VPS41

Summary

VPS41 (VPS41 subunit of HOPS complex, HGNC:12713) is a protein-coding gene on chromosome 7p14.1, encoding Vacuolar protein sorting-associated protein 41 homolog (P49754). Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. It is a selective cancer dependency (DepMap: 82.0% of cell lines).

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human ortholog of yeast Vps41 protein which is also conserved in Drosophila, tomato, and Arabidopsis. Expression studies in yeast and human indicate that this protein may be involved in the formation and fusion of transport vesicles from the Golgi. Several transcript variants encoding different isoforms have been described for this gene, however, the full-length nature of not all is known.

Source: NCBI Gene 27072 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive 29 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 227 total — 4 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 44
• Cancer dependency (DepMap): dependent in 82.0% of screened cell lines
• MANE Select transcript: NM_014396

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12713
Approved symbol	VPS41
Name	VPS41 subunit of HOPS complex
Location	7p14.1
Locus type	gene with protein product
Status	Approved
Aliases	HVSP41
Ensembl gene	ENSG00000006715
Ensembl biotype	protein_coding
OMIM	605485
Entrez	27072

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000265745, ENST00000310301, ENST00000395969, ENST00000413141, ENST00000414632, ENST00000418457, ENST00000439468, ENST00000448833, ENST00000457055, ENST00000462429, ENST00000466017, ENST00000482217, ENST00000485955, ENST00000490924, ENST00000862385, ENST00000862386, ENST00000862387, ENST00000862388, ENST00000862389, ENST00000862390, ENST00000862391, ENST00000934107, ENST00000951459, ENST00000951460, ENST00000951461, ENST00000951462

RefSeq mRNA: 2 — MANE Select: NM_014396 NM_014396, NM_080631

CCDS: CCDS5457, CCDS5458

Canonical transcript exons

ENST00000310301 — 29 exons

Exon	Start	End
ENSE00000460377	38817817	38817882
ENSE00000679004	38745559	38745613
ENSE00000679007	38752176	38752313
ENSE00000679011	38754702	38754752
ENSE00000679014	38754895	38754936
ENSE00000679016	38756838	38756982
ENSE00000679019	38758354	38758481
ENSE00000679023	38765580	38765661
ENSE00000679025	38767537	38767598
ENSE00000679027	38771198	38771254
ENSE00000679029	38772522	38772637
ENSE00000679068	38821203	38821265
ENSE00000679136	38830254	38830328
ENSE00001188384	38862545	38862622
ENSE00001351846	38722974	38726326
ENSE00001755942	38909154	38909191
ENSE00003464293	38763455	38763547
ENSE00003516319	38728692	38728791
ENSE00003540548	38795465	38795611
ENSE00003571679	38869146	38869253
ENSE00003573033	38743402	38743542
ENSE00003578270	38728542	38728586
ENSE00003608818	38774115	38774244
ENSE00003609940	38776679	38776776
ENSE00003639714	38898091	38898129
ENSE00003649225	38741985	38742121
ENSE00003659310	38789801	38789867
ENSE00003674918	38726909	38726988
ENSE00003787385	38796745	38796864

