SVIP

Summary

SVIP (small VCP interacting protein, HGNC:25238) is a protein-coding gene on chromosome 11p14.3, encoding Small VCP/p97-interacting protein (Q8NHG7). Negative regulator of the ER-associated degradation pathway (ERAD) of misfolded proteins.

Endoplasmic reticulum-associated degradation (ERAD) is the pathway by which misfolded proteins in the endoplasmic reticulum are targeted to the proteasome for degradation. Multiple specialized proteins interact with one another during ERAD to complete this process. The protein encoded by this gene is an inhibitor of ERAD, functioning to disrupt the interaction of these protein components. This downregulation of ERAD may be needed to protect the cell from overactive protein degradation. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 258010 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_148893

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25238
Approved symbol	SVIP
Name	small VCP interacting protein
Location	11p14.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp313A2432
Ensembl gene	ENSG00000198168
Ensembl biotype	protein_coding
OMIM	620965
Entrez	258010

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000354193, ENST00000525670, ENST00000529848, ENST00000530199, ENST00000533774

RefSeq mRNA: 4 — MANE Select: NM_148893 NM_001320340, NM_001320341, NM_001320342, NM_148893

CCDS: CCDS41627

Canonical transcript exons

ENST00000354193 — 4 exons

Exon	Start	End
ENSE00001413097	22818927	22823133
ENSE00001418455	22829695	22829801
ENSE00003463898	22827207	22827320
ENSE00003514261	22827824	22827874

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 97.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.5917 / max 597.0157, expressed in 1782 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119017	18.0225	1758
119016	14.3887	1678
119015	0.1805	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	97.83	gold quality
sperm	CL:0000019	97.63	gold quality
spinal cord	UBERON:0002240	97.62	gold quality
bone marrow cell	CL:0002092	97.61	gold quality
trigeminal ganglion	UBERON:0001675	96.44	gold quality
corpus callosum	UBERON:0002336	95.99	gold quality
bone marrow	UBERON:0002371	95.83	gold quality
sural nerve	UBERON:0015488	95.64	gold quality
epithelial cell of pancreas	CL:0000083	95.49	gold quality
left testis	UBERON:0004533	95.45	gold quality
inferior vagus X ganglion	UBERON:0005363	95.45	gold quality
subthalamic nucleus	UBERON:0001906	95.42	gold quality
right testis	UBERON:0004534	95.39	gold quality
pons	UBERON:0000988	94.73	gold quality
tibial nerve	UBERON:0001323	94.45	gold quality
islet of Langerhans	UBERON:0000006	94.44	gold quality
dorsal root ganglion	UBERON:0000044	94.43	gold quality
substantia nigra	UBERON:0002038	94.29	gold quality
midbrain	UBERON:0001891	94.04	gold quality
calcaneal tendon	UBERON:0003701	93.66	gold quality
medulla oblongata	UBERON:0001896	93.65	gold quality
testis	UBERON:0000473	93.52	gold quality
corpus epididymis	UBERON:0004359	93.47	gold quality
colonic epithelium	UBERON:0000397	93.46	gold quality
adenohypophysis	UBERON:0002196	93.14	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.10	gold quality
pituitary gland	UBERON:0000007	92.94	gold quality
parotid gland	UBERON:0001831	92.93	gold quality
hypothalamus	UBERON:0001898	92.81	gold quality
kidney epithelium	UBERON:0004819	92.81	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.59
E-MTAB-9801	yes	6.69
E-GEOD-75367	no	338.17
E-MTAB-7606	no	298.08
E-MTAB-5061	no	3.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting SVIP, 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-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478

Literature-anchored findings (GeneRIF, showing 9)

