VPS37A

Summary

VPS37A (VPS37A subunit of ESCRT-I, HGNC:24928) is a protein-coding gene on chromosome 8p22, encoding Vacuolar protein sorting-associated protein 37A (Q8NEZ2). Component of the ESCRT-I complex, a regulator of vesicular trafficking process. In precision oncology, VPS37A Underexpression is associated with resistance to Cetuximab in Ovarian Cancer (CIViC Level D). It is a selective cancer dependency (DepMap: 41.6% of cell lines).

This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 137492 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 53 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 260 total — 2 pathogenic
• Phenotypes (HPO): 27
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 41.6% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_152415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24928
Approved symbol	VPS37A
Name	VPS37A subunit of ESCRT-I
Location	8p22
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32642, HCRP1, SPG53
Ensembl gene	ENSG00000155975
Ensembl biotype	protein_coding
OMIM	609927
Entrez	137492

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 24 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000324849, ENST00000425020, ENST00000518038, ENST00000519381, ENST00000519515, ENST00000520140, ENST00000520997, ENST00000521005, ENST00000521162, ENST00000521829, ENST00000521976, ENST00000880479, ENST00000880480, ENST00000880481, ENST00000880482, ENST00000880483, ENST00000880484, ENST00000880485, ENST00000880486, ENST00000880487, ENST00000967262, ENST00000967263, ENST00000967264, ENST00000967265, ENST00000967266, ENST00000967267, ENST00000967268, ENST00000967269, ENST00000967270, ENST00000967271

RefSeq mRNA: 9 — MANE Select: NM_152415 NM_001145152, NM_001363167, NM_001363168, NM_001363169, NM_001363170, NM_001363171, NM_001363172, NM_001363173, NM_152415

CCDS: CCDS47811, CCDS6001

Canonical transcript exons

ENST00000324849 — 12 exons

Exon	Start	End
ENSE00001023723	17268856	17268956
ENSE00001023741	17274733	17274958
ENSE00001266714	17294987	17298024
ENSE00002101448	17246958	17247369
ENSE00003501592	17280375	17280443
ENSE00003504555	17276397	17276467
ENSE00003524388	17286347	17286427
ENSE00003555401	17280028	17280155
ENSE00003610455	17280239	17280297
ENSE00003611815	17284473	17284616
ENSE00003672407	17265907	17265981
ENSE00003788358	17268258	17268372

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 94.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.2376 / max 201.6748, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87534	29.1821	1820
87537	1.4614	1007
87535	0.8090	554
87536	0.7851	532

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	94.89	gold quality
gastrocnemius	UBERON:0001388	93.65	gold quality
adrenal tissue	UBERON:0018303	93.47	gold quality
muscle of leg	UBERON:0001383	93.14	gold quality
calcaneal tendon	UBERON:0003701	93.06	gold quality
left ventricle myocardium	UBERON:0006566	92.80	gold quality
right testis	UBERON:0004534	92.65	gold quality
tibialis anterior	UBERON:0001385	92.50	gold quality
secondary oocyte	CL:0000655	92.45	gold quality
left testis	UBERON:0004533	92.32	gold quality
smooth muscle tissue	UBERON:0001135	92.11	gold quality
heart left ventricle	UBERON:0002084	92.05	gold quality
stromal cell of endometrium	CL:0002255	91.86	gold quality
cardiac ventricle	UBERON:0002082	91.78	gold quality
oocyte	CL:0000023	91.74	gold quality
right atrium auricular region	UBERON:0006631	91.72	gold quality
sural nerve	UBERON:0015488	91.72	gold quality
heart	UBERON:0000948	91.34	gold quality
testis	UBERON:0000473	91.27	gold quality
cardiac atrium	UBERON:0002081	91.24	gold quality
popliteal artery	UBERON:0002250	90.88	gold quality
tibial artery	UBERON:0007610	90.87	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.78	gold quality
lower esophagus	UBERON:0013473	90.53	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.52	gold quality
heart right ventricle	UBERON:0002080	90.49	gold quality
colonic epithelium	UBERON:0000397	90.37	gold quality
right lung	UBERON:0002167	90.33	gold quality
deltoid	UBERON:0001476	90.30	gold quality
mucosa of stomach	UBERON:0001199	90.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

