagenesis-validated functional residues (1)

Position	Phenotype
106	loss of glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 12; 9 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-5678895	Defective CFTR causes cystic fibrosis ⚕	curated
R-HSA-5655302	Signaling by FGFR1 in disease ⚕	curated
R-HSA-8853336	Signaling by plasma membrane FGFR1 fusions ⚕	curated
R-HSA-382556	ABC-family protein mediated transport	curated
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	curated
R-HSA-5619084	ABC transporter disorders ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-5619115	Disorders of transmembrane transporters ⚕	—
R-HSA-1839124	FGFR1 mutant receptor activation ⚕	—
R-HSA-1226099	Signaling by FGFR in disease ⚕	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 398 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, ACTACCT_MIR196A_MIR196B, TAATAAT_MIR126, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (8): cholesterol metabolic process (GO:0008203), SREBP signaling pathway (GO:0032933), ERAD pathway (GO:0036503), regulation of cholesterol biosynthetic process (GO:0045540), negative regulation of cholesterol biosynthetic process (GO:0045541), negative regulation of fatty acid biosynthetic process (GO:0045717), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202)

GO Molecular Function (3): cholesterol binding (GO:0015485), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), protein-containing complex (GO:0032991), membrane raft (GO:0045121)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Disease	2
Transport of small molecules	1
Signaling by FGFR in disease	1
ABC transporter disorders	1
FGFR1 mutant receptor activation	1
Regulation of PD-L1(CD274) Post-translational modification	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Signaling by FGFR1 in disease	1
Disorders of transmembrane transporters	1

GO top-level categories

35 GO namespaces:

Category	Terms
cholesterol biosynthetic process	2
sterol metabolic process	1
secondary alcohol metabolic process	1
ER-nucleus signaling pathway	1
cellular response to sterol depletion	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
regulation of cholesterol metabolic process	1
regulation of sterol biosynthetic process	1
regulation of alcohol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
negative regulation of cholesterol metabolic process	1
negative regulation of sterol biosynthetic process	1
negative regulation of alcohol biosynthetic process	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
sterol binding	1
alcohol binding	1
ubiquitin-like protein ligase binding	1
binding	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
membrane	1
cell periphery	1
cellular_component	1
membrane microdomain	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 16 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
ERAD pathway	BP	direct assay
SREBP signaling pathway	BP	mutant phenotype
negative regulation of cholesterol biosynthetic process	BP	mutant phenotype
negative regulation of fatty acid biosynthetic process	BP	mutant phenotype
regulation of cholesterol biosynthetic process	BP	direct assay
endoplasmic reticulum	CC	direct assay
endoplasmic reticulum membrane	CC	direct assay
membrane raft	CC	direct assay
protein-containing complex	CC	direct assay
ubiquitin protein ligase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,346 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERLIN2	ITPR1	Q14643	748
ERLIN2	TMUB1	Q9BVT8	666
ERLIN2	RNF170	Q96K19	646
ERLIN2	DDHD2	O94830	621
ERLIN2	PLPBP	O94903	571
ERLIN2	STOM	P27105	559
ERLIN2	TM2D2	Q9BX73	557
ERLIN2	ZNF703	Q9H7S9	550
ERLIN2	AP4E1	Q9UPM8	508
ERLIN2	REEP2	Q9BRK0	506
ERLIN2	REEP1	Q9H902	504
ERLIN2	AP5Z1	O43299	504
ERLIN2	SPG11	Q96JI7	493
ERLIN2	AP4B1	Q9Y6B7	490
ERLIN2	UBQLN2	Q9UHD9	489

IntAct

Human interaction partners of ERLIN2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
ERLIN1	physical association	0.740	1
AMFR	physical association	0.660	5
TMUB1	physical association	0.660	3
SYVN1	physical association	0.560	1
HMGCR	physical association	0.500	2
PRRC2B	physical association	0.400	1
RNF139	physical association	0.400	1
STOM	physical association	0.000	1

BioGRID (601 interactions; top human partners by supporting records in a sample of 600 records): ERLIN1 (Affinity Capture-MS; 23 records), TMUB1 (Affinity Capture-MS; 10 records), RNF185 (Affinity Capture-Western; 7 records), AMFR (Affinity Capture-MS; 6 records), HSPA5 (Affinity Capture-MS; 5 records), RNF170 (Affinity Capture-Western; 5 records), CANX (Affinity Capture-MS; 4 records), INSIG1 (Affinity Capture-MS; 4 records), ITPR1 (Affinity Capture-Western; 4 records), RIPK2 (Affinity Capture-MS; 4 records), TMEM259 (Affinity Capture-MS; 4 records), FAP (Affinity Capture-MS; 3 records), FBXO6 (Affinity Capture-MS; 3 records), FKBP14 (Affinity Capture-MS; 3 records), GSTM5 (Affinity Capture-MS; 3 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
ERLIN2	“form complex”	Erlin	binding