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 97.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.3822 / max 2454.4680, expressed in 1807 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83716	39.2203	1807
83717	0.1618	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.32	gold quality
adrenal tissue	UBERON:0018303	96.07	gold quality
gall bladder	UBERON:0002110	95.32	gold quality
colonic epithelium	UBERON:0000397	94.95	gold quality
islet of Langerhans	UBERON:0000006	94.76	gold quality
ventricular zone	UBERON:0003053	94.57	gold quality
stromal cell of endometrium	CL:0002255	94.07	gold quality
cortical plate	UBERON:0005343	93.97	gold quality
ganglionic eminence	UBERON:0004023	93.87	gold quality
monocyte	CL:0000576	93.85	gold quality
endothelial cell	CL:0000115	93.69	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.49	gold quality
mononuclear cell	CL:0000842	93.48	gold quality
leukocyte	CL:0000738	93.26	gold quality
corpus callosum	UBERON:0002336	93.13	gold quality
prefrontal cortex	UBERON:0000451	92.96	gold quality
right frontal lobe	UBERON:0002810	92.88	gold quality
spinal cord	UBERON:0002240	92.43	gold quality
left ovary	UBERON:0002119	92.32	gold quality
popliteal artery	UBERON:0002250	92.08	gold quality
tibial artery	UBERON:0007610	92.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.01	gold quality
sural nerve	UBERON:0015488	91.88	gold quality
descending thoracic aorta	UBERON:0002345	91.85	gold quality
aorta	UBERON:0000947	91.77	gold quality
artery	UBERON:0001637	91.76	gold quality
middle temporal gyrus	UBERON:0002771	91.67	gold quality
thoracic aorta	UBERON:0001515	91.56	gold quality
pancreas	UBERON:0001264	91.55	gold quality
ascending aorta	UBERON:0001496	91.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.11
E-ENAD-17	no	723.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

97 targeting VPS41, 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-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
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-196A-1-3P	99.99	72.15	2772
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3686	99.90	70.53	2432

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 82.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• These data show that hVPS41 is protective against both alpha-syn and neurotoxic-mediated injury in invertebrate and cellular models of PD. (PMID:19850127)
• Both a functional heterotetrameric adaptor protein complex and a homotypic fusion and vacuole protein sorting-tethering complex are required for VPS41 to elicit neuroprotection in a transgenic model of Parkinson’s disease. (PMID:22323726)
• Vps41 knockdown impairs late endosome fusion and fusion between late endosomes and lysosomes. (PMID:23167963)
• hVps41 and VAMP7 are specifically involved in the fusion of trans-Golgi network-derived lysosome-associated membrane protein carriers with late endosomes. (PMID:23322049)
• VPS41 subunit of HOPS complex was defined to be the major partner for interacting with RILP. (PMID:25445562)
• VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction (PMID:28931724)
• Our results indicate that an ARF-like GTPase gene product, ARL-8, mitigates endocytic Ab neurodegeneration in a VPS-41-dependent manner, rather than through RAB-7 and AP3 as with alpha-synuclein..we demonstrate that the LC3 orthologue, LGG-2, plays a critical role in Ab toxicity with ARL-8. (PMID:30508205)
• Here, the authors show that Vps8 overexpression inhibits homotypic fusion and vacuole protein sorting (HOPS)-dependent trafficking routes including late endosome maturation, autophagosome-lysosome fusion, crinophagy and lysosome-related organelle formation. Mechanistically, Vps8 overexpression abolishes the late endosomal localization of HOPS-specific Vps41/Lt and prevents HOPS assembly. (PMID:31194677)
• Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities. (PMID:32808683)
• Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking. (PMID:33764426)
• Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation. (PMID:33851776)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps41	ENSDARG00000063573
mus_musculus	Vps41	ENSMUSG00000041236
rattus_norvegicus	Vps41	ENSRNOG00000012940
drosophila_melanogaster	lt	FBGN0002566
caenorhabditis_elegans		WBGENE00017974

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 41 homolog — P49754 (reviewed: P49754)

Alternative names: S53

All UniProt accessions (8): P49754, C9J2U9, C9J3F8, C9JU58, C9JZ11, H7BXH3, H7BZX6, H7C0K2

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Acts as a component of the HOPS endosomal tethering complex. This complex is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes implicated in degradation of endocytosed cargo. Required for fusion of autophagosomes with lysosomes. Links the HOPS complex to endosomal Rab7 via its association with RILP and to lysosomal membranes via its association with ARL8B, suggesting that these interactions may bring the compartments to close proximity for fusion. Involved in the direct trans-Golgi network to late endosomes transport of lysosomal membrane proteins independently of HOPS. Involved in sorting to the regulated secretory pathway presumably implicating the AP-3 adapter complex. May play a role in HOPS-independent function in the regulated secretory pathway.