139 targeting VPS37A, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-10527-5P	99.91	72.28	3754

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 41.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• Our results strongly suggest that HCRP1 might be a growth inhibitory protein and associated with decreasing the invasion of HCC cells (PMID:14623289)
• HCRP1 is a subunit of mammalian ESCRT-I, and its function is essential for lysosomal sorting of EGF receptors. (PMID:15240819)
• Data show hVps37A mRNA downregulation in ovarian cancer. (PMID:22016507)
• The missense mutation c.1146A>T in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. (PMID:22717650)
• Low HCRP1 expression was found to be of adverse prognostic significance in patients with oral and oropharyngeal squamous cell carcinoma who received preoperative chemoradiotherapy (PMID:22891969)
• The present data indicate that HCRP1 inhibits breast cancer metastasis through downregulating EGFR phosphorylation. (PMID:27311861)
• HCRP1 is a negative regulator in prostate cancer progression, metastasis and multi-drug resistance. (PMID:28458158)
• this study identifies HCRP1 downregulation correlates with tumor stage, nodal metastasis, and poor patient survival in human gastric cancer (PMID:28963677)
• HCRP-1 regulates EGFR-AKT-BIM-mediated anoikis resistance and serves as a prognostic marker in human colon cancer. (PMID:30518879)
• The VPS37A coordinates the recruitment of a unique set of ESCRT machinery components for phagophore closure in mammalian cells. (PMID:31519728)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps37a	ENSDARG00000017119
mus_musculus	Vps37a	ENSMUSG00000031600
rattus_norvegicus	Vps37a	ENSRNOG00000012001
drosophila_melanogaster	Vsp37A	FBGN0016038
caenorhabditis_elegans		WBGENE00016990

Paralogs (3): VPS37B (ENSG00000139722), VPS37C (ENSG00000167987), VPS37D (ENSG00000176428)

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 37A — Q8NEZ2 (reviewed: Q8NEZ2)

Alternative names: ESCRT-I complex subunit VPS37A, Hepatocellular carcinoma-related protein 1

All UniProt accessions (6): Q8NEZ2, E5RG91, E5RHB8, E5RJ10, E5RJX6, H0YBN0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in cell growth and differentiation.

Subunit / interactions. Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with TSG101, VPS28 and HGS. Component of an ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, VPS37A and UBAP1 in a 1:1:1:1 stoichiometry.

Subcellular location. Late endosome membrane. Nucleus.

Tissue specificity. Widely expressed. Examined tissues include heart, brain, placenta, liver, skeletal muscle, kidney and pancreas. More abundant in liver. Strongly decreased or undetected in hepatomas.

Disease relevance. Spastic paraplegia 53, autosomal recessive (SPG53) [MIM:614898] 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. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. SPG53 is characterized by pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the VPS37 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NEZ2-1	1	yes
Q8NEZ2-2	2, beta
Q8NEZ2-3	3

RefSeq proteins (9): NP_001138624, NP_001350096, NP_001350097, NP_001350098, NP_001350099, NP_001350100, NP_001350101, NP_001350102, NP_689628* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009851	Mod_r	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR029012	Helix_hairpin_bin_sf	Homologous_superfamily
IPR037202	ESCRT_assembly_dom	Homologous_superfamily

Pfam: PF07200

UniProt features (22 total): strand 5, helix 3, splice variant 3, sequence variant 3, sequence conflict 2, turn 2, chain 1, domain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8E22	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEZ2-F1	77.48	0.57

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): 18

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-174490	Membrane binding and targetting of GAG proteins
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)
R-HSA-9610379	HCMV Late Events
R-HSA-9615710	Late endosomal microautophagy

MSigDB gene sets: 282 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_ENDOSOME_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_VESICLE_ORGANIZATION, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (9): protein targeting to membrane (GO:0006612), protein targeting to vacuole (GO:0006623), macroautophagy (GO:0016236), multivesicular body assembly (GO:0036258), viral budding via host ESCRT complex (GO:0039702), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043328), membrane fission (GO:0090148), protein transport (GO:0015031)

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

GO Cellular Component (15): ESCRT I complex (GO:0000813), acrosomal vesicle (GO:0001669), nucleoplasm (GO:0005654), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), endosome membrane (GO:0010008), late endosome membrane (GO:0031902), perinuclear theca (GO:0033011), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), nucleus (GO:0005634), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Late Phase of HIV Life Cycle	1
Synthesis And Processing Of GAG, GAGPOL Polyproteins	1
Membrane Trafficking	1
HCMV Infection	1
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
sperm flagellum	3
protein targeting	2
intracellular protein transport	2
protein localization to vacuole	2
establishment of protein localization to vacuole	2
endosome membrane	2
microtubule organizing center	2
establishment of protein localization to membrane	1
vacuolar transport	1
autophagosome assembly	1
autophagy	1
multivesicular body organization	1
organelle assembly	1
viral budding	1
ubiquitin-dependent protein catabolic process	1
protein catabolic process in the vacuole	1
multivesicular body sorting pathway	1
late endosome to vacuole transport via multivesicular body sorting pathway	1
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1
membrane organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
binding	1
ESCRT complex	1
membrane protein complex	1
secretory granule	1
nuclear lumen	1
centriole	1
intracellular membraneless organelle	1
cytoplasm	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
late endosome	1
cytoskeleton	1
perinuclear region of cytoplasm	1
intracellular membrane-bounded organelle	1
endomembrane system	1

Protein interactions and networks

STRING

817 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS37A	VPS28	Q9UK41	999
VPS37A	TSG101	Q99816	998
VPS37A	UBAP1	Q9NZ09	949
VPS37A	MVB12A	Q96EY5	916
VPS37A	MVB12B	Q9H7P6	838
VPS37A	VPS25	Q9BRG1	802
VPS37A	VPS36	Q86VN1	778
VPS37A	CHMP2A	O43633	777
VPS37A	LAMP1	P11279	679
VPS37A	CHMP3	Q9Y3E7	644
VPS37A	A0A140T963	A0A140T963	644
VPS37A	AP4S1	Q9Y587	618
VPS37A	AP4B1	Q9Y6B7	607
VPS37A	CHMP1A	Q9HD42	597
VPS37A	AP5Z1	O43299	580

IntAct

99 interactions, top by confidence:

A	B	Type	Score
TSG101	VPS37A	psi-mi:“MI:0915”(physical association)	0.840
VPS37A	TSG101	psi-mi:“MI:0915”(physical association)	0.840
TSG101	VPS37C	psi-mi:“MI:0914”(association)	0.780
ARRDC1	NEDD4	psi-mi:“MI:0914”(association)	0.640
VPS28	VPS37A	psi-mi:“MI:0914”(association)	0.640
VPS37A	DMWD	psi-mi:“MI:0915”(physical association)	0.560
VPS37A		psi-mi:“MI:0915”(physical association)	0.560
VPS37A	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	GRN	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	GSN	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	HRAS	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	NF2	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
TSC1	VPS37A	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	WFS1	psi-mi:“MI:0915”(physical association)	0.560
KLF11	VPS37A	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	NUP58	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	RNF11	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	GDAP1	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	JPH3	psi-mi:“MI:0915”(physical association)	0.560
VPS37A	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
HTT	VPS37A	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	VPS37A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (84): VPS37A (Two-hybrid), TRIM42 (Two-hybrid), VPS37A (Affinity Capture-MS), VPS37A (Affinity Capture-MS), UBAP1 (Affinity Capture-Western), TSG101 (Affinity Capture-Western), VPS37A (Two-hybrid), VPS37A (Affinity Capture-MS), VPS37A (Affinity Capture-MS), VPS37A (Affinity Capture-MS), VPS37A (Affinity Capture-MS), VPS37A (Affinity Capture-MS), TSG101 (Two-hybrid), VPS37A (Affinity Capture-MS), VPS37A (Reconstituted Complex)

ESM2 similar proteins: A3LXQ8, A8WSQ9, E3VNM4, F4HVA6, F4KAU9, O13821, O13965, O55012, O60167, O60641, O75886, O80910, O88811, O93436, P24345, P34489, P40343, P46609, P47160, P70297, P78813, Q05140, Q09345, Q0CJV3, Q10237, Q10PR4, Q13492, Q20374, Q41558, Q43484, Q52MZ2, Q53Q70, Q5XHY7, Q6CL17, Q6E3D2, Q6FQJ1, Q6IVC2, Q6NQK0, Q755J9, Q7M6Y3

Diamond homologs: Q8CHS8, Q8NEZ2, Q8R0J7, Q9H9H4, A5D8V6, Q5R9T2, Q810I0, Q86XT2, Q8R105

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
VPS37A	“form complex”	“ESCRT-I complex, VPS37A-UBAP1 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Budding and maturation of HIV virion	5	63.7×	1e-06
Endosomal Sorting Complex Required For Transport (ESCRT)	5	57.6×	2e-06
Late endosomal microautophagy	5	51.0×	2e-06
HCMV Late Events	6	18.5×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	5	135.0×	6e-08
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	6	83.6×	4e-08
multivesicular body assembly	5	67.5×	2e-06
membrane fission	5	52.7×	5e-06
regulation of cell cycle	5	9.6×	9e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	129
Likely benign	81
Benign	26

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
149660	GRCh38/hg38 8p23.3-q24.3(chr8:241605-145054781)x3	Pathogenic
39741	NM_152415.3(VPS37A):c.1146A>T (p.Lys382Asn)	Pathogenic

SpliceAI

2020 predictions. Top by Δscore:

Variant	Effect	Δscore
8:17265902:TGCA:T	acceptor_loss	1.0000
8:17265903:GCA:G	acceptor_loss	1.0000
8:17265904:CA:C	acceptor_loss	1.0000
8:17265905:A:AG	acceptor_gain	1.0000
8:17265905:AGT:A	acceptor_loss	1.0000
8:17265906:G:GG	acceptor_gain	1.0000
8:17265906:GT:G	acceptor_gain	1.0000
8:17265906:GTAT:G	acceptor_gain	1.0000
8:17265906:GTATA:G	acceptor_gain	1.0000
8:17265979:TAT:T	donor_gain	1.0000
8:17265981:TG:T	donor_loss	1.0000
8:17265982:G:GG	donor_gain	1.0000
8:17265982:GTGA:G	donor_loss	1.0000
8:17265983:TGA:T	donor_loss	1.0000
8:17265984:GAG:G	donor_loss	1.0000
8:17268238:A:AG	acceptor_gain	1.0000
8:17268238:ATCT:A	acceptor_gain	1.0000
8:17268239:T:G	acceptor_gain	1.0000
8:17268241:T:TA	acceptor_gain	1.0000
8:17268247:A:AG	acceptor_gain	1.0000
8:17268248:C:G	acceptor_gain	1.0000
8:17268340:G:GT	donor_gain	1.0000
8:17268340:GGAGT:G	donor_gain	1.0000
8:17268341:G:GT	donor_gain	1.0000
8:17268342:A:T	donor_gain	1.0000
8:17268343:GT:G	donor_gain	1.0000
8:17268368:ACAAT:A	donor_gain	1.0000
8:17268369:CAAT:C	donor_gain	1.0000
8:17268371:AT:A	donor_gain	1.0000
8:17268373:G:GG	donor_gain	1.0000

