NSF

Summary

NSF (N-ethylmaleimide sensitive factor, vesicle fusing ATPase, HGNC:8016) is a protein-coding gene on chromosome 17q21.31, encoding Vesicle-fusing ATPase (P46459). Required for vesicle-mediated transport. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Enables PDZ domain binding activity and ionotropic glutamate receptor binding activity. Involved in intracellular protein transport; positive regulation of protein catabolic process; and positive regulation of receptor recycling. Located in Golgi apparatus; cytosol; and plasma membrane. Implicated in developmental and epileptic encephalopathy 96.

Source: NCBI Gene 4905 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy 96 (Moderate, GenCC)
• GWAS associations: 28
• Clinical variants (ClinVar): 7 total — 1 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_006178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8016
Approved symbol	NSF
Name	N-ethylmaleimide sensitive factor, vesicle fusing ATPase
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	SKD2, SEC18
Ensembl gene	ENSG00000073969
Ensembl biotype	protein_coding
OMIM	601633
Entrez	4905

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 17 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000398238, ENST00000465370, ENST00000486366, ENST00000571172, ENST00000571864, ENST00000575068, ENST00000576040, ENST00000576346, ENST00000706373, ENST00000706374, ENST00000706391, ENST00000706392, ENST00000706393, ENST00000706394, ENST00000706395, ENST00000706396, ENST00000706397, ENST00000706398, ENST00000706399, ENST00000706400, ENST00000706401, ENST00000706402, ENST00000706403, ENST00000706404, ENST00000706405, ENST00000706406, ENST00000891010, ENST00000891011, ENST00000891012, ENST00000946851

RefSeq mRNA: 1 — MANE Select: NM_006178 NM_006178

CCDS: CCDS42354

Canonical transcript exons

ENST00000398238 — 21 exons

Exon	Start	End
ENSE00001830581	46755802	46757464
ENSE00002645985	46590669	46590787
ENSE00003239783	46630411	46630450
ENSE00003249239	46640643	46640718
ENSE00003258850	46704759	46704854
ENSE00003279351	46693847	46693921
ENSE00003314289	46674414	46674613
ENSE00003342268	46710963	46711119
ENSE00003350572	46751503	46751616
ENSE00003369133	46755314	46755369
ENSE00003370945	46692903	46693068
ENSE00003373127	46749773	46749907
ENSE00003406902	46728855	46728934
ENSE00003410448	46694475	46694662
ENSE00003433209	46643104	46643259
ENSE00003442507	46726549	46726615
ENSE00003480141	46713853	46713986
ENSE00003560679	46624244	46624329
ENSE00003574751	46637376	46637542
ENSE00003619459	46640054	46640161
ENSE00003670425	46626613	46626712

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3445 / max 54.2742, expressed in 120 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161327	0.3445	120

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
superior frontal gyrus	UBERON:0002661	99.25	gold quality
prefrontal cortex	UBERON:0000451	98.27	gold quality
primary visual cortex	UBERON:0002436	98.06	gold quality
frontal cortex	UBERON:0001870	97.87	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.75	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.59	gold quality
right frontal lobe	UBERON:0002810	97.09	gold quality
cerebral cortex	UBERON:0000956	97.08	gold quality
cerebellar cortex	UBERON:0002129	96.61	gold quality
cerebellum	UBERON:0002037	96.60	gold quality
anterior cingulate cortex	UBERON:0009835	96.59	gold quality
cerebellar hemisphere	UBERON:0002245	96.55	gold quality
nucleus accumbens	UBERON:0001882	96.54	gold quality
hypothalamus	UBERON:0001898	96.53	gold quality
islet of Langerhans	UBERON:0000006	96.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.23	gold quality
brain	UBERON:0000955	96.02	gold quality
Ammon’s horn	UBERON:0001954	95.13	gold quality
caudate nucleus	UBERON:0001873	95.12	gold quality
putamen	UBERON:0001874	95.03	gold quality
temporal lobe	UBERON:0001871	94.74	gold quality
amygdala	UBERON:0001876	94.69	gold quality
substantia nigra	UBERON:0002038	93.93	gold quality
cortical plate	UBERON:0005343	93.28	gold quality
pituitary gland	UBERON:0000007	93.11	gold quality
corpus callosum	UBERON:0002336	92.87	gold quality
rectum	UBERON:0001052	92.54	gold quality
adenohypophysis	UBERON:0002196	92.46	gold quality
pancreas	UBERON:0001264	91.68	gold quality
tonsil	UBERON:0002372	91.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	42.88
E-HCAD-25	yes	9.54
E-ANND-3	yes	3.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting NSF, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 17)

