CALY

Summary

CALY (calcyon neuron specific vesicular protein, HGNC:17938) is a protein-coding gene on chromosome 10q26.3, encoding Neuron-specific vesicular protein calcyon (Q9NYX4). Interacts with clathrin light chain A and stimulates clathrin self-assembly and clathrin-mediated endocytosis.

The protein encoded by this gene is a type II single transmembrane protein. It is required for maximal stimulated calcium release after stimulation of purinergic or muscarinic but not beta-adrenergic receptors. The encoded protein interacts with D1 dopamine receptor and may interact with other DA receptor subtypes and/or GPCRs.

Source: NCBI Gene 50632 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_015722

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17938
Approved symbol	CALY
Name	calcyon neuron specific vesicular protein
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Aliases	CALCYON, NSG3
Ensembl gene	ENSG00000130643
Ensembl biotype	protein_coding
OMIM	604647
Entrez	50632

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 retained_intron

ENST00000252939, ENST00000368555, ENST00000368558, ENST00000467433, ENST00000467611, ENST00000872635, ENST00000872636, ENST00000872637, ENST00000872638, ENST00000956088, ENST00000956089, ENST00000956091, ENST00000956093, ENST00000956094, ENST00000956095, ENST00000956096

RefSeq mRNA: 2 — MANE Select: NM_015722 NM_001321617, NM_015722

CCDS: CCDS7678

Canonical transcript exons

ENST00000252939 — 6 exons

Exon	Start	End
ENSE00000729139	133327905	133328015
ENSE00000729143	133326878	133326991
ENSE00000876601	133328855	133329009
ENSE00000876602	133325799	133326120
ENSE00001829549	133336834	133336896
ENSE00003468539	133324072	133325566

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 98.12.

FANTOM5 (CAGE): breadth broad, TPM avg 16.8960 / max 941.2124, expressed in 386 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112121	16.2570	238
112118	0.3039	155
112115	0.1450	72
112116	0.0879	50
112117	0.0805	37
112119	0.0216	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	98.12	gold quality
right frontal lobe	UBERON:0002810	98.02	gold quality
hypothalamus	UBERON:0001898	97.47	gold quality
pituitary gland	UBERON:0000007	97.36	gold quality
anterior cingulate cortex	UBERON:0009835	97.25	gold quality
cingulate cortex	UBERON:0003027	97.17	gold quality
caudate nucleus	UBERON:0001873	97.08	gold quality
prefrontal cortex	UBERON:0000451	96.51	gold quality
adenohypophysis	UBERON:0002196	96.43	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.38	gold quality
amygdala	UBERON:0001876	96.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.70	gold quality
cerebellar hemisphere	UBERON:0002245	95.69	gold quality
cerebellar cortex	UBERON:0002129	95.63	gold quality
putamen	UBERON:0001874	95.57	gold quality
frontal cortex	UBERON:0001870	95.41	gold quality
neocortex	UBERON:0001950	94.65	gold quality
forebrain	UBERON:0001890	93.98	gold quality
telencephalon	UBERON:0001893	93.65	gold quality
cerebellum	UBERON:0002037	93.62	gold quality
cerebral cortex	UBERON:0000956	93.32	gold quality
brain	UBERON:0000955	93.26	gold quality
pons	UBERON:0000988	92.50	gold quality
Ammon’s horn	UBERON:0001954	92.40	gold quality
temporal lobe	UBERON:0001871	92.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.10	gold quality
superior vestibular nucleus	UBERON:0007227	91.04	gold quality
superior frontal gyrus	UBERON:0002661	90.92	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.78	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	278.44
E-GEOD-81547	yes	246.62
E-GEOD-84465	yes	6.78
E-HCAD-30	no	833.97
E-HCAD-31	no	4.13
E-ANND-3	no	2.49

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

• CaMKII is a key effector in the Ca2+ and microtubule-dependent delivery of calcyon to the cell surface. (PMID:14534309)
• Genetic variants in the CALCYON gene do not play a major role in predisposition to either schizophrenia or cocaine dependence i (PMID:14755439)
• Quantitative trait analyses of most common haplotype, designated C1, showed significant relationships with both the inattentive and hyperactive/impulsive dimensions of the disorder. (PMID:16172615)
• Using the calcyon cytosolic domain as bait, we isolated clathrin light chain in a yeast two-hybrid screen. The interaction domain was mapped to the heavy chain binding domain and C-terminal regions of light chain. (PMID:16595675)
• mobility and storage properties of calcyon-containing vesicles imply that they play a role in brain plasticity (PMID:17885599)
• Association of the calcyon neuron-specific vesicular protein gene (CALY) with adolescent smoking initiation. (PMID:21415033)
• Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 protein and plays a role in dopamine receptor internalization (PMID:22843680)
• This review focuses on two closely related, neuron-enriched endosomal proteins: NEEP21 and Calcyon which perform distinct roles in regulating receptor endocytosis, recycling, and degradation–{REVIEW} (PMID:25376768)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	caly	ENSDARG00000036008
mus_musculus	Caly	ENSMUSG00000025468
rattus_norvegicus	Caly	ENSRNOG00000018337

Paralogs (2): NSG1 (ENSG00000168824), NSG2 (ENSG00000170091)

Protein

Protein identifiers

Neuron-specific vesicular protein calcyon — Q9NYX4 (reviewed: Q9NYX4)

All UniProt accessions (1): Q9NYX4

UniProt curated annotations — full annotation on UniProt →

Function. Interacts with clathrin light chain A and stimulates clathrin self-assembly and clathrin-mediated endocytosis.