• SVIP is an endogenous inhibitor of ERAD that acts through regulating the assembly of the gp78-p97/VCP-Derlin1 complex. (PMID:17872946)
• SVIP plays a regulatory role in p97 subcellular localization and is a novel regulator of autophagy. (PMID:21909394)
• A major portion of SVIP is intrinsically disordered in solution. (PMID:24055875)
• the interactions between P97 and these motifs, including VCP-binding motif (VBM) and VCP-interacting motif (VIM). The solution structures of the VBM motif from HRD1 and the VIM motif from SVIP are both comprised mainly of a single alpha-helix. (PMID:24100225)
• overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of alpha-1 antitrypsin deficiency (PMID:28301499)
• Overexpression of SVIP can protect HepG2 cells from the toxicity of CCl4, which could be enhanced by starvation. (PMID:30683843)
• SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan. (PMID:33479240)
• A Determination of p97/VCP (Valosin Containing Protein) and SVIP (Small VCP Interacting Protein) Expression Patterns in Human Testis. (PMID:37374283)
• Differential Expression and Function of SVIP in Breast Cancer Cell Lines and In Silico Analysis of Its Expression and Prognostic Potential in Human Breast Cancer. (PMID:37408196)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Svip	ENSMUSG00000074093
rattus_norvegicus	Svip	ENSRNOG00000037137

Protein

Protein identifiers

Small VCP/p97-interacting protein — Q8NHG7 (reviewed: Q8NHG7)

All UniProt accessions (1): Q8NHG7

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of the ER-associated degradation pathway (ERAD) of misfolded proteins. It competes with AMFR/gp78 for binding VCP/p97, and inhibits AMFR/gp78-VCP/p97 complex formation that is required for degradation of ERAD substrates. Involved in the regulation of adrenal cortisol and dehydroepiandrosterone (DHEA) biosynthesis.

Subunit / interactions. Interacts (via VIM motif) with VCP/p97. Forms a complex with VCP/p97 and DERL1.

Subcellular location. Membrane. Smooth endoplasmic reticulum membrane. Golgi apparatus membrane. Cell membrane. Lysosome membrane.

Similarity. Belongs to the SVIP family.

RefSeq proteins (3): NP_001307270, NP_001307271, NP_683691* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031632	SVIP	Family
IPR055366	SVIP_metazoa	Family

Pfam: PF15811

UniProt features (14 total): mutagenesis site 3, region of interest 3, lipid moiety-binding region 3, initiator methionine 1, chain 1, sequence variant 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHG7-F1	71.90	0.00

Functional residue map

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

Post-translational modifications (4): 46, 2, 4, 7

Mutagenesis-validated functional residues (3):

Position	Phenotype
2	loss of myristoylation. does not localize to membranes but is exclusively localized in the cytosol. has no effect on pro
4	decreased palmitoylation. loss of palmitoylation; when associated in cis with s-7.
7	decreased palmitoylation. loss of palmitoylation; when associated in cis with s-4.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 226 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE, FISCHER_G1_S_CELL_CYCLE, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (6): positive regulation of autophagy (GO:0010508), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of protein lipidation (GO:1903061), negative regulation of retrograde protein transport, ER to cytosol (GO:1904153), negative regulation of VCP-NPL4-UFD1 AAA ATPase complex assembly (GO:1904240), negative regulation of ERAD pathway (GO:1904293)

GO Molecular Function (2): ATPase binding (GO:0051117), protein binding (GO:0005515)

GO Cellular Component (12): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), secretory granule membrane (GO:0030667), smooth endoplasmic reticulum membrane (GO:0030868), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	3
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
protein lipidation	1
positive regulation of protein modification process	1
positive regulation of lipoprotein metabolic process	1
regulation of protein lipidation	1
retrograde protein transport, ER to cytosol	1
negative regulation of protein exit from endoplasmic reticulum	1
regulation of retrograde protein transport, ER to cytosol	1
negative regulation of protein-containing complex assembly	1
VCP-NPL4-UFD1 AAA ATPase complex assembly	1
regulation of VCP-NPL4-UFD1 AAA ATPase complex assembly	1
ERAD pathway	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of response to endoplasmic reticulum stress	1
regulation of ERAD pathway	1
enzyme binding	1
binding	1
Golgi apparatus	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
secretory granule	1
cytoplasmic vesicle membrane	1
endoplasmic reticulum membrane	1
smooth endoplasmic reticulum	1
extracellular vesicle	1