Subunit / interactions. Component of the homotypic fusion and vacuole protein sorting (HOPS) complex; the core of which composed of the class C Vps proteins VPS11, VPS16, VPS18 and VPS33A, is associated with VPS39 and VPS41. Interacts with RILP, MON1B. Interacts with ARL8B (GTP-bound form); involved in recruitment to lysosomes and probably hierarchial assembly of the HOPS complex at lysosomal membranes. In vitro can self-assemble into a lattice. Associates with adapter protein complex 3 (AP-3) and clathrin:AP-3 complexes. Interacts with STX17; this interaction is increased in the absence of TMEM39A. Interacts with ARL8B and PLEKHM1; the interaction mediates the recruitment of the HOPS complex to lysosomes. Interacts with RAB7, RAB2A and RAB2B. Interacts with RAB39A (GTP-bound) and RAB39B (GTP-bound); interaction with RAB39A leads to a functional HOPS complex that mediates autophagosome-lysosome membrane tethering. (Microbial infection) The interaction with STX17 is decreased in presence of SARS coronavirus-2/SARS-CoV-2 ORF3A protein.

Subcellular location. Endosome membrane. Late endosome membrane. Early endosome membrane. Lysosome membrane. Golgi apparatus. trans-Golgi network. Cytoplasmic vesicle. Clathrin-coated vesicle. Cytoplasm. Cytosol.

Tissue specificity. Expressed in cerebral cortex and cerebellum. Highly expressed in Purkinje cells.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 29 (SCAR29) [MIM:619389] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR29 is a progressive disease characterized by delayed motor development in early infancy followed by difficulty walking due to an ataxic gait or inability to walk, hypotonia, and variably impaired intellectual development. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Protective against both alpha-synuclein and neurotoxic-mediated injury in invertebrate and cellular models of Parkinson’s disease (PD); the function requires the AP-3 adapter complex and the HOPS complex.

Similarity. Belongs to the VPS41 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P49754-1	1	yes
P49754-2	2
P49754-3	3

RefSeq proteins (2): NP_055211, NP_542198 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000547	Clathrin_H-chain/VPS_repeat	Repeat
IPR001841	Znf_RING	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016902	Vps41	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR045111	Vps41/Vps8	Family
IPR057779	Znf_RING_Vps41	Domain
IPR057780	Beta-prop_Vps41	Domain

Pfam: PF23411, PF23555, PF23556

UniProt features (20 total): sequence variant 8, sequence conflict 3, splice variant 3, region of interest 2, chain 1, repeat 1, zinc finger region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49754-F1	86.63	0.48

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9754560	SARS-CoV-2 modulates autophagy

MSigDB gene sets: 315 (showing top): GOBP_LYSOSOMAL_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_MEMBRANE_FUSION, GOBP_PROTEIN_TARGETING, GOBP_VACUOLAR_TRANSPORT, AACYNNNNTTCCS_UNKNOWN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, XU_HGF_SIGNALING_NOT_VIA_AKT1_48HR_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_MACROAUTOPHAGY, MORF_ZNF10

GO Biological Process (13): protein targeting to vacuole (GO:0006623), endosome to lysosome transport (GO:0008333), cellular response to starvation (GO:0009267), vesicle-mediated transport (GO:0016192), macroautophagy (GO:0016236), endosomal vesicle fusion (GO:0034058), regulation of SNARE complex assembly (GO:0035542), Golgi vesicle transport (GO:0048193), late endosome to lysosome transport (GO:1902774), intracellular protein transport (GO:0006886), autophagy (GO:0006914), protein transport (GO:0015031), intracellular transport (GO:0046907)

