ERLIN1

Summary

ERLIN1 (ER lipid raft associated 1, HGNC:16947) is a protein-coding gene on chromosome 10q24.31, encoding Erlin-1 (O75477). Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs).

The protein encoded by this gene is part of a protein complex that mediates degradation of inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum. The encoded protein also binds cholesterol and regulates the SREBP signaling pathway, which promotes cellular cholesterol homeostasis. Defects in this gene have been associated with spastic paraplegia 62.

Source: NCBI Gene 10613 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 62 (Definitive, ClinGen)
• GWAS associations: 18
• Clinical variants (ClinVar): 187 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• MANE Select transcript: NM_006459

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16947
Approved symbol	ERLIN1
Name	ER lipid raft associated 1
Location	10q24.31
Locus type	gene with protein product
Status	Approved
Aliases	KE04, Erlin-1, SPG62
Ensembl gene	ENSG00000107566
Ensembl biotype	protein_coding
OMIM	611604
Entrez	10613

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000370408, ENST00000407654, ENST00000421367, ENST00000971770

RefSeq mRNA: 8 — MANE Select: NM_006459 NM_001100626, NM_001347856, NM_001347857, NM_001347858, NM_001347859, NM_001347860, NM_001347861, NM_006459

CCDS: CCDS7487

Canonical transcript exons

ENST00000421367 — 11 exons

Exon	Start	End
ENSE00000720450	100167348	100167406
ENSE00000720451	100174208	100174281
ENSE00000720456	100183756	100183837
ENSE00000987316	100156145	100156234
ENSE00001614541	100175945	100176070
ENSE00001712262	100185514	100186029
ENSE00001751571	100164004	100164095
ENSE00001881075	100150094	100152352
ENSE00002481546	100178133	100178194
ENSE00002515720	100179201	100179247
ENSE00003785045	100154860	100154939

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6020 / max 111.9375, expressed in 1761 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111024	8.6137	1733
111023	1.8829	1090
111019	0.1054	30

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	98.17	gold quality
oocyte	CL:0000023	97.06	gold quality
esophagus squamous epithelium	UBERON:0006920	96.93	gold quality
squamous epithelium	UBERON:0006914	96.82	gold quality
cervix squamous epithelium	UBERON:0006922	96.82	gold quality
palpebral conjunctiva	UBERON:0001812	96.70	gold quality
gingival epithelium	UBERON:0001949	96.62	gold quality
tibia	UBERON:0000979	96.30	gold quality
epithelium of esophagus	UBERON:0001976	96.13	gold quality
gingiva	UBERON:0001828	95.83	gold quality
bronchial epithelial cell	CL:0002328	95.53	gold quality
epithelium of bronchus	UBERON:0002031	95.42	gold quality
trabecular bone tissue	UBERON:0002483	95.36	gold quality
bronchus	UBERON:0002185	95.29	gold quality
penis	UBERON:0000989	95.08	gold quality
liver	UBERON:0002107	95.07	gold quality
jejunal mucosa	UBERON:0000399	94.73	gold quality
placenta	UBERON:0001987	94.65	gold quality
tongue squamous epithelium	UBERON:0006919	94.54	gold quality
urethra	UBERON:0000057	94.51	gold quality
colonic mucosa	UBERON:0000317	94.40	gold quality
mammalian vulva	UBERON:0000997	94.34	gold quality
nasal cavity epithelium	UBERON:0005384	94.33	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.26	gold quality
cervix epithelium	UBERON:0004801	94.25	gold quality
decidua	UBERON:0002450	94.14	gold quality
upper leg skin	UBERON:0004262	94.14	gold quality
pylorus	UBERON:0001166	94.04	gold quality
epithelium of nasopharynx	UBERON:0001951	93.99	gold quality
duodenum	UBERON:0002114	93.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	15.80
E-CURD-112	yes	8.56
E-MTAB-9801	yes	4.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

119 targeting ERLIN1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1305	99.91	71.43	3443

Literature-anchored findings (GeneRIF, showing 12)

• 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)
• 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)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of fatty liver accumulation to hepatic inflammation. (PMID:23477746)
• Erlin-1 and the related erlin-2 were found to selectively bind cholesterol. Knockdown of the proteins by RNAi in cultured cells resulted in high levels of cholesterol and fatty acid biosynthesis in the presence of cholesterol sufficiency. (PMID:24217618)
• Here we show that the multimeric ER proteins erlins-1 and -2 are additional sterol regulatory element binding protein regulators. (PMID:24217618)
• erlin-1 protein is required early in the infection, downstream of cell entry and primary translation, specifically to initiate RNA replication, and later in the infection to support infectious virus production. This study identifies erlin-1 protein as an important cellular factor regulating HCV infection. (PMID:31810281)
• Disruption of the ERLIN-TM6SF2-APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease. (PMID:32776921)
• Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection. (PMID:37683630)
• The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD. (PMID:38776916)
• 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	erlin1	ENSDARG00000021991
mus_musculus	Erlin1	ENSMUSG00000025198
rattus_norvegicus	Erlin1	ENSRNOG00000012911
caenorhabditis_elegans		WBGENE00016592