• binding of NSF to GluR2-containing AMPARs in stabilizing these receptors in the synaptic membrane and impeding their regulated endocytosis. (PMID:12011465)
• role of interaction with GluR2 in regulation of AMPA receptors by brain-derived neurotrophic factor (PMID:12130635)
• Nitric oxide regulates exocytosis by S-nitrosylation of NSF. (PMID:14567912)
• Expressing a biochemically defined NSF mutant that lacks ATPase activity results in a dramatic inhibition of stimulated mast cell exocytosis. (PMID:14607937)
• NSF dissociates the VAMP-2.SNAP-25.syntaxin 13 complex, but has no effect on the Hrs-containing complex. (PMID:14769786)
• Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein (PMID:16461345)
• dual regulation on hbeta2AR trafficking and signaling by NSF through direct binding to cargo receptor and its ATPase activity. (PMID:17510209)
• Data show that NSF is an inclusion body component in neuronal intranuclear inclusion disease identified by anti-SUMO-1-immunocapture. (PMID:18836734)
• Data show that phosphorylation of N-ethylmaleimide-sensitive factor on tyrosine residues prevents its SNARE complex dissociation activity and establish a role for PTP1B in the modulation of the membrane fusion machinery. (PMID:19208619)
• analysis of human NSF possible binding mode to GABARAP and GATE-16 (PMID:19533740)
• NSF independent fusion of Salmonella-containing late phagosomes with early endosomes. (PMID:20176016)
• Knockdown of TRX1 increases the level of S-nitrosylated NSF, prolongs the inhibition of exocytosis, and suppresses leukocyte (PMID:21324905)
• Single and multiple-marker analyses revealed a strong association between cocaine dependence and the NSF gene. (PMID:21426264)
• a processive helicase-like mechanism for NSF in which approximately 1 residue is unwound for every hydrolyzed ATP molecule. (PMID:23775070)
• A large copy number variant (CNV) that encompasses part of the NSF gene contributes to cocaine dependence. (PMID:27498889)
• NSF deficiency in HeLa cells barely affected cell viability, anterograde trafficking of vesicular stomatitis virus glycoprotein G and transferrin endocytosis. (PMID:27995606)
• De novo NSF mutations cause early infantile epileptic encephalopathy. (PMID:31675180)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsfa	ENSDARG00000007654
danio_rerio	nsfb	ENSDARG00000038991
mus_musculus	Nsf	ENSMUSG00000034187
rattus_norvegicus	Nsf	ENSRNOG00000003905
drosophila_melanogaster	comt	FBGN0000346
drosophila_melanogaster	CG31495	FBGN0051495
drosophila_melanogaster	Nsf2	FBGN0266464
caenorhabditis_elegans	nsf-1	WBGENE00003818

Protein

Protein identifiers

Vesicle-fusing ATPase — P46459 (reviewed: P46459)

Alternative names: N-ethylmaleimide-sensitive fusion protein, Vesicular-fusion protein NSF

All UniProt accessions (14): P46459, A0A384MTI6, A0A994J5C5, A0A994J5C9, A0A994J5K9, A0A994J5X2, A0A994J5X9, A0A994J5Y2, A0A994J7T3, A0A994J855, B4DH19, I3L0N3, I3L4Q9, K7EQD6

UniProt curated annotations — full annotation on UniProt →

Function. Required for vesicle-mediated transport. Catalyzes the fusion of transport vesicles within the Golgi cisternae. Is also required for transport from the endoplasmic reticulum to the Golgi stack. Seems to function as a fusion protein required for the delivery of cargo proteins to all compartments of the Golgi stack independent of vesicle origin. Interaction with AMPAR subunit GRIA2 leads to influence GRIA2 membrane cycling.

Subunit / interactions. Homohexamer. Interacts with GABARAP and GABARAPL2. Interacts with GRIA2. Interacts with PLK2, leading to disrupt the interaction with GRIA2. Interacts with MUSK; may regulate MUSK endocytosis and activity. Interacts with CDK16.