GO Molecular Function (5): microtubule binding (GO:0008017), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (21): lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), Golgi apparatus (GO:0005794), Golgi-associated vesicle (GO:0005798), cytosol (GO:0005829), endosome membrane (GO:0010008), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), HOPS complex (GO:0030897), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), lysosomal HOPS complex (GO:1902501), cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), endomembrane system (GO:0012505), AP-3 adaptor complex (GO:0030123), cytoplasmic vesicle (GO:0031410), clathrin complex (GO:0071439)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transport	3
endosome	3
cytoplasm	3
lysosomal transport	2
intercellular transport	2
vesicle-mediated transport	2
intracellular protein localization	2
intracellular anatomical structure	2
endomembrane system	2
cytoplasmic vesicle	2
endosome membrane	2
protein targeting	1
intracellular protein transport	1
vacuolar transport	1
protein localization to vacuole	1
establishment of protein localization to vacuole	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
cellular process	1
autophagosome assembly	1
autophagy	1
vesicle fusion	1
SNARE complex assembly	1
regulation of protein-containing complex assembly	1
protein transport	1
intracellular transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
establishment of protein localization	1
cellular localization	1
establishment of localization in cell	1
tubulin binding	1
transition metal ion binding	1
protein binding	1
binding	1
cation binding	1
lytic vacuole	1

Protein interactions and networks

STRING

858 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS41	VPS39	Q96JC1	983
VPS41	VPS18	Q9P253	976
VPS41	VPS16	Q9H269	974
VPS41	VPS11	Q9H270	972
VPS41	VPS8	Q8N3P4	839
VPS41	CRIM1	Q9NZV1	770
VPS41	VPS33A	Q96AX1	758
VPS41	TGFBRAP1	Q8WUH2	643
VPS41	VTI1B	Q9UEU0	618
VPS41	VPS45	Q9NRW7	604
VPS41	VAMP7	P51809	575
VPS41	CCZ1B	P86790	565
VPS41	NSF	P46459	552
VPS41	YKT6	O15498	541
VPS41	RPS21	P35265	541

IntAct

81 interactions, top by confidence:

A	B	Type	Score
VPS18	VPS41	psi-mi:“MI:0915”(physical association)	0.800
VPS18	VPS41	psi-mi:“MI:0914”(association)	0.800
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
VPS41	PLEKHM1	psi-mi:“MI:0915”(physical association)	0.740
PLEKHM1	VPS41	psi-mi:“MI:0914”(association)	0.740
VPS11	VPS41	psi-mi:“MI:0914”(association)	0.710
VPS41	VPS11	psi-mi:“MI:0914”(association)	0.710
VPS41	VPS11	psi-mi:“MI:0915”(physical association)	0.710
	VPS41	psi-mi:“MI:0914”(association)	0.690
	VPS41	psi-mi:“MI:0915”(physical association)	0.690
VPS16	VPS41	psi-mi:“MI:0914”(association)	0.640
VIPAS39	VPS41	psi-mi:“MI:0914”(association)	0.610
VPS41	VIPAS39	psi-mi:“MI:0915”(physical association)	0.610
STX17	VPS41	psi-mi:“MI:0915”(physical association)	0.590
VPS41	STX17	psi-mi:“MI:0915”(physical association)	0.590
RILP	VPS41	psi-mi:“MI:0915”(physical association)	0.570
RILP	VPS41	psi-mi:“MI:0403”(colocalization)	0.570
RILP	VPS41	psi-mi:“MI:0407”(direct interaction)	0.570
PLEKHM1	MTOR	psi-mi:“MI:0914”(association)	0.540
VPS33A	VPS41	psi-mi:“MI:0914”(association)	0.530
CT55	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TGFBRAP1	VPS41	psi-mi:“MI:0914”(association)	0.530

BioGRID (129): VPS41 (Affinity Capture-MS), TGFBRAP1 (Affinity Capture-MS), VPS33A (Affinity Capture-MS), VPS16 (Affinity Capture-MS), VPS18 (Affinity Capture-MS), VPS11 (Affinity Capture-MS), VPS41 (Reconstituted Complex), VPS41 (Reconstituted Complex), VPS41 (Affinity Capture-MS), VPS41 (Affinity Capture-MS), VPS41 (Affinity Capture-MS), VPS41 (Affinity Capture-MS), VPS41 (Affinity Capture-MS), VPS41 (Affinity Capture-MS), VPS41 (Affinity Capture-MS)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A2AGL3, A7MB89, B0LPN4, E9Q401, O60733, P30957, P42694, P49754, P97570, P97819, Q15413, Q29RM5, Q2KIX2, Q2T9K6, Q32PW3, Q3SX45, Q4V890, Q59H18, Q5F361, Q5GIG6, Q5KU39, Q5RF15, Q5U2S6, Q5ZKK2, Q66H07, Q66H63, Q6B858, Q6DFV5, Q6NYU2, Q7T3P8, Q7TQP6, Q8C0T1, Q8CEF1, Q8K0L0, Q8K114, Q8TC84, Q91W86, Q92736