Subunit / interactions. Interacts with CLTA.

Subcellular location. Cytoplasmic vesicle membrane. Cell membrane.

Tissue specificity. Expressed in the pyramidal cells of the prefrontal cortex, in hypothalamus and in caudate nucleus. No expression in spleen. Up-regulated in the prefrontal cortex of schizophrenic patients with nearly twice the levels of non-schizophrenics.

Post-translational modifications. Glycosylated.

Similarity. Belongs to the NSG family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NYX4-1	1	yes
Q9NYX4-2	2
Q9NYX4-3	3

RefSeq proteins (2): NP_001308546, NP_056537* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009431	NSG	Family

Pfam: PF06387

UniProt features (10 total): splice variant 3, topological domain 2, region of interest 2, chain 1, transmembrane region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYX4-F1	54.90	0.04

Functional residue map

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

Glycosylation sites (1): 73

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 78 (showing top): GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_DN, GOBP_CLATHRIN_COAT_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN, MYOD_01, GOBP_RECEPTOR_INTERNALIZATION, GOBP_REGULATION_OF_ENDOCYTOSIS, RFX1_02, GOBP_POSITIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_TRANSPORT, GOBP_IMPORT_INTO_CELL, GOBP_ENDOCYTOSIS, GOCC_POSTSYNAPSE

GO Biological Process (5): endosomal transport (GO:0016197), positive regulation of endocytosis (GO:0045807), clathrin coat assembly (GO:0048268), postsynaptic neurotransmitter receptor internalization (GO:0098884), endocytosis (GO:0006897)

GO Molecular Function (2): clathrin light chain binding (GO:0032051), protein binding (GO:0005515)

GO Cellular Component (7): endosome (GO:0005768), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), postsynaptic endocytic zone (GO:0098843), glutamatergic synapse (GO:0098978)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vesicle-mediated transport	2
cytoplasmic vesicle	2
cellular anatomical structure	2
intracellular transport	1
endocytosis	1
regulation of endocytosis	1
positive regulation of transport	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor internalization	1
postsynaptic endocytosis	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
clathrin binding	1
binding	1
endomembrane system	1
membrane	1
cell periphery	1
vesicle membrane	1
cytoplasm	1
intracellular vesicle	1
clathrin coat	1
postsynapse	1
synapse	1

Protein interactions and networks

STRING

1436 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALY	TSSK4	Q6SA08	658
CALY	TSSK6	Q9BXA6	603
CALY	TSSK3	Q96PN8	594
CALY	TSSK2	Q96PF2	565
CALY	TSSK1B	Q9BXA7	555
CALY	DRD1	P21728	490
CALY	CRABP1	P29762	486
CALY	SIGLEC1	Q9BZZ2	480
CALY	ENKD1	Q9H0I2	475
CALY	LGALS4	P56470	441
CALY	SAMD5	Q5TGI4	430
CALY	C10orf90	Q96M02	419
CALY	CLHC1	Q8NHS4	410
CALY	FUOM	A2VDF0	392
CALY	KBTBD6	Q86V97	392

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CLTA	CALY	psi-mi:“MI:0915”(physical association)	0.610
CLTA	CALY	psi-mi:“MI:0407”(direct interaction)	0.610
CLTA	CALY	psi-mi:“MI:0403”(colocalization)	0.610
CALY	AP3D1	psi-mi:“MI:0915”(physical association)	0.400
CALY	H1-5	psi-mi:“MI:0915”(physical association)	0.400
CALY	H1-2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): NRG1 (Affinity Capture-Western), CALY (Proximity Label-MS), CALY (Proximity Label-MS), CALY (Affinity Capture-RNA)

ESM2 similar proteins: A0JPB5, A2A699, A5PLA0, A6QPA0, A8MVW0, B0BN44, B4DS77, D3ZZP4, O35451, P04921, P28906, Q06186, Q08DP3, Q08EA8, Q13113, Q1LVN1, Q28270, Q5F3A4, Q5FVQ7, Q5HZE8, Q5R5B8, Q60846, Q640B5, Q64314, Q7TNI2, Q810F0, Q86VZ4, Q8C4Q9, Q8CB67, Q8IUW5, Q8K064, Q8K201, Q8K2J7, Q8NC54, Q8NEA5, Q8R138, Q8TBP5, Q8WWG9, Q96L08, Q99941