Subcellular location. Cytoplasm.

Post-translational modifications. Phosphorylation at Ser-569 interferes with homohexamerization.

Disease relevance. Developmental and epileptic encephalopathy 96 (DEE96) [MIM:619340] A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE96 is an autosomal dominant form characterized by onset of seizures in the first days or weeks of life. Affected infants also have hypotonia with respiratory insufficiency that may result in premature death. The disease may be caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Mg(2+) ion per subunit.

Similarity. Belongs to the AAA ATPase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P46459-1	1	yes
P46459-2	2

RefSeq proteins (1): NP_006169* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003338	CDC4_N-term_subdom	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR004201	Cdc48_dom2	Domain
IPR009010	Asp_de-COase-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029067	CDC48_domain_2-like_sf	Homologous_superfamily
IPR039812	Vesicle-fus_ATPase	Family
IPR041569	AAA_lid_3	Domain
IPR054419	NSF_ATPase_lid	Domain

Pfam: PF00004, PF02359, PF02933, PF17862, PF21964

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (24 total): sequence conflict 11, modified residue 4, binding site 3, sequence variant 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6KZQ	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46459-F1	85.70	0.45

Functional residue map

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

Ligand- & substrate-binding residues (3): 505–510; 545–552; 550

Post-translational modifications (4): 105, 207, 259, 569

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-416993	Trafficking of GluR2-containing AMPA receptors
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-6811438	Intra-Golgi traffic
R-HSA-6811440	Retrograde transport at the Trans-Golgi-Network

MSigDB gene sets: 267 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_INTRA_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (12): positive regulation of receptor recycling (GO:0001921), potassium ion transport (GO:0006813), intracellular protein transport (GO:0006886), exocytosis (GO:0006887), intra-Golgi vesicle-mediated transport (GO:0006891), vesicle-mediated transport (GO:0016192), regulation of exocytosis (GO:0017157), SNARE complex disassembly (GO:0035494), Golgi to plasma membrane protein transport (GO:0043001), obsolete plasma membrane fusion (GO:0045026), positive regulation of protein catabolic process (GO:0045732), protein transport (GO:0015031)

GO Molecular Function (14): SNARE binding (GO:0000149), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), syntaxin-1 binding (GO:0017075), protein kinase binding (GO:0019901), PDZ domain binding (GO:0030165), ionotropic glutamate receptor binding (GO:0035255), protein-containing complex binding (GO:0044877), metal ion binding (GO:0046872), ATP-dependent protein disaggregase activity (GO:0140545), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), syntaxin binding (GO:0019905)

GO Cellular Component (13): acrosomal vesicle (GO:0001669), lysosomal membrane (GO:0005765), Golgi apparatus (GO:0005794), Golgi stack (GO:0005795), cytosol (GO:0005829), plasma membrane (GO:0005886), dendritic shaft (GO:0043198), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), GABA-ergic synapse (GO:0098982), postsynaptic specialization, intracellular component (GO:0099091), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	2
Intra-Golgi and retrograde Golgi-to-ER traffic	2
Trafficking of AMPA receptors	1
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
sperm flagellum	3
intracellular protein localization	2
protein transport	2
vesicle-mediated transport	2
transport	2
protein binding	2
ATP-dependent activity	2
binding	2
cytoplasm	2
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
metal ion transport	1
intracellular transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
Golgi vesicle transport	1
cellular process	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
protein-containing complex disassembly	1
Golgi to plasma membrane transport	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
establishment of protein localization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
syntaxin binding	1
kinase binding	1
protein domain specific binding	1
glutamate receptor binding	1
cation binding	1

Protein interactions and networks

STRING

3256 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSF	NAPA	P54920	991
NSF	YKT6	O15498	867
NSF	VTI1B	Q9UEU0	840
NSF	NAPG	Q99747	828
NSF	STXBP1	P61764	795
NSF	SNAP25	P13795	789
NSF	GRIA2	P42262	786
NSF	VPS39	Q96JC1	774
NSF	DNM1L	O00429	721
NSF	STX5	Q13190	718
NSF	STXBP3	O00186	702
NSF	SYT1	P21579	696
NSF	VAMP2	P19065	679
NSF	SYN2	Q92777	677
NSF	NAPB	Q9H115	673