Paralogs (1): ERLIN2 (ENSG00000147475)

Protein

Protein identifiers

Erlin-1 — O75477 (reviewed: O75477)

Alternative names: Endoplasmic reticulum lipid raft-associated protein 1, Protein KE04, Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 1

All UniProt accessions (2): O75477, B0QZ43

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). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. Binds cholesterol and may promote ER retention of the SCAP-SREBF complex. (Microbial infection) Required early in hepatitis C virus (HCV) infection to initiate RNA replication, and later in the infection to support infectious virus production.

Subunit / interactions. Forms a heteromeric complex with ERLIN2. In complex with ERLIN2, interacts with RNF170. Interacts with AMFR and SYVN1.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in heart, placenta, liver, kidney, pancreas, prostate, testis, ovary and small intestine.

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

Disease relevance. Spastic paraplegia 62, autosomal recessive (SPG62) [MIM:615681] 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. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (8): NP_001094096, NP_001334785, NP_001334786, NP_001334787, NP_001334788, NP_001334789, NP_001334790, NP_006450* (*=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 (10 total): topological domain 2, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1, modified residue 1, glycosylation site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9VVJ	ELECTRON MICROSCOPY	2.6
9VVG	ELECTRON MICROSCOPY	2.7
9O9U	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75477-F1	85.49	0.73

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): 269

Glycosylation sites (1): 108

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-382556	ABC-family protein mediated transport
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)

MSigDB gene sets: 352 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, CMYB_01, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_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 (4): cholesterol binding (GO:0015485), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), protein-containing complex (GO:0032991), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Transport of small molecules	1
ABC transporter disorders	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cholesterol biosynthetic process	2
binding	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
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
cellular_component	1
membrane microdomain	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1081 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERLIN1	PHB1	P35232	981
ERLIN1	ERLIN2	O94905	917
ERLIN1	RNF170	Q96K19	818
ERLIN1	GPT	P24298	704
ERLIN1	CHUK	O15111	637
ERLIN1	AMFR	P26442	633
ERLIN1	TMUB1	Q9BVT8	625
ERLIN1	FAF2	Q96CS3	586
ERLIN1	RNF185	Q96GF1	583
ERLIN1	CWF19L1	Q69YN2	572
ERLIN1	CCDC47	Q96A33	564
ERLIN1	UBAC2	Q8NBM4	563
ERLIN1	STOM	P27105	551
ERLIN1	HMGCR	P04035	536
ERLIN1	VCP	P55072	513

IntAct

196 interactions, top by confidence:

A	B	Type	Score
ERLIN1	ERLIN2	psi-mi:“MI:0915”(physical association)	0.740
ERLIN2	ERLIN1	psi-mi:“MI:0914”(association)	0.740
ERLIN1	ERLIN2	psi-mi:“MI:0914”(association)	0.740
AGR3	ERLIN1	psi-mi:“MI:0915”(physical association)	0.720
SEC22A	ERLIN1	psi-mi:“MI:0915”(physical association)	0.720
ERLIN1	AGR3	psi-mi:“MI:0915”(physical association)	0.720
ERLIN1	SEC22A	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
rep	EIF4E2	psi-mi:“MI:0914”(association)	0.640
ERLIN1	C6orf120	psi-mi:“MI:0915”(physical association)	0.620
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
	ERLIN1	psi-mi:“MI:0915”(physical association)	0.560
VMA12	ERLIN1	psi-mi:“MI:0915”(physical association)	0.560
ERLIN1	VMA12	psi-mi:“MI:0915”(physical association)	0.560
ERLIN1		psi-mi:“MI:0915”(physical association)	0.560

BioGRID (283): ERLIN1 (Affinity Capture-MS), SEC22A (Two-hybrid), FA2H (Two-hybrid), TMEM199 (Two-hybrid), AGR3 (Two-hybrid), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), ERLIN1 (Proximity Label-MS), ERLIN1 (Affinity Capture-MS)

ESM2 similar proteins: A3QK16, B5DEH2, B5DGH9, B9N1F9, O54734, O54956, O75477, O89000, O94905, P11029, P11497, P35232, P48440, P67778, P67779, P84173, Q05AY2, Q12882, Q13085, Q1LUA8, Q1RMU4, Q28007, Q28559, Q28943, Q28DX1, Q28J34, Q39258, Q3B8M3, Q3T165, Q58EG2, Q5R7C5, Q5R895, Q5RCJ9, Q5SWU9, Q5XH03, Q5ZLA5, Q641X8, Q641Y0, Q6DKC0, Q6DRI1