AlphaMissense

2627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:17265935:T:G	Y52D	1.000
8:17284512:G:C	A337P	1.000
8:17284524:G:C	A341P	1.000
8:17284587:T:C	F362L	1.000
8:17284588:T:C	F362S	1.000
8:17284589:T:A	F362L	1.000
8:17284589:T:G	F362L	1.000
8:17284613:A:C	R370S	1.000
8:17284613:A:T	R370S	1.000
8:17247351:T:A	L36H	0.999
8:17247351:T:C	L36P	0.999
8:17265935:T:C	Y52H	0.999
8:17265936:A:C	Y52S	0.999
8:17265981:T:A	I67K	0.999
8:17268263:T:A	L69H	0.999
8:17268263:T:C	L69P	0.999
8:17268274:T:C	F73L	0.999
8:17268275:T:C	F73S	0.999
8:17268276:T:A	F73L	0.999
8:17268276:T:G	F73L	0.999
8:17268277:C:T	P74S	0.999
8:17268278:C:A	P74H	0.999
8:17268290:C:A	P78Q	0.999
8:17268290:C:G	P78R	0.999
8:17268302:T:A	V82D	0.999
8:17284504:T:C	L334S	0.999
8:17284515:G:C	A338P	0.999
8:17284537:C:T	S345F	0.999
8:17284558:T:C	F352S	0.999
8:17284591:T:C	L363P	0.999

dbSNP variants (sampled 300 via entrez): RS1000024559 (8:17245390 A>T), RS1000031599 (8:17302096 G>A), RS1000033426 (8:17307212 A>G), RS1000055281 (8:17323477 C>T), RS1000063887 (8:17333761 A>C), RS1000077765 (8:17273870 A>T), RS1000107279 (8:17251151 T>A), RS1000135745 (8:17248735 G>A), RS1000165158 (8:17284821 G>C), RS1000181221 (8:17330884 A>G), RS1000224113 (8:17298960 A>C), RS1000305852 (8:17269614 C>T), RS1000348123 (8:17302882 A>AC), RS1000361473 (8:17306445 G>A), RS1000379611 (8:17282835 G>A,C)

Disease associations

OMIM: gene MIM:609927 | disease phenotypes: MIM:614898, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 53	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex hereditary spastic paraplegia	Limited	AR

Mondo (2): hereditary spastic paraplegia 53 (MONDO:0013962), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (2): Autosomal recessive spastic paraplegia type 53 (Orphanet:319199), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000372	Abnormal auditory canal morphology
HP:0000750	Delayed speech and language development
HP:0000768	Pectus carinatum
HP:0000998	Hypertrichosis
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0002119	Ventriculomegaly
HP:0002169	Clonus
HP:0002451	Limb dystonia
HP:0002495	Impaired vibratory sensation
HP:0002539	Cortical dysplasia
HP:0002808	Kyphosis
HP:0003593	Infantile onset
HP:0006895	Lower limb hypertonia
HP:0007350	Upper limb hyperreflexia
HP:0010831	Impaired proprioception
HP:0011463	Childhood onset
HP:0100543	Cognitive impairment
HP:0200049	Upper limb hypertonia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000107_10	Tonometry	2.000000e-06
GCST004946_93	Schizophrenia	3.000000e-12
GCST009391_158	Metabolite levels	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010486	glucuronate 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: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
VPS37A Underexpression	Cetuximab	Ovarian Cancer	Resistance	CIViC D	EID1981

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Cisplatin	increases response to substance	1
Clorgyline	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	increases expression	1
Fluorouracil	increases response to substance	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Phenobarbital	affects expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1RC	Abcam K-562 VPS37A KO	Cancer cell line	Female
CVCL_D2MZ	Abcam Raji VPS37A KO	Cancer cell line	Male
CVCL_E0T0	Ubigene HeLa VPS37A KO	Cancer cell line	Female
CVCL_WQ81	Abcam Jurkat VPS37A KO	Cancer cell line	Male

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