Diamond homologs: P02683, P42857, P47759, P58821, Q0VCZ0, Q3KR51, Q4R5Q3, Q5RF46, Q62092, Q8QFP1, Q9DCA7, Q9NYX4, Q9Y328

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1764 predictions. Top by Δscore:

Variant	Effect	Δscore
10:133326116:TTGTG:T	acceptor_gain	1.0000
10:133326118:GTGCT:G	acceptor_loss	1.0000
10:133326119:TG:T	acceptor_gain	1.0000
10:133326121:C:CC	acceptor_gain	1.0000
10:133326121:C:CG	acceptor_loss	1.0000
10:133326876:AC:A	donor_gain	1.0000
10:133326877:C:CG	donor_loss	1.0000
10:133326877:CC:C	donor_gain	1.0000
10:133326877:CCCG:C	donor_gain	1.0000
10:133326989:CAG:C	acceptor_gain	1.0000
10:133326992:C:CC	acceptor_gain	1.0000
10:133327903:AC:A	donor_gain	1.0000
10:133327904:CC:C	donor_gain	1.0000
10:133327911:C:CA	donor_gain	1.0000
10:133327915:T:A	donor_gain	1.0000
10:133328012:CCAC:C	acceptor_gain	1.0000
10:133328013:CAC:C	acceptor_gain	1.0000
10:133328013:CACC:C	acceptor_gain	1.0000
10:133328013:CACCT:C	acceptor_loss	1.0000
10:133328014:ACCTG:A	acceptor_loss	1.0000
10:133328015:CCTGT:C	acceptor_loss	1.0000
10:133328016:C:CG	acceptor_loss	1.0000
10:133328017:T:C	acceptor_loss	1.0000
10:133328849:CCTCA:C	donor_loss	1.0000
10:133328850:CTCA:C	donor_loss	1.0000
10:133328851:TCA:T	donor_loss	1.0000
10:133328852:CACCT:C	donor_loss	1.0000
10:133328853:ACCTG:A	donor_loss	1.0000
10:133328854:C:CT	donor_loss	1.0000
10:133336828:G:C	donor_gain	1.0000

AlphaMissense

1413 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:133326887:G:C	F117L	0.997
10:133326887:G:T	F117L	0.997
10:133326889:A:G	F117L	0.997
10:133326946:A:G	C98R	0.997
10:133326110:C:T	C124Y	0.996
10:133326109:G:C	C124W	0.995
10:133326110:C:G	C124S	0.995
10:133326111:A:G	C124R	0.995
10:133326111:A:T	C124S	0.995
10:133326901:A:G	C113R	0.995
10:133326926:C:A	K104N	0.995
10:133326926:C:G	K104N	0.995
10:133326949:C:G	G97R	0.995
10:133326900:C:T	C113Y	0.994
10:133326888:A:C	F117C	0.992
10:133326899:G:C	C113W	0.992
10:133326948:C:T	G97D	0.992
10:133326110:C:A	C124F	0.990
10:133326888:A:G	F117S	0.990
10:133326900:C:G	C113S	0.990
10:133326901:A:T	C113S	0.990
10:133326957:G:T	A94E	0.989
10:133326969:G:T	A90D	0.989
10:133326900:C:A	C113F	0.985
10:133326939:A:C	L100R	0.985
10:133326960:A:C	M93R	0.985
10:133326960:A:T	M93K	0.985
10:133326936:A:T	I101N	0.984
10:133326931:A:C	Y103D	0.982
10:133326104:G:T	P126Q	0.981

dbSNP variants (sampled 300 via entrez): RS1000190134 (10:133329387 TTCTTC>T), RS1000240062 (10:133334738 G>A,C), RS1000421501 (10:133336341 C>T), RS1000679428 (10:133328032 C>A,T), RS1000981551 (10:133327764 G>A,C), RS1001184407 (10:133323843 A>T), RS1001282209 (10:133332358 T>G), RS1001310082 (10:133332783 T>C,G), RS1001548070 (10:133335625 C>G,T), RS1001834640 (10:133335499 G>A), RS1001996157 (10:133327081 T>A,G), RS1002400606 (10:133329870 C>A), RS1002438944 (10:133333459 C>G,T), RS1002725939 (10:133335290 A>C,G), RS1002830398 (10:133324369 C>A)

Disease associations

OMIM: gene MIM:604647 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007250_1	Nonunion in individuals with fractures	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009707	fractures, ununited

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	2
ethyl-p-hydroxybenzoate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects cotreatment, decreases expression	1
Dopamine	decreases secretion	1
Epinephrine	decreases secretion	1
Estradiol	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Norepinephrine	increases secretion	1
Thiram	increases expression	1
Sodium Chloride, Dietary	increases expression, increases reaction, increases response to substance	1
Cadmium Chloride	increases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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