Diamond homologs: A3QK16, A3QMC6, B5DEH2, O75477, O94905, Q1RMU4, Q28DX1, Q28J34, Q58EG2, Q5R7C5, Q5RCJ9, Q5XH03, Q6DKC0, Q8BFZ9, Q91X78

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ERLIN1	“form complex”	Erlin	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 183 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	6	22.7×	3e-05
RHOH GTPase cycle	6	16.5×	1e-04
Defective CFTR causes cystic fibrosis	7	13.7×	7e-05
RHOQ GTPase cycle	8	12.9×	3e-05
RHOD GTPase cycle	7	12.8×	1e-04
Ovarian tumor domain proteases	5	12.4×	2e-03
RHOF GTPase cycle	5	11.6×	3e-03
Hh mutants are degraded by ERAD	5	10.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
bicarbonate transport	6	32.8×	6e-06
regulation of intracellular pH	7	28.7×	1e-06
ERAD pathway	12	14.8×	4e-08
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	6	13.8×	1e-03
transmembrane transport	11	12.6×	7e-07
endoplasmic reticulum to Golgi vesicle-mediated transport	10	9.2×	3e-05
positive regulation of protein ubiquitination	6	8.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	75
Likely benign	64
Benign	20

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
226427	NM_006459.4(ERLIN1):c.149G>T (p.Gly50Val)	Pathogenic
2500861	NM_006459.4(ERLIN1):c.196-1G>A	Pathogenic
873226	NM_006459.4(ERLIN1):c.281T>C (p.Val94Ala)	Pathogenic
1344325	NM_006459.4(ERLIN1):c.753del (p.Phe252fs)	Likely pathogenic
4537457	NM_006459.4(ERLIN1):c.273del (p.Ile91fs)	Likely pathogenic

SpliceAI

1695 predictions. Top by Δscore:

Variant	Effect	Δscore
10:100152348:TTGTG:T	acceptor_gain	1.0000
10:100152351:TG:T	acceptor_gain	1.0000
10:100152353:C:CC	acceptor_gain	1.0000
10:100152355:G:C	acceptor_gain	1.0000
10:100152355:G:GC	acceptor_gain	1.0000
10:100154855:GTCAC:G	donor_loss	1.0000
10:100154856:TCACC:T	donor_loss	1.0000
10:100154857:CACCT:C	donor_loss	1.0000
10:100154858:ACCTT:A	donor_loss	1.0000
10:100154859:C:A	donor_loss	1.0000
10:100154936:GCAT:G	acceptor_gain	1.0000
10:100154936:GCATC:G	acceptor_loss	1.0000
10:100154937:CAT:C	acceptor_gain	1.0000
10:100154937:CATC:C	acceptor_gain	1.0000
10:100154938:ATCTA:A	acceptor_loss	1.0000
10:100154939:TCT:T	acceptor_loss	1.0000
10:100154940:C:A	acceptor_loss	1.0000
10:100154940:C:CC	acceptor_gain	1.0000
10:100154941:T:C	acceptor_loss	1.0000
10:100156230:TGCTT:T	acceptor_gain	1.0000
10:100156232:CTT:C	acceptor_gain	1.0000
10:100156235:C:CC	acceptor_gain	1.0000
10:100156242:CA:C	acceptor_gain	1.0000
10:100156243:A:AC	acceptor_gain	1.0000
10:100156243:A:C	acceptor_gain	1.0000
10:100167346:A:AC	donor_gain	1.0000
10:100167347:C:CC	donor_gain	1.0000
10:100174295:C:CT	acceptor_gain	1.0000
10:100174296:A:T	acceptor_gain	1.0000
10:100175938:CACTT:C	donor_loss	1.0000

AlphaMissense

2292 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:100156232:C:G	A220P	1.000
10:100164013:C:G	A216P	1.000
10:100164034:C:G	A209P	1.000
10:100167387:G:T	P175H	1.000
10:100167389:T:A	K174N	1.000
10:100167389:T:G	K174N	1.000
10:100174212:A:T	I167K	1.000
10:100174263:A:G	L150P	1.000
10:100175946:A:C	F143L	1.000
10:100175946:A:T	F143L	1.000
10:100175947:A:C	F143C	1.000
10:100175948:A:G	F143L	1.000
10:100175985:G:C	C130W	1.000
10:100175986:C:T	C130Y	1.000
10:100175987:A:G	C130R	1.000
10:100175998:A:G	L126P	1.000
10:100179210:C:T	C78Y	1.000
10:100179211:A:G	C78R	1.000
10:100154901:C:G	A262P	0.999
10:100156211:C:G	A227P	0.999
10:100164075:A:G	L195P	0.999
10:100167381:A:G	I177T	0.999
10:100167387:G:C	P175R	0.999
10:100167388:G:A	P175S	0.999
10:100167390:T:A	K174I	0.999
10:100167391:T:C	K174E	0.999
10:100167396:A:T	V172D	0.999
10:100167399:C:G	R171P	0.999
10:100167402:A:T	V170E	0.999
10:100167406:C:G	A169P	0.999

dbSNP variants (sampled 300 via entrez): RS1000007649 (10:100151016 G>C), RS1000023150 (10:100172068 TAA>T), RS1000152327 (10:100165899 T>C), RS1000250074 (10:100178833 G>A,T), RS1000424640 (10:100171502 T>G), RS1000456648 (10:100172328 C>A,T), RS1000475292 (10:100159467 G>GATTCA), RS1000518486 (10:100157603 C>A,T), RS1000577948 (10:100176661 A>C), RS1000578261 (10:100183859 T>G), RS1000705644 (10:100170099 T>C), RS1000719168 (10:100165654 T>C,G), RS1000806616 (10:100161123 T>A), RS1000847600 (10:100159821 AAACTT>A), RS1000940598 (10:100155027 A>G)

Disease associations

OMIM: gene MIM:611604 | disease phenotypes: MIM:615681, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 62	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary spastic paraplegia 62	Definitive	AR

Mondo (3): hereditary spastic paraplegia 62 (MONDO:0014302), hereditary spastic paraplegia (MONDO:0019064), juvenile amyotrophic lateral sclerosis (MONDO:0017593)

Orphanet (3): Autosomal recessive spastic paraplegia type 62 (Orphanet:401785), Hereditary spastic paraplegia (Orphanet:685), Juvenile amyotrophic lateral sclerosis (Orphanet:300605)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001317	Abnormal cerebellum morphology
HP:0001347	Hyperreflexia
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002169	Clonus
HP:0002380	Fasciculations
HP:0002395	Lower limb hyperreflexia
HP:0002943	Thoracic scoliosis
HP:0003202	Skeletal muscle atrophy
HP:0003487	Babinski sign
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0006380	Knee flexion contracture
HP:0006844	Absent patellar reflexes
HP:0011448	Ankle clonus
HP:0011463	Childhood onset
HP:0012514	Lower limb pain
HP:0030051	Tip-toe gait
HP:0031993	Hoffmann sign

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000248_3	Liver enzyme levels	2.000000e-08
GCST001859_34	Thiazide-induced adverse metabolic effects in hypertensive patients	2.000000e-06
GCST002431_3	Response to radiotherapy in cancer (late toxicity)	2.000000e-06
GCST004750_28	Squamous cell lung carcinoma	5.000000e-07
GCST006269_319	General cognitive ability	1.000000e-11
GCST006611_13	HDL cholesterol	7.000000e-11
GCST006979_601	Heel bone mineral density	6.000000e-17
GCST008595_144	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	2.000000e-08
GCST010002_298	Refractive error	3.000000e-22
GCST010241_181	Apolipoprotein A1 levels	2.000000e-29
GCST010242_48	HDL cholesterol levels	1.000000e-14
GCST011352_37	Alanine aminotransferase levels	1.000000e-16
GCST012226_334	Waist circumference adjusted for body mass index	2.000000e-08
GCST90011898_71	Alanine aminotransferase levels	3.000000e-114
GCST90011899_173	Aspartate aminotransferase levels	3.000000e-73
GCST90013405_35	Liver enzyme levels (alanine transaminase)	9.000000e-215
GCST90013663_35	Alanine aminotransferase levels	2.000000e-161
GCST90013664_12	Aspartate aminotransferase levels	9.000000e-86

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004337	intelligence
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009270	heel bone mineral density
EFO:0004784	self reported educational attainment
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067009 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.36	Kd	4.42	nM	CHEMBL5653589
8.36	ED50	4.42	nM	CHEMBL5653589
6.43	Kd	367.1	nM	CHEMBL3752910
6.43	ED50	367.1	nM	CHEMBL3752910

PubChem BioAssay actives

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

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148333: Binding affinity to human ERLIN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0044	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148333: Binding affinity to human ERLIN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.3671	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases mutagenesis	3
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, increases abundance	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
trichostatin A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Nickel	decreases expression	1
Silicon Dioxide	decreases expression	1
Theophylline	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases expression	1
Sodium Selenite	increases expression	1
Oleic Acid	affects cotreatment, affects expression	1
Palmitic Acid	affects cotreatment, affects 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
CHEMBL5651375	Binding	Binding affinity to human ERLIN1 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)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	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	ENROLLING_BY_INVITATION	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	RECRUITING	Enhancement of Quality of Work And Life
NCT06680063	Not specified	COMPLETED	Correlation Between Clinical Assessment and Neurophysiological Assessment in Spinal Cord Injury