IntAct

196 interactions, top by confidence:

A	B	Type	Score
APP	APBB1	psi-mi:“MI:0914”(association)	0.910
GOSR2	BET1	psi-mi:“MI:0914”(association)	0.810
STX18	NBAS	psi-mi:“MI:0914”(association)	0.810
NAPA	SNAP23	psi-mi:“MI:0914”(association)	0.780
NSF	NAPA	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
STX5	GOSR2	psi-mi:“MI:0914”(association)	0.670
STX6	GOSR2	psi-mi:“MI:0914”(association)	0.670
APP	CRYAB	psi-mi:“MI:0914”(association)	0.670
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
BNIP1	NBAS	psi-mi:“MI:0914”(association)	0.640
NAPG	NSF	psi-mi:“MI:0914”(association)	0.640
SEC22B	ZW10	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
GABBR2	NSF	psi-mi:“MI:0915”(physical association)	0.610
NSF	GABBR2	psi-mi:“MI:0407”(direct interaction)	0.610
NSF	GABBR2	psi-mi:“MI:0403”(colocalization)	0.610
BTN3A2	BTN3A1	psi-mi:“MI:0914”(association)	0.600
BET1	NSF	psi-mi:“MI:0914”(association)	0.570
GABBR1	NSF	psi-mi:“MI:0407”(direct interaction)	0.570
GABBR1	NSF	psi-mi:“MI:0403”(colocalization)	0.570
NSF	GABBR1	psi-mi:“MI:0915”(physical association)	0.570
RBKS	NSF	psi-mi:“MI:0915”(physical association)	0.560
NSF	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
RBKS	NSF	psi-mi:“MI:0914”(association)	0.560
PTPN9	NSF	psi-mi:“MI:0203”(dephosphorylation reaction)	0.540

BioGRID (312): NSF (Affinity Capture-MS), NSF (Affinity Capture-MS), NSF (Affinity Capture-MS), NSF (Reconstituted Complex), NSF (Affinity Capture-MS), NSF (Affinity Capture-MS), NSF (Two-hybrid), NSF (Reconstituted Complex), ATP6V0D1 (Co-fractionation), MRPL9 (Co-fractionation), NSF (Co-fractionation), RAP2A (Co-fractionation), SCFD1 (Co-fractionation), SEC31A (Co-fractionation), SNAP25 (Co-fractionation)

ESM2 similar proteins: A0A023PXF5, A6QSQ0, A6SBT4, A7EY76, F1RCY6, O13559, O18475, O48534, P18708, P40105, P40434, P40889, P43538, P46063, P46459, P46460, P46461, P54351, Q14527, Q1EB85, Q2TBP1, Q2U587, Q3B7N1, Q3E7Y4, Q5R410, Q5RF63, Q6AYJ1, Q6PCN7, Q7ZU90, Q86WJ1, Q8NHQ9, Q8R5F7, Q95216, Q96C10, Q99J87, Q9BYX4, Q9CXF7, Q9DGP9, Q9EPU0, Q9FF61

Diamond homologs: A0A8I6AGW3, A4QE83, A6NMB9, A9BJK3, B1VDV2, B1ZMG6, B4NBP4, B7PXE3, E9QEA3, F4JEX5, J3QK54, O05209, P18708, P36612, P40327, P46459, P46460, Q503S1, Q55BV5, Q5HY92, Q5R410, Q6AZT2, Q6DDU8, Q6GX84, Q6PIW4, Q7QBW0, Q8BPY9, Q8FTE3, Q8NQD8, Q9ERZ6, Q9QUL6, Q9ZNT0, A0JWY3, A0LU46, A0QFB2, A1R6Q4, A1SK07, A4G0S4, A4TB65, A6VHR1