Diamond homologs: E7F590, P49754, P93043, P93231, Q5KU39, Q7PL76, Q9P7N3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	VPS41	ubiquitination
VPS41	“form complex”	“HOPS tethering complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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.

GO biological processes:

GO term	Partners	Fold	FDR
endosomal vesicle fusion	6	99.1×	3e-09
endosome to lysosome transport	9	44.6×	2e-10
intracellular protein transport	11	10.5×	8e-07
protein transport	10	6.5×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	6
Uncertain significance	121
Likely benign	10
Benign	45

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1065412	NM_014396.4(VPS41):c.450+1G>T	Pathogenic
1175719	NM_014396.4(VPS41):c.2372G>T (p.Cys791Phe)	Pathogenic
1175720	NM_014396.4(VPS41):c.1423-2A>G	Pathogenic
1175722	NM_014396.4(VPS41):c.1898G>C (p.Arg633Pro)	Pathogenic
1175718	NM_014396.4(VPS41):c.853T>C (p.Ser285Pro)	Likely pathogenic
1175721	NM_014396.4(VPS41):c.1984C>T (p.Arg662Ter)	Likely pathogenic
2431434	NM_014396.4(VPS41):c.1999C>T (p.Arg667Ter)	Likely pathogenic
4076109	NM_014396.4(VPS41):c.385-2A>G	Likely pathogenic
4076110	NM_014396.4(VPS41):c.1247G>A (p.Arg416His)	Likely pathogenic
4845792	NM_014396.4(VPS41):c.1836C>A (p.Tyr612Ter)	Likely pathogenic

SpliceAI

5893 predictions. Top by Δscore:

Variant	Effect	Δscore
7:38726903:ACT:A	donor_loss	1.0000
7:38726904:CTCA:C	donor_loss	1.0000
7:38726905:T:TA	donor_loss	1.0000
7:38726906:C:CC	donor_loss	1.0000
7:38726908:C:A	donor_loss	1.0000
7:38726908:CCATG:C	donor_gain	1.0000
7:38726993:C:CT	acceptor_gain	1.0000
7:38726994:G:T	acceptor_gain	1.0000
7:38727002:C:CT	acceptor_gain	1.0000
7:38728587:C:CC	acceptor_gain	1.0000
7:38741983:A:AC	donor_gain	1.0000
7:38741983:ACTTG:A	donor_gain	1.0000
7:38741984:C:CT	donor_gain	1.0000
7:38741984:CT:C	donor_gain	1.0000
7:38741984:CTT:C	donor_gain	1.0000
7:38741984:CTTG:C	donor_gain	1.0000
7:38741984:CTTGC:C	donor_gain	1.0000
7:38742117:AAATG:A	acceptor_gain	1.0000
7:38742118:AATG:A	acceptor_gain	1.0000
7:38742118:AATGC:A	acceptor_loss	1.0000
7:38742119:ATG:A	acceptor_gain	1.0000
7:38742119:ATGC:A	acceptor_loss	1.0000
7:38742120:TG:T	acceptor_gain	1.0000
7:38742120:TGC:T	acceptor_loss	1.0000
7:38742121:GCT:G	acceptor_loss	1.0000
7:38742122:C:CC	acceptor_gain	1.0000
7:38742122:CTA:C	acceptor_loss	1.0000
7:38742123:T:A	acceptor_loss	1.0000
7:38742133:CACA:C	acceptor_gain	1.0000
7:38742136:A:C	acceptor_gain	1.0000

AlphaMissense

5710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:38728784:A:G	L756P	1.000
7:38742004:A:G	L747P	1.000
7:38742076:G:T	P723Q	1.000
7:38742103:A:G	L714S	1.000
7:38742106:A:G	L713S	1.000
7:38743436:C:A	W696C	1.000
7:38743436:C:G	W696C	1.000
7:38743438:A:G	W696R	1.000
7:38743438:A:T	W696R	1.000
7:38743464:G:T	A687D	1.000
7:38743515:A:G	L670P	1.000
7:38758457:A:G	W483R	1.000
7:38758457:A:T	W483R	1.000
7:38772544:A:G	L369P	1.000
7:38772580:G:T	A357D	1.000
7:38795512:A:G	W224R	1.000
7:38795512:A:T	W224R	1.000
7:38796780:A:G	W179R	1.000
7:38796780:A:T	W179R	1.000
7:38726308:A:G	C835R	0.999
7:38728575:A:G	C791R	0.999
7:38728760:A:G	L764P	0.999
7:38728781:C:G	R757P	0.999
7:38728784:A:T	L756H	0.999
7:38742016:A:C	L743W	0.999
7:38742016:A:G	L743S	0.999
7:38742028:A:C	L739W	0.999
7:38742028:A:G	L739S	0.999
7:38742067:A:G	L726P	0.999
7:38742067:A:T	L726Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000013464 (7:38849491 A>G), RS1000032757 (7:38893711 T>C), RS1000034394 (7:38803808 C>G), RS1000060959 (7:38899663 G>A,C), RS1000064173 (7:38826357 A>G), RS1000069658 (7:38758108 T>C), RS1000074141 (7:38826104 C>G,T), RS1000085544 (7:38811132 T>C), RS1000106194 (7:38802410 A>G), RS1000124620 (7:38875136 T>C), RS1000142742 (7:38738162 T>C), RS1000178527 (7:38889760 G>A,C), RS1000209694 (7:38890089 T>C), RS1000221657 (7:38845953 A>C,T), RS1000283067 (7:38783371 C>T)

Disease associations

OMIM: gene MIM:605485 | disease phenotypes: MIM:619389, MIM:260920

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 29	Strong	Autosomal recessive
autosomal recessive cerebellar ataxia-saccadic intrusion syndrome	Supportive	Autosomal recessive

Mondo (3): spinocerebellar ataxia, autosomal recessive 29 (MONDO:0030312), hyperimmunoglobulinemia D with periodic fever (MONDO:0009849), autosomal recessive cerebellar ataxia-saccadic intrusion syndrome (MONDO:0011811)

Orphanet (1): Hyperimmunoglobulinemia D with periodic fever (Orphanet:343)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000496	Abnormality of eye movement
HP:0000543	Optic disc pallor
HP:0000570	Abnormal saccadic eye movements
HP:0000639	Nystagmus
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001761	Pes cavus
HP:0002058	Myopathic facies
HP:0002061	Lower limb spasticity
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002078	Truncal ataxia
HP:0002317	Unsteady gait
HP:0002366	Abnormal lower motor neuron morphology
HP:0002380	Fasciculations
HP:0002454	Eye of the tiger anomaly of globus pallidus
HP:0002493	Upper motor neuron dysfunction
HP:0002540	Inability to walk
HP:0003474	Somatic sensory dysfunction
HP:0003477	Peripheral axonal neuropathy

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000477_59	Cognitive performance	6.000000e-06
GCST006035_12	Breast cancer and/or colorectal cancer	5.000000e-06
GCST006035_14	Breast cancer and/or colorectal cancer	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537310	Spinocerebellar ataxia, autosomal recessive 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression	4
Valproic Acid	affects expression, increases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants, Occupational	decreases expression	1
Ascorbic Acid	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Coumestrol	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Indomethacin	decreases expression, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	decreases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2NV	HAP1 VPS41 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT01568736	Not specified	WITHDRAWN	B7 Coreceptor Molecules in Hyper IgD Syndrome Form of Mevalonate Kinase Deficiency
NCT06838143	Not specified	RECRUITING	Ilaris NIS in Korea