Protein interactions and networks

STRING

496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SVIP	VCP	P55072	847
SVIP	AMFR	P26442	716
SVIP	SEC13	P55735	702
SVIP	UBXN2A	P68543	588
SVIP	SAR1B	Q9Y6B6	549
SVIP	LPCAT3	Q6P1A2	545
SVIP	UBXN6	Q9BZV1	514
SVIP	UFD1	Q92890	510
SVIP	UBXN1	Q04323	476
SVIP	UBXN7	O94888	470
SVIP	FABP1	P07148	454
SVIP	C12orf76	Q8N812	435
SVIP	NPLOC4	Q8TAT6	415
SVIP	LYRM4	Q9HD34	415
SVIP	FAF1	Q9UNN5	402

IntAct

21 interactions, top by confidence:

A	B	Type	Score
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
SVIP	UBXN6	psi-mi:“MI:0915”(physical association)	0.560
DMC1	POTEF	psi-mi:“MI:0914”(association)	0.530
HOXB5	VPS37C	psi-mi:“MI:0914”(association)	0.530
GJB7	PALM3	psi-mi:“MI:0914”(association)	0.530
MGST3	GAPDHS	psi-mi:“MI:0914”(association)	0.530
TMEM185A	TSPAN6	psi-mi:“MI:0914”(association)	0.530
VCPIP1	VCP	psi-mi:“MI:0914”(association)	0.530
TACC3	HSPA8	psi-mi:“MI:0914”(association)	0.530
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
DUSP22	POTEF	psi-mi:“MI:0914”(association)	0.350
CPA5	ARVCF	psi-mi:“MI:0914”(association)	0.350
ATP6V1B1	ATP6V1G1	psi-mi:“MI:0914”(association)	0.350
SLC16A14	GNAQ	psi-mi:“MI:0914”(association)	0.350
STX7	SCAMP1	psi-mi:“MI:0914”(association)	0.350
VCL	UBXN8	psi-mi:“MI:0914”(association)	0.350
BTBD2	TTC4	psi-mi:“MI:0914”(association)	0.350
UBXN6	PSMD11	psi-mi:“MI:0914”(association)	0.350
UBXN6	SVIP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Affinity Capture-MS), SVIP (Two-hybrid)

ESM2 similar proteins: A5JSS4, B1MTI8, O88892, P02641, P06398, P09739, P0C0A9, P12620, P45378, P84101, P84102, Q05310, Q0UVD1, Q148I0, Q1E554, Q28HN4, Q28IN9, Q2KIT1, Q2TBR9, Q2TBV6, Q32P76, Q3E7B7, Q4I5Z5, Q5R5J3, Q5R6N0, Q5R7C4, Q5R8X8, Q5REM2, Q5ZHK9, Q68EY7, Q6DD17, Q6GNG8, Q6NVR5, Q6PHE8, Q75NG9, Q7SDA6, Q7ZY35, Q8MKI3, Q8NHG7, Q8R1F0

Diamond homologs: P0C0A9, Q3UZP4, Q5R6N0, Q8NHG7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SVIP	“down-regulates activity”	L3MBTL1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

534 predictions. Top by Δscore:

Variant	Effect	Δscore
11:22827331:T:TC	acceptor_gain	1.0000
11:22827332:T:C	acceptor_gain	1.0000
11:22827332:T:TC	acceptor_gain	1.0000
11:22827818:TCTTA:T	donor_loss	1.0000
11:22827819:CTTA:C	donor_loss	1.0000
11:22827820:TTACC:T	donor_loss	1.0000
11:22827821:TA:T	donor_loss	1.0000
11:22827822:A:AC	donor_gain	1.0000
11:22827822:A:C	donor_loss	1.0000
11:22827823:C:CC	donor_gain	1.0000
11:22827823:CCT:C	donor_gain	1.0000
11:22827885:G:C	acceptor_gain	1.0000
11:22829690:CTCA:C	donor_loss	1.0000
11:22829691:TCA:T	donor_loss	1.0000
11:22829692:CA:C	donor_loss	1.0000
11:22827202:CTTA:C	donor_loss	0.9900
11:22827203:TTA:T	donor_loss	0.9900
11:22827204:TAC:T	donor_loss	0.9900
11:22827205:A:AC	donor_gain	0.9900
11:22827205:A:AG	donor_loss	0.9900
11:22827206:C:CT	donor_gain	0.9900
11:22827330:A:AC	acceptor_gain	0.9900
11:22827330:A:C	acceptor_gain	0.9900
11:22827331:T:C	acceptor_gain	0.9900
11:22827335:A:AC	acceptor_gain	0.9900
11:22827335:A:C	acceptor_gain	0.9900
11:22827871:CTTC:C	acceptor_gain	0.9900
11:22827872:TTC:T	acceptor_gain	0.9900
11:22827872:TTCC:T	acceptor_loss	0.9900
11:22827873:TC:T	acceptor_gain	0.9900

AlphaMissense

484 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:22823133:A:G	W74R	0.996
11:22823133:A:T	W74R	0.996
11:22827833:T:A	R32S	0.996
11:22827833:T:G	R32S	0.996
11:22823131:C:A	W74C	0.995
11:22823131:C:G	W74C	0.995
11:22827834:C:G	R32T	0.995
11:22827847:C:G	A28P	0.989
11:22827844:C:G	A29P	0.986
11:22827863:T:A	R22S	0.986
11:22827863:T:G	R22S	0.986
11:22827835:T:C	R32G	0.985
11:22823132:C:G	W74S	0.984
11:22827308:C:G	G40R	0.984
11:22827308:C:T	G40R	0.984
11:22827307:C:T	G40E	0.983
11:22827855:A:G	L25P	0.982
11:22827211:A:T	L72H	0.981
11:22827304:A:C	I41S	0.981
11:22827320:C:G	A36P	0.981
11:22827853:C:G	A26P	0.981
11:22827304:A:G	I41T	0.978
11:22823132:C:A	W74L	0.977
11:22827307:C:A	G40V	0.974
11:22823126:A:T	V76D	0.972
11:22827834:C:A	R32I	0.972
11:22827304:A:T	I41N	0.970
11:22827864:C:G	R22T	0.969
11:22827310:C:G	R39P	0.966
11:22827843:G:T	A29E	0.962

dbSNP variants (sampled 300 via entrez): RS1000036585 (11:22818814 A>C), RS1000086772 (11:22819147 C>A,T), RS1000399963 (11:22820691 T>A), RS1000523794 (11:22823789 G>A), RS1000573423 (11:22825808 T>C), RS1000685486 (11:22819504 G>C), RS1000694128 (11:22829184 A>G), RS1000707330 (11:22829351 C>T), RS1001335788 (11:22829941 GC>G,GCC), RS1001379059 (11:22831492 G>A,C), RS1001404365 (11:22831514 C>A,T), RS1001648079 (11:22826317 C>A), RS1002248071 (11:22824548 C>T), RS1002251030 (11:22825187 G>A), RS1002368221 (11:22829825 C>G,T)

Disease associations

OMIM: gene MIM:620965 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001066_22	Dialysis-related mortality	6.000000e-06
GCST002550_15	Allergic rhinitis	7.000000e-07
GCST002550_16	Allergic rhinitis	7.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Cyclosporine	affects expression, decreases expression	2
dicrotophos	decreases expression	1
urushiol	increases expression	1
triphenyl phosphate	affects expression	1
potassium chromate(VI)	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
torcetrapib	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Coal	decreases expression, increases abundance	1
Curcumin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Quercetin	affects expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	increases expression	1
Vanadates	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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