CLVS2

Summary

CLVS2 (clavesin 2, HGNC:23046) is a protein-coding gene on chromosome 6q22.31, encoding Clavesin-2 (Q5SYC1). Required for normal morphology of late endosomes and/or lysosomes in neurons.

This gene encodes a protein that belongs to the SEC14/CRAL-TRIO family of proteins. A similar protein in rat is thought to function in the endosomal pathway between early endosomes and mature lysosomes.

Source: NCBI Gene 134829 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 32 total — 1 pathogenic
• MANE Select transcript: NM_001010852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23046
Approved symbol	CLVS2
Name	clavesin 2
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	bA160A10.4
Ensembl gene	ENSG00000146352
Ensembl biotype	protein_coding
OMIM	616945
Entrez	134829

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000275162, ENST00000368438, ENST00000875569

RefSeq mRNA: 1 — MANE Select: NM_001010852 NM_001010852

CCDS: CCDS34525

Canonical transcript exons

ENST00000275162 — 6 exons

Exon	Start	End
ENSE00000975468	123048622	123048732
ENSE00000975469	123055806	123056026
ENSE00001281966	122997219	122998166
ENSE00001606604	123063674	123072925
ENSE00001652256	122996235	122996746
ENSE00003531674	123010985	123011159

Expression profiles

Bgee: expression breadth broad, 90 present calls, max score 85.37.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7574 / max 263.0450, expressed in 254 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69561	2.1778	243
69559	0.2137	78
69560	0.1441	73
69558	0.1050	65
69556	0.0733	42
69557	0.0435	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar cortex	UBERON:0002129	85.37	gold quality
cerebellar hemisphere	UBERON:0002245	85.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.73	gold quality
ganglionic eminence	UBERON:0004023	83.62	gold quality
cerebellum	UBERON:0002037	83.17	gold quality
cortical plate	UBERON:0005343	83.05	gold quality
ventricular zone	UBERON:0003053	82.31	gold quality
prefrontal cortex	UBERON:0000451	80.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.75	gold quality
anterior cingulate cortex	UBERON:0009835	74.05	gold quality
right frontal lobe	UBERON:0002810	74.04	gold quality
frontal cortex	UBERON:0001870	73.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.04	gold quality
neocortex	UBERON:0001950	72.92	gold quality
calcaneal tendon	UBERON:0003701	72.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	69.77	gold quality
nucleus accumbens	UBERON:0001882	69.70	gold quality
cerebral cortex	UBERON:0000956	69.24	gold quality
brain	UBERON:0000955	67.93	gold quality
caudate nucleus	UBERON:0001873	66.72	gold quality
forebrain	UBERON:0001890	66.62	gold quality
hypothalamus	UBERON:0001898	66.42	gold quality
amygdala	UBERON:0001876	66.30	gold quality
putamen	UBERON:0001874	64.88	gold quality
Ammon’s horn	UBERON:0001954	62.41	gold quality
tendon	UBERON:0000043	62.00	gold quality
corpus callosum	UBERON:0002336	60.42	gold quality
adenohypophysis	UBERON:0002196	60.32	gold quality
pituitary gland	UBERON:0000007	60.22	gold quality
primary visual cortex	UBERON:0002436	59.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.05
E-GEOD-98556	no	174.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

361 targeting CLVS2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-196A-1-3P	99.99	72.15	2772
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

Literature-anchored findings (GeneRIF, showing 1)