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
HRD1 complex	13	AUP1, BSG, ERLEC1, FAM8A1, HSP90B1, OS9, SYVN1, UBE2J1, DERL2, ERLIN2, FAF2, HSPA5, SEL1L
erlin1/2-RNF170 complex	3	RNF170, ERLIN1, ERLIN2
AMFR-ERLIN2-TMUB1 complex	3	AMFR, ERLIN2, TMUB1

Disease & clinical

Genetic variants

Variant evidence for ERLIN2: 229 ClinVar records (32 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	12
Uncertain significance	95
Likely benign	64
Benign	13

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 32 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
280398	NM_007175.8(ERLIN2):c.17del (p.Ala6fs)	Pathogenic	criteria provided, single submitter	1
374613	NM_007175.8(ERLIN2):c.237-1G>A	Pathogenic	criteria provided, single submitter	1
639125	NM_007175.8(ERLIN2):c.46del (p.Cys16fs)	Pathogenic	criteria provided, single submitter	1
817651	NM_007175.8(ERLIN2):c.353del (p.Asn118fs)	Pathogenic	criteria provided, single submitter	1
834707	NM_007175.8(ERLIN2):c.303T>A (p.Tyr101Ter)	Pathogenic	criteria provided, single submitter	1
959955	NM_007175.8(ERLIN2):c.853A>T (p.Lys285Ter)	Pathogenic	criteria provided, single submitter	1
989002	NM_007175.8(ERLIN2):c.374A>G (p.Asn125Ser)	Pathogenic	criteria provided, single submitter	1
989003	NM_007175.8(ERLIN2):c.430A>G (p.Ile144Val)	Pathogenic	criteria provided, single submitter	1
989004	NM_007175.8(ERLIN2):c.799A>G (p.Lys267Glu)	Pathogenic	criteria provided, single submitter	1
989005	NM_007175.8(ERLIN2):c.819G>A (p.Lys273=)	Pathogenic	criteria provided, single submitter	1
989006	NM_007175.8(ERLIN2):c.877A>G (p.Ser293Gly)	Pathogenic	criteria provided, single submitter	1
1071452	NM_007175.8(ERLIN2):c.367G>T (p.Glu123Ter)	Pathogenic	criteria provided, single submitter	1
2579114	NM_007175.8(ERLIN2):c.47_48delinsAA (p.Cys16Ter)	Pathogenic	criteria provided, single submitter	1
2663863	NM_007175.8(ERLIN2):c.660del (p.Val221fs)	Pathogenic	criteria provided, single submitter	1
2735636	NM_007175.8(ERLIN2):c.303del (p.Val100_Tyr101insTer)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ERLIN2’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; 26 predictions of 1,182):

Position(s)	Effect	Δscore	Sites
8:37749557–37749558	acceptor_loss	1.0000	6
8:37749633–37749634	donor_loss	1.0000	4
8:37749853–37749854	donor_loss	1.0000	3
8:37754062	donor_gain	1.0000
8:37754108	donor_gain	1.0000
8:37749553	acceptor_gain	0.9900
8:37749633–37749634	donor_loss	0.9900	2
8:37749792–37749793	acceptor_loss	0.9900	6
8:37749853	donor_loss	0.9900
8:37750470	donor_gain	0.9900

AlphaMissense

1,280 missense substitutions predicted likely pathogenic (of 2,247 scored), across 273 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
F141	8	0.999	1.000
D145	8	0.999	1.000
D69	8	0.998	0.999
D112	8	0.998	1.000
H122	8	0.998	1.000
H121	8	0.994	1.000
N125	8	0.994	1.000
S129	8	0.994	1.000
N93	8	0.987	1.000
H24	8	0.985	0.998
F127	8	0.983	0.999
D142	8	0.982	0.997
F86	8	0.962	0.999
H50	8	0.958	0.998
H131	8	0.958	0.999
M186	8	0.919	0.979
D247	8	0.917	0.988
N182	8	0.894	0.994
D155	8	0.880	0.983
D87	8	0.869	0.986

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.43e-08
Kidney Chromophobe (TCGA)	unfavorable	0.000331

Disease associations

OMIM: gene MIM:611605 | disease phenotypes: MIM:303350 (MASA syndrome), MIM:611225 (Spastic paraplegia 18, autosomal recessive), MIM:620512 (Spastic paraplegia 18A, autosomal dominant)

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
hereditary spastic paraplegia 18	Strong	Autosomal recessive	3
spastic paraplegia 18b, autosomal recessive	Strong	Autosomal recessive	2
spastic paraplegia 18a, autosomal dominant	Strong	Autosomal dominant
juvenile primary lateral sclerosis	Supportive	Autosomal recessive
recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

2 validity classifications:

Disease	Classification	Inheritance
hereditary spastic paraplegia 18	Limited	AD
hereditary spastic paraplegia 18	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
Adult-onset neurological disorders	green
Hereditary spastic paraplegia	green
Hereditary spastic paraplegia, adult onset	green
Hereditary spastic paraplegia, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green

Mondo (6): hereditary spastic paraplegia 18 (MONDO:0012639), spastic paraplegia 18b, autosomal recessive (MONDO:0700309), spastic paraplegia 18a, autosomal dominant (MONDO:0957788), juvenile primary lateral sclerosis (MONDO:0011663), recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome (MONDO:0017232), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (2): Autosomal spastic paraplegia type 18 (Orphanet:209951), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

showing 60 of 75 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000014	Abnormality of the bladder
HP:0000020	Urinary incontinence
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000218	High palate
HP:0000322	Short philtrum
HP:0000377	Abnormal pinna morphology
HP:0000486	Strabismus
HP:0000574	Thick eyebrow
HP:0000664	Synophrys
HP:0000666	Horizontal nystagmus
HP:0000763	Sensory neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001583	Rotary nystagmus
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002079	Hypoplasia of the corpus callosum
HP:0002127	Abnormal upper motor neuron morphology
HP:0002141	Gait imbalance
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002193	Pseudobulbar affect
HP:0002371	Loss of speech
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002376	Developmental regression
HP:0002378	Hand tremor
HP:0002460	Distal muscle weakness
HP:0002464	Spastic dysarthria
HP:0002505	Loss of ambulation
HP:0002540	Inability to walk
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0002987	Elbow flexion contracture
HP:0003121	Limb joint contracture
HP:0003202	Skeletal muscle atrophy
HP:0003273	Hip contracture
HP:0003306	Spinal rigidity
HP:0003401	Paresthesia
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0003677	Slowly progressive
HP:0005830	Flexion contracture of toe
HP:0005997	Neck joint contracture

GWAS associations

1 association:

Study	Trait	p-value
GCST002115_11	Axial length	3e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0005318	axial length measurement

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C536416	Primary lateral sclerosis juvenile *(supp.)*
C567628	Spastic Paraplegia 18, Autosomal Recessive *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739672 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.51	Kd	3055	nM	CHEMBL5653589
5.51	ED50	3055	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148334: Binding affinity to human ERLIN2 incubated for 45 mins by Kinobead based pull down assay	kd	3.0553	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
sodium arsenite	affects methylation, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
cobaltous chloride	decreases expression	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	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
bisphenol B	increases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Benztropine	affects cotreatment, increases expression	1
Cadmium	increases abundance, increases expression	1
Cuprizone	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Diethylstilbestrol	decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4700046	Binding	Binding affinity to ERLIN2 in human K562 cells at 1 mM incubated for 2 hrs by LC-MS/MS analysis based pull down assay relative to control	Understanding the mechanism of action of pyrrolo[3,2-b]quinoxaline-derivatives as kinase inhibitors — *RSC Med Chem*

Clinical trials (associated diseases)

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

55 trials:

NCT	Phase	Status	Title
NCT07542548	Phase 4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT07803276	Phase 4	RECRUITING	Comparison Between Palpatory and Ultrasound-guided Methods for Botulinum Toxin Administration in Spastic Paraplegia
NCT03961906	Phase 2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	Phase 2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	Phase 1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	Phase 2/3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	Phase 1/2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (Serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	Phase 1/2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	Early Phase 1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	ACTIVE_NOT_RECRUITING	Enhancement of Quality of Work And Life
NCT06680063	Not specified	COMPLETED	Correlation Between Clinical Assessment and Neurophysiological Assessment in Spinal Cord Injury
NCT06728787	Not specified	RECRUITING	Robot-assisted Walking Treatment in Hereditary Spastic Paraplegia (HSP)
NCT06740006	Not specified	COMPLETED	Retrospective Study on the WalkOn AFO in Children or Teenagers With Neurological Pathologies
NCT06742697	Not specified	RECRUITING	Flexibility, Resistance, Aerobic, Movement Execution Training in Adults With Hereditary Spastic Paraplegia
NCT06844734	Not specified	RECRUITING	A Prospective Cohort Study of ITB Treatment for HSP
NCT06936163	Not specified	RECRUITING	A Prospective Cohort Study of Surgical Treatment for Foot Deformities in HSP
NCT07090057	Not specified	RECRUITING	The Effect of Targeting the Plantaris Muscle-tendon in Surgical Correction of Ankle Equinus in Children
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07352085	Not specified	COMPLETED	Exoskeleton-assisted Neurorehabilitation
NCT07417943	Not specified	RECRUITING	Neuromodulation to Enhance Motor Function in HSP
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT07561359	Not specified	ENROLLING_BY_INVITATION	12-Week Strength and Functional Exercise Program for Hereditary Spastic Paraplegia Trial (HSPMOVE)
NCT07706517	Not specified	COMPLETED	Assessing Transition Practices for Children With Disabilities: Pathways to a Successful Adulthood
NCT07798674	Not specified	RECRUITING	TreatHSP Platform: Adaptive Natural History Platform for Ataxias, HSPs, and Spastic Ataxias
NCT07799233	Not specified	COMPLETED	Dental-Oral and Craniofacial Characteristics of Hereditary Spastic Paraplegia: A Preliminary Study

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ERLIN2 across ~30M SureChEMBL compounds — explore on Sugi Predict.