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PTPN9	down-regulates	NSF	dephosphorylation
NSF	“down-regulates activity”	SNAP25	binding
LRRK2	“up-regulates activity”	NSF	phosphorylation
PRKCE	“up-regulates activity”	NSF	phosphorylation
CDK16	“down-regulates activity”	NSF	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 208 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
Intra-Golgi traffic	10	17.9×	5e-08
Retrograde transport at the Trans-Golgi-Network	10	15.2×	1e-07
trans-Golgi Network Vesicle Budding	6	10.5×	2e-03
COPII-mediated vesicle transport	9	10.1×	2e-05
Intra-Golgi and retrograde Golgi-to-ER traffic	14	10.1×	5e-08
COPI-dependent Golgi-to-ER retrograde traffic	13	9.9×	9e-08
COPI-mediated anterograde transport	11	8.3×	8e-06
RAB geranylgeranylation	6	7.2×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
vesicle fusion	13	41.8×	1e-15
obsolete vesicle docking	9	36.9×	3e-10
post-Golgi vesicle-mediated transport	6	33.8×	2e-06
response to lead ion	5	25.0×	1e-04
membrane fusion	7	23.4×	2e-06
intra-Golgi vesicle-mediated transport	8	22.5×	3e-07
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	10	18.0×	3e-08
retrograde transport, endosome to Golgi	12	13.2×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	4
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1699024	NM_006178.4(NSF):c.1590_1592dup (p.Ser531_Asp532insSer)	Likely pathogenic

SpliceAI

3288 predictions. Top by Δscore:

Variant	Effect	Δscore
17:46590783:GCCGG:G	donor_gain	1.0000
17:46590786:GG:G	donor_gain	1.0000
17:46590787:GG:G	donor_gain	1.0000
17:46590787:GGT:G	donor_loss	1.0000
17:46590788:G:GG	donor_gain	1.0000
17:46590789:T:A	donor_loss	1.0000
17:46624238:TTACA:T	acceptor_loss	1.0000
17:46624241:CAG:C	acceptor_gain	1.0000
17:46624242:A:AG	acceptor_gain	1.0000
17:46624242:A:G	acceptor_loss	1.0000
17:46624242:AGA:A	acceptor_gain	1.0000
17:46624243:G:GA	acceptor_gain	1.0000
17:46624243:GA:G	acceptor_gain	1.0000
17:46624243:GAG:G	acceptor_gain	1.0000
17:46624243:GAGC:G	acceptor_gain	1.0000
17:46624325:GGCCA:G	donor_gain	1.0000
17:46624326:GCCA:G	donor_gain	1.0000
17:46624326:GCCAG:G	donor_gain	1.0000
17:46624327:CCA:C	donor_gain	1.0000
17:46624328:CA:C	donor_gain	1.0000
17:46624328:CAGT:C	donor_loss	1.0000
17:46624329:AG:A	donor_loss	1.0000
17:46624330:G:GG	donor_gain	1.0000
17:46624330:GTG:G	donor_loss	1.0000
17:46624331:TGA:T	donor_loss	1.0000
17:46624332:GAG:G	donor_loss	1.0000
17:46624333:AGTA:A	donor_loss	1.0000
17:46626610:TAGG:T	acceptor_loss	1.0000
17:46626611:A:AG	acceptor_gain	1.0000
17:46626612:G:GG	acceptor_gain	1.0000

AlphaMissense

4937 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:46626701:A:C	S63R	1.000
17:46626703:T:A	S63R	1.000
17:46626703:T:G	S63R	1.000
17:46643176:G:A	G221E	1.000
17:46643182:T:C	L223P	1.000
17:46643212:G:C	R233P	1.000
17:46643217:T:C	F235L	1.000
17:46643219:T:A	F235L	1.000
17:46643219:T:G	F235L	1.000
17:46674431:G:C	G255R	1.000
17:46674432:G:A	G255D	1.000
17:46674438:T:C	L257P	1.000
17:46674446:G:A	G260R	1.000
17:46674446:G:C	G260R	1.000
17:46674447:G:A	G260E	1.000
17:46674447:G:T	G260V	1.000
17:46674455:G:C	G263R	1.000
17:46674455:G:T	G263C	1.000
17:46674456:G:A	G263D	1.000
17:46674459:G:A	C264Y	1.000
17:46674460:T:G	C264W	1.000
17:46674461:G:C	G265R	1.000
17:46674462:G:A	G265D	1.000
17:46674462:G:C	G265A	1.000
17:46674462:G:T	G265V	1.000
17:46674477:C:A	A270D	1.000
17:46674522:T:A	V285D	1.000
17:46674527:G:A	G287R	1.000
17:46674527:G:C	G287R	1.000
17:46674527:G:T	G287W	1.000

dbSNP variants (sampled 300 via entrez): RS1000107824 (17:46667916 T>C), RS1000128205 (17:46706740 G>A), RS1000148147 (17:46722417 A>G), RS1000157251 (17:46746222 G>A), RS1000217818 (17:46631534 A>G), RS1000244780 (17:46661473 G>A), RS1000277643 (17:46754608 T>G), RS1000371301 (17:46691848 G>A), RS1000373373 (17:46735397 A>G), RS1000385531 (17:46738617 G>C), RS1000392911 (17:46679209 C>G,T), RS1000521418 (17:46722714 A>C,G), RS1000555647 (17:46717674 T>G), RS1000558313 (17:46635454 G>A), RS1000586670 (17:46717451 G>A,C)

Disease associations

OMIM: gene MIM:601633 | disease phenotypes: MIM:619340

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 96	Moderate	Autosomal dominant

Mondo (1): developmental and epileptic encephalopathy 96 (MONDO:0023659)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001518	Small for gestational age
HP:0001522	Death in infancy
HP:0001789	Hydrops fetalis
HP:0002187	Profound intellectual disability
HP:0002643	Neonatal respiratory distress
HP:0010851	EEG with burst suppression
HP:0011097	Epileptic spasm
HP:0011451	Primary microcephaly
HP:0032792	Tonic seizure
HP:0200134	Epileptic encephalopathy

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000528_5	Parkinson’s disease	1.000000e-14
GCST001189_1	Parkinson’s disease	3.000000e-07
GCST003174_13	Sense of smell	4.000000e-06
GCST003174_6	Sense of smell	3.000000e-06
GCST005316_213	Intelligence (MTAG)	5.000000e-09
GCST005951_16	Body mass index	4.000000e-08
GCST006268_484	Reaction time	1.000000e-16
GCST006394_105	Intraocular pressure	4.000000e-08
GCST006661_283	Male-pattern baldness	4.000000e-27
GCST006716_14	Alcohol use disorder (total score)	5.000000e-10
GCST006899_15	Thyroid stimulating hormone levels	4.000000e-10
GCST006976_14	Macular thickness	3.000000e-28
GCST007592_2	Handedness (Left-handed vs. non-left-handed)	1.000000e-09
GCST007594_2	Handedness (Right-handed vs. non-right-handed)	2.000000e-08
GCST007709_139	General factor of neuroticism	3.000000e-16
GCST007709_140	General factor of neuroticism	6.000000e-16
GCST009325_106	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	9.000000e-67
GCST010002_124	Refractive error	8.000000e-16
GCST010083_12	Hemoglobin levels	1.000000e-11
GCST010083_185	Hemoglobin levels	3.000000e-52
GCST010226_13	Cortical surface area (global PC1)	1.000000e-31
GCST010226_14	Cortical surface area (global PC1)	2.000000e-10
GCST010703_91	Brain morphology (MOSTest)	2.000000e-65
GCST011205_9	Hypertrophic cardiomyopathy (MTAG)	5.000000e-13
GCST011211_4	Hypertrophic cardiomyopathy	7.000000e-16
GCST011616_4	Cortical volume	2.000000e-13
GCST011617_1	Cortical surface area	1.000000e-43
GCST011617_15	Cortical surface area	8.000000e-18

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004340	body mass index
EFO:0008393	reaction time measurement
EFO:0004695	intraocular pressure measurement
EFO:0009458	alcohol use disorder measurement
EFO:0009902	handedness
EFO:0007660	neuroticism measurement
EFO:0004509	hemoglobin measurement
EFO:0008381	total cortical area measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2311231 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.46	Kd	3511	nM	CHEMBL5653589
5.46	ED50	3511	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 7 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	2148889: Binding affinity to human NSF incubated for 45 mins by Kinobead based pull down assay	kd	3.5107	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, increases expression	3
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	decreases expression, increases expression, affects cotreatment, affects localization	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	increases reaction, affects binding	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	1
dimethylarsinous acid	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Irinotecan	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Benztropine	decreases expression	1
Clozapine	decreases expression	1
Cocaine	decreases expression	1
Furaldehyde	decreases expression, affects localization, increases expression, affects cotreatment	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2317270	Binding	Inhibition of NSF (unknown origin) at 10 uM	Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. — J Med Chem

Clinical trials (associated diseases)

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