• Clavesin protein family appears to provide a unique neuron-specific regulation of late endosome/lysosome morphology. (PMID:19651769)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	clvs2	ENSDARG00000053122
mus_musculus	Clvs2	ENSMUSG00000019785
rattus_norvegicus	Clvs2	ENSRNOG00000012122
drosophila_melanogaster	CG3191	FBGN0023525
drosophila_melanogaster	CG3091	FBGN0029608
drosophila_melanogaster	CG3823	FBGN0029863
drosophila_melanogaster	CG1902	FBGN0033434
drosophila_melanogaster	CG12926	FBGN0033437
drosophila_melanogaster	CG10301	FBGN0039106
drosophila_melanogaster	CG10300	FBGN0039107
drosophila_melanogaster	CG30339	FBGN0050339
drosophila_melanogaster	CG31636	FBGN0051636
drosophila_melanogaster	CG33514	FBGN0053514
drosophila_melanogaster	CG33965	FBGN0053965
drosophila_melanogaster	CG33966	FBGN0053966

Paralogs (3): TTPAL (ENSG00000124120), RLBP1 (ENSG00000140522), CLVS1 (ENSG00000177182)

Protein

Protein identifiers

Clavesin-2 — Q5SYC1 (reviewed: Q5SYC1)

Alternative names: Retinaldehyde-binding protein 1-like 2, clathrin vesicle-associated Sec14 protein 2

All UniProt accessions (1): Q5SYC1

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal morphology of late endosomes and/or lysosomes in neurons. Binds phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).

Subunit / interactions. Forms a complex with clathrin heavy chain and gamma-adaptin.

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Cytoplasmic vesicle. Clathrin-coated vesicle. Early endosome membrane.

Domain organisation. The CRAL-TRIO domain is required for targeting to the membrane and for binding PtdIns(3,5)P2.

Miscellaneous. Binding to PtdIns(3,5)P2 is not required for localization.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5SYC1-1	1	yes
Q5SYC1-2	2

RefSeq proteins (1): NP_001010852* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001251	CRAL-TRIO_dom	Domain
IPR011074	CRAL/TRIO_N_dom	Domain
IPR036273	CRAL/TRIO_N_dom_sf	Homologous_superfamily
IPR036865	CRAL-TRIO_dom_sf	Homologous_superfamily

Pfam: PF00650, PF03765

UniProt features (5 total): chain 1, domain 1, region of interest 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5SYC1-F1	86.15	0.80

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): 325

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-432720	Lysosome Vesicle Biogenesis

MSigDB gene sets: 138 (showing top): GOBP_VACUOLE_ORGANIZATION, REACTOME_MEMBRANE_TRAFFICKING, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, GOCC_TRANS_GOLGI_NETWORK, GOCC_COATED_VESICLE, GOBP_LYTIC_VACUOLE_ORGANIZATION, GOCC_CLATHRIN_COATED_VESICLE, GOCC_EARLY_ENDOSOME_MEMBRANE, GOCC_TRANS_GOLGI_NETWORK_MEMBRANE, GOCC_ORGANELLE_SUBCOMPARTMENT, GOMF_PHOSPHATIDYLINOSITOL_3_5_BISPHOSPHATE_BINDING, ATGTAGC_MIR221_MIR222, GOMF_PHOSPHATIDYLINOSITOL_PHOSPHATE_BINDING, GOMF_PHOSPHATIDYLINOSITOL_BINDING, chr6q22

GO Biological Process (1): lysosome organization (GO:0007040)

GO Molecular Function (4): phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), phosphatidylinositol bisphosphate binding (GO:1902936), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): endosome (GO:0005768), trans-Golgi network (GO:0005802), clathrin-coated vesicle (GO:0030136), early endosome membrane (GO:0031901), trans-Golgi network membrane (GO:0032588), Golgi apparatus (GO:0005794), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
endomembrane system	2
cytoplasm	2
lytic vacuole organization	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
anion binding	1
cytoplasmic vesicle	1
Golgi apparatus subcompartment	1
coated vesicle	1
early endosome	1
endosome membrane	1
trans-Golgi network	1
organelle membrane	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

1630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLVS2	CCDC175	P0C221	614
CLVS2	VWC2	Q2TAL6	506
CLVS2	NWD1	Q149M9	494
CLVS2	WDR74	Q6RFH5	489
CLVS2	ZNF207	O43670	470
CLVS2	VWC2L	B2RUY7	456
CLVS2	MKLN1	Q9UL63	439
CLVS2	RWDD1	Q9H446	431
CLVS2	ZFYVE19	Q96K21	429
CLVS2	MND1	Q9BWT6	414
CLVS2	EXD1	Q8NHP7	411
CLVS2	C3orf52	Q5BVD1	408
CLVS2	PDE1A	P54750	407
CLVS2	CNKSR3	Q6P9H4	397
CLVS2	ROPN1B	Q9BZX4	394

IntAct

56 interactions, top by confidence:

A	B	Type	Score
GFUS	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
NDEL1	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
S100A7A	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
PHETA2	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	NDEL1	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
MYH7	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
PGAM2	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	PHETA2	psi-mi:“MI:0915”(physical association)	0.560
GYS1	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	EMSY	psi-mi:“MI:0915”(physical association)	0.560
GSTM3	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	FLAD1	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	PCYT2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	S100A7A	psi-mi:“MI:0915”(physical association)	0.560
PAFAH1B2	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	KAZN	psi-mi:“MI:0915”(physical association)	0.560
TACC2	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
S100A7	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	FBXW2	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
CLVS2	MEOX2	psi-mi:“MI:0915”(physical association)	0.000
GYS1	CLVS2	psi-mi:“MI:0915”(physical association)	0.000
EMSY	CLVS2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): CLVS2 (Co-fractionation), CLVS2 (Co-fractionation), CLVS2 (Co-fractionation), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), CLVS2 (Two-hybrid), C11orf30 (Two-hybrid), FLAD1 (Two-hybrid), PGAM2 (Two-hybrid), PAFAH1B2 (Two-hybrid)

ESM2 similar proteins: A0A3L7I2I8, A6JFQ6, A6JUQ6, A7MBL8, E1C3P4, O08874, O60733, O70291, O94806, P41034, P49638, P97570, P97819, Q02384, Q07889, Q07890, Q16513, Q2KIX2, Q3LAC4, Q4R678, Q5E9G6, Q5F361, Q5M7E1, Q5RCA6, Q5SPP0, Q5SYC1, Q641K1, Q66H63, Q6NRC7, Q70Z35, Q8BG92, Q8BM85, Q8BWP5, Q8BWW9, Q8CA95, Q8IUQ0, Q8K1Y2, Q8NHP6, Q8TEA7, Q8W4D4

Diamond homologs: A6JFQ6, A6JUQ6, E1C1U1, P10123, P12271, P41034, P49638, Q19895, Q5M7E1, Q5RCA6, Q5RFR0, Q5SPP0, Q5SYC1, Q8BG92, Q8BWP5, Q8IUQ0, Q95KF7, Q9BTX7, Q9D3D0, Q9D4C9, Q9Z275, P53989, P49193, O76054, P45816, Q99J08, Q99MS0, Q8R0F9, Q9UDX3, A3LPR9, A5DEQ9, Q56WK6, Q56Z59, Q56ZI2, Q75DK1, Q94C59, Q9M0R2, Q9SCU1, O35239, P43378

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58443	GRCh38/hg38 6q22.31(chr6:118975015-125713307)x1	Pathogenic

SpliceAI

1535 predictions. Top by Δscore:

Variant	Effect	Δscore
6:123048611:T:G	acceptor_gain	1.0000
6:123048621:GGATA:G	acceptor_gain	1.0000
6:123048731:GG:G	donor_gain	1.0000
6:123048732:GG:G	donor_gain	1.0000
6:123048733:G:T	donor_gain	1.0000
6:123055804:A:AG	acceptor_gain	1.0000
6:123055805:G:GG	acceptor_gain	1.0000
6:123055805:GAT:G	acceptor_gain	1.0000
6:123055805:GATAT:G	acceptor_gain	1.0000
6:123055989:G:GT	donor_gain	1.0000
6:123056023:AGAG:A	donor_loss	1.0000
6:123056024:GAG:G	donor_gain	1.0000
6:123056024:GAGG:G	donor_loss	1.0000
6:123056025:AGG:A	donor_loss	1.0000
6:123056026:GG:G	donor_loss	1.0000
6:123056027:G:C	donor_loss	1.0000
6:123056028:T:G	donor_loss	1.0000
6:123063798:A:T	donor_gain	1.0000
6:122996166:GCTGA:G	donor_gain	0.9900
6:122996167:C:G	donor_gain	0.9900
6:122996705:G:GT	donor_gain	0.9900
6:122998125:G:GT	donor_gain	0.9900
6:123011155:TGCAG:T	donor_loss	0.9900
6:123011157:CAG:C	donor_loss	0.9900
6:123011158:AGG:A	donor_loss	0.9900
6:123011159:GGTAG:G	donor_loss	0.9900
6:123011160:G:GC	donor_loss	0.9900
6:123011161:T:C	donor_loss	0.9900
6:123048610:A:AG	acceptor_gain	0.9900
6:123048610:AT:A	acceptor_gain	0.9900

AlphaMissense

2181 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:122997934:T:C	F53L	1.000
6:122997936:C:A	F53L	1.000
6:122997936:C:G	F53L	1.000
6:122997946:T:C	F57L	1.000
6:122997948:C:A	F57L	1.000
6:122997948:C:G	F57L	1.000
6:122997959:G:T	R61M	1.000
6:122997989:T:C	L71P	1.000
6:122998013:G:C	R79P	1.000
6:122998076:T:C	L100P	1.000
6:122998153:T:A	W126R	1.000
6:122998153:T:C	W126R	1.000
6:123011008:G:C	R138P	1.000
6:123011064:G:T	G157W	1.000
6:123011065:G:A	G157E	1.000
6:123011065:G:T	G157V	1.000
6:123011085:T:A	W164R	1.000
6:123011085:T:C	W164R	1.000
6:123048659:T:A	V201D	1.000
6:123048683:C:A	A209D	1.000
6:123048710:T:C	L218P	1.000
6:123055882:G:A	G251E	1.000
6:122997882:G:C	R35S	0.999
6:122997882:G:T	R35S	0.999
6:122997913:T:C	F46L	0.999
6:122997915:T:A	F46L	0.999
6:122997915:T:G	F46L	0.999
6:122997947:T:C	F57S	0.999
6:122997953:G:C	R59P	0.999
6:122997956:C:A	A60D	0.999

dbSNP variants (sampled 300 via entrez): RS1000007431 (6:123036935 G>A,T), RS1000038524 (6:123037216 T>C), RS1000108653 (6:123001291 TATTGTAAAG>T), RS1000184099 (6:123060555 C>A), RS1000244058 (6:123053744 G>A,C), RS1000256984 (6:123011591 T>G), RS1000304830 (6:123024611 G>A), RS1000311479 (6:123067285 G>A), RS1000320698 (6:123067508 T>A,C,G), RS1000357550 (6:123027579 G>A,T), RS1000389799 (6:123034345 A>G), RS1000421118 (6:123060335 T>C), RS1000485538 (6:123022017 A>G), RS1000511656 (6:123046806 G>A), RS1000528433 (6:123065203 A>T)

Disease associations

OMIM: gene MIM:616945 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009391_500	Metabolite levels	2.000000e-06
GCST010002_334	Refractive error	4.000000e-11
GCST012317_1	Triglyceride levels x SSRI levels (escitalopram or citalopram) interaction in schizophrenia or bipolar disorder	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010521	phosphocreatine measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
pirinixic acid	affects binding, increases activity, increases expression	1
decabromobiphenyl ether	affects expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
abrine	increases expression	1
Acetaminophen	increases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	increases methylation	1
Mercuric Chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery