CALCOCO2

Summary

CALCOCO2 (calcium binding and coiled-coil domain 2, HGNC:29912) is a protein-coding gene on chromosome 17q21.32, encoding Calcium-binding and coiled-coil domain-containing protein 2 (Q13137). Xenophagy-specific receptor required for autophagy-mediated intracellular bacteria degradation.

This gene encodes a coiled-coil domain-containing protein. The encoded protein functions as a receptor for ubiquitin-coated bacteria and plays an important role in innate immunity by mediating macroautophagy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 10241 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 65 total
• Druggable target: yes
• MANE Select transcript: NM_005831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29912
Approved symbol	CALCOCO2
Name	calcium binding and coiled-coil domain 2
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	MGC17318, NDP52
Ensembl gene	ENSG00000136436
Ensembl biotype	protein_coding
OMIM	604587
Entrez	10241

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 28 protein_coding, 11 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000258947, ENST00000372317, ENST00000416445, ENST00000448105, ENST00000502761, ENST00000503463, ENST00000505071, ENST00000506971, ENST00000507076, ENST00000507306, ENST00000508679, ENST00000509014, ENST00000509112, ENST00000509415, ENST00000509507, ENST00000509784, ENST00000510356, ENST00000510997, ENST00000511697, ENST00000511816, ENST00000513119, ENST00000514006, ENST00000514267, ENST00000514962, ENST00000570513, ENST00000575461, ENST00000575560, ENST00000576582, ENST00000866560, ENST00000866561, ENST00000866562, ENST00000866563, ENST00000866564, ENST00000866565, ENST00000866566, ENST00000945215, ENST00000945216, ENST00000945217, ENST00000945218, ENST00000945219, ENST00000945220, ENST00000945221, ENST00000945222, ENST00000945223

RefSeq mRNA: 5 — MANE Select: NM_005831 NM_001261390, NM_001261391, NM_001261393, NM_001261395, NM_005831

CCDS: CCDS11538, CCDS58558, CCDS58559, CCDS58560, CCDS58561

Canonical transcript exons

ENST00000258947 — 13 exons

Exon	Start	End
ENSE00000736220	48848322	48848455
ENSE00001193163	48862838	48865245
ENSE00002031081	48831035	48831078
ENSE00003469848	48849252	48849377
ENSE00003502827	48848064	48848166
ENSE00003509420	48856092	48856187
ENSE00003519816	48851089	48851177
ENSE00003520930	48852926	48853012
ENSE00003527764	48860314	48860449
ENSE00003533873	48851559	48851628
ENSE00003551196	48852506	48852628
ENSE00003563449	48862276	48862304
ENSE00003669218	48841698	48841887

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 85.4956 / max 2004.3277, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161463	83.4679	1826
161468	0.7986	306
161466	0.7081	226
161467	0.3089	131
161465	0.1628	87
161464	0.0494	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.04	gold quality
mucosa of stomach	UBERON:0001199	98.95	gold quality
right lung	UBERON:0002167	98.89	gold quality
colonic epithelium	UBERON:0000397	98.85	gold quality
sural nerve	UBERON:0015488	98.76	gold quality
left testis	UBERON:0004533	98.43	gold quality
tibial nerve	UBERON:0001323	98.32	gold quality
right testis	UBERON:0004534	98.29	gold quality
rectum	UBERON:0001052	98.16	gold quality
popliteal artery	UBERON:0002250	98.13	gold quality
tibial artery	UBERON:0007610	98.12	gold quality
monocyte	CL:0000576	98.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.10	gold quality
lower esophagus	UBERON:0013473	98.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.08	gold quality
artery	UBERON:0001637	98.04	gold quality
mononuclear cell	CL:0000842	98.02	gold quality
left coronary artery	UBERON:0001626	97.99	gold quality
right atrium auricular region	UBERON:0006631	97.98	gold quality
leukocyte	CL:0000738	97.96	gold quality
descending thoracic aorta	UBERON:0002345	97.96	gold quality
omental fat pad	UBERON:0010414	97.94	gold quality
ectocervix	UBERON:0012249	97.94	gold quality
heart left ventricle	UBERON:0002084	97.93	gold quality
peritoneum	UBERON:0002358	97.93	gold quality
apex of heart	UBERON:0002098	97.89	gold quality
cardiac ventricle	UBERON:0002082	97.87	gold quality
aorta	UBERON:0000947	97.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.83	gold quality
endocervix	UBERON:0000458	97.79	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	432.20
E-MTAB-7303	no	122.39
E-MTAB-6678	no	3.49
E-CURD-112	no	2.70
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting CALCOCO2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-12124	99.68	69.17	2700

Literature-anchored findings (GeneRIF, showing 40)

• interacts with ICP4 regulatory protein of HSV-1 during early stage of infection (PMID:14747555)
• NDP52 was identified as a myosin VI binding protein; results suggest that myosin VI-T6BP-NDP52 complexes may play a role in coordinating cytokine signalling and membrane transport pathways with actin filament organisation and cell adhesion (PMID:17635994)
• NDP52 recognizes ubiquitin-coated Salmonella enterica and recruits TBK1. (PMID:19820708)
• p62 and NDP52 act cooperatively to drive efficient antibacterial autophagy by targeting the protein complexes they coordinate to distinct microdomains associated with bacteria (PMID:21079414)
• ND10 and ND10 components might be important defensive factors against the CMV cross-species infection (PMID:21552525)
• p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. (PMID:21646350)
• a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF-TRAF6. (PMID:21964925)
• Data show that the selectivity of the autophagy receptor NDP52 for LC3C is crucial for innate immunity since cells lacking either protein cannot protect their (PMID:23022382)
• Data show that the miRNA-processing enzyme, DICER and the main miRNA effector, AGO2, are targeted for degradation as miRNA-free entities (PMID:23143396)
• Autophagy of Tax1bp1/Ndp52 promotes non-canonical NF-kappaB signalling. (PMID:23209807)
• Data indicate that the binding site in galectin-8 is essential for the recruitment of the autophagy receptor NDP52 to cytosol-exposed Salmonella Typhimurium. (PMID:23386746)
• Dimeric NDP52 forms a ternary complex with two monomeric galectin-8 molecules as well as two LC3C molecules (PMID:23511477)
• The missense SNP rs2303015 (Val248Ala) in the NDP52 was associated with Crohn’s disease. (PMID:23624108)
• the role of ORF75 in the antagonization of ND10-mediated intrinsic immunity (PMID:24453968)
• data support a model in which non-ND10 resident Sp100 acts as a negative regulator of polycomb repressive complex-2 (PRC2) recruitment, and suggest that KSHV may actively escape ND10 silencing mechanisms to promote establishment of latent chromatin. (PMID:25033267)
• control retrotransposon insertion in the genome (PMID:25366815)
• These data show that NDP52 promotes the maturation of autophagosomes via its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct LC3-interacting region, and with MYOSIN VI. (PMID:25771791)
• two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy (PMID:26266977)
• Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis. (PMID:26493630)
• insight into how CALCOCO2 targets ubiquitin-decorated pathogens for autophagic degradations (PMID:26506893)
• The authors identify calcium-binding and coiled-coil domain 2 (CALCOCO2, also known as NDP52) as a binding partner of influenza A virus PB1-F2. (PMID:28613140)
• The authors propose that Rab35-GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52. (PMID:28848034)
• findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. (PMID:28965816)
• Backfolding of MVI regulates its ability to bind DNA and that a putative transcription co-activator NDP52 relieves the auto-inhibition of MVI to enable DNA binding. Additionally, we show that the MVI-NDP52 complex binds RNAPII, which is critical for transcription, and that depletion of NDP52 or MVI reduces steady-state mRNA levels. (PMID:29187741)
• Studies suggest that the nature of the regulatory mechanism(s) that governs nuclear dot protein 52 (NDP52) engagement during autophagosome maturation remains to be determined [Review]. (PMID:29395717)
• The CALCOCO2, but not SQSTM1, suppresses the antiviral type I interferon signaling by promoting autophagy-mediated degradation of the mitochondrial antiviral signaling (MAVS) protein. (PMID:30154446)
• These results indicate that NDP52 and MTPAP form an autophagy receptor complex, which enhances autophagic elimination of damaged mitochondria. (PMID:30309841)
• evaluated the currently known TBK1-mediated phosphorylation sites in the SKICH domains of NDP52 and TAX1BP1 on the basis of their interactions with NAP1 (PMID:30459273)
• The capability of NDP52 to induce mitophagy is dependent on its interaction with the FIP200/ULK1 complex, which is facilitated by TBK1. Ectopically tethering ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. (PMID:30853401)
• we show that, essential for anti-bacterial autophagy, the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, which are subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively. FIP200 and SINTBAD/NAP1 are each recruited independently to bacteria via NDP52, as revealed by selective point mutations in their respective binding sites (PMID:30853402)
• The altered expression of NRBP2 and CALCOCO2 is associated with left ventricular dysfunction parameters in human dilated cardiomyopathy. (PMID:31009519)
• The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. (PMID:32773036)
• Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy. (PMID:33723372)
• Crosstalk Between NDP52 and LUBAC in Innate Immune Responses, Cell Death, and Xenophagy. (PMID:33815386)
• Baicalein Activates Parkin-Dependent Mitophagy through NDP52 and OPTN. (PMID:35406696)
• NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy. (PMID:36514953)
• Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells. (PMID:37777549)
• NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling. (PMID:37942585)
• CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway. (PMID:38752371)
• Vangl2 suppresses NF-kappaB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation. (PMID:39269442)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	calcoco2	ENSDARG00000052515
mus_musculus	Calcoco2	ENSMUSG00000006056
rattus_norvegicus		ENSRNOG00000091290

Paralogs (2): CALCOCO1 (ENSG00000012822), TAX1BP1 (ENSG00000106052)

Protein

Protein identifiers

Calcium-binding and coiled-coil domain-containing protein 2 — Q13137 (reviewed: Q13137)

Alternative names: Antigen nuclear dot 52 kDa protein, Nuclear domain 10 protein NDP52, Nuclear dot protein 52

All UniProt accessions (10): D6RBF9, D6RBI4, D6REB0, D6RF70, Q13137, D6RJE7, H0Y9G3, H0YBP4, I3L493, I3L4E1

UniProt curated annotations — full annotation on UniProt →

Function. Xenophagy-specific receptor required for autophagy-mediated intracellular bacteria degradation. Acts as an effector protein of galectin-sensed membrane damage that restricts the proliferation of infecting pathogens such as Salmonella typhimurium upon entry into the cytosol by targeting LGALS8-associated bacteria for autophagy. Initially orchestrates bacteria targeting to autophagosomes and subsequently ensures pathogen degradation by regulating pathogen-containing autophagosome maturation. Bacteria targeting to autophagosomes relies on its interaction with MAP1LC3A, MAP1LC3B and/or GABARAPL2, whereas regulation of pathogen-containing autophagosome maturation requires the interaction with MAP3LC3C. May play a role in ruffle formation and actin cytoskeleton organization and seems to negatively regulate constitutive secretion.

Subunit / interactions. Dimer. Part of a complex consisting of CALCOCO2, TAX1BP1 and MYO6. Interacts with MYO6. Interacts with GEMIN4. Interacts with ATG8 family members MAP1LC3A, MAP1LC3B, GABARAP, GABARAPL1 and GABARAPL2. Interacts with ATG8 family member MAP1LC3C. Interacts with LGALS8. Interacts with TOM1; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and CALCOCO2. Interacts with AZI2. (Microbial infection) Interacts with Lassa virus protein Z. (Microbial infection) Interacts with Mopeia virus protein Z.

Subcellular location. Cytoplasm. Perinuclear region. Cytoskeleton. Cytoplasmic vesicle. Autophagosome membrane.

Tissue specificity. Expressed in all tissues tested with highest expression in skeletal muscle and lowest in brain.

Post-translational modifications. (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation. Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication.

Domain organisation. The MYO6-binding domain is required for autophagy-mediated degradation of infecting bacteria such as Salmonella typhimurium, but not for bacteria targeting to autophagosomes. The CLIR (LC3C-interacting region) motif is required for interaction with MAP1LC3C, but dispensable for CALCOCO2-mediated autophagosome maturation. The LIR-like motif is required for interaction with MAP1LC3A, MAP1LC3B and GABARAPL2, as well as for CALCOCO2-mediated autophagosome maturation. The LGALS8-binding domain is essential for the recruitment to cytosol-exposed infecting bacteria.

Induction. Treatment with IFNB1/IFN-beta and IFNG/IFN-gamma show an increase in number and size of CALCOCO2-specific dots and partial redistribution to the cytoplasm. IFNG/IFN-gamma increases gene expression only slightly and IFNB does not increase expression.

Similarity. Belongs to the CALCOCO family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q13137-1	1	yes
Q13137-2	2
Q13137-3	3
Q13137-4	4
Q13137-5	5

RefSeq proteins (5): NP_001248319, NP_001248320, NP_001248322, NP_001248324, NP_005822* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR041611	SKICH	Domain
IPR041641	CALCOCO1/2_Zn_UBZ1	Domain
IPR051002	UBA_autophagy_assoc_protein	Family

Pfam: PF17751

UniProt features (58 total): strand 15, mutagenesis site 8, helix 8, sequence variant 5, binding site 4, splice variant 4, region of interest 3, sequence conflict 2, turn 2, short sequence motif 2, chain 1, zinc finger region 1, modified residue 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3VVV	X-RAY DIFFRACTION	1.35
5Z7L	X-RAY DIFFRACTION	2.02
4GXL	X-RAY DIFFRACTION	2.02
4XKL	X-RAY DIFFRACTION	2.1
5Z7A	X-RAY DIFFRACTION	2.38
3VVW	X-RAY DIFFRACTION	2.5
4HAN	X-RAY DIFFRACTION	2.55
7EAA	X-RAY DIFFRACTION	2.6
2MXP	SOLUTION NMR
5AAQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13137-F1	81.16	0.56

Functional residue map

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

Ligand- & substrate-binding residues (4): 425; 440; 444; 422

Post-translational modifications (1): 445

Mutagenesis-validated functional residues (8):

Position	Phenotype
136	abrogates the interaction with map1lc3c.
203–206	abrogates interaction with maplc3a, maplc3b and gabarapl2.
374	severely reduces affinity for lgals8.
376	severely reduces affinity for lgals8.
378	prevents interaction with lgals8.
380	severely reduced affinity for lgals8.
400	does not affect interaction with myo6.
425	fails interact with myo6 and to promote maturation of autophagosomes.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 141 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, GOBP_XENOPHAGY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_MACROAUTOPHAGY, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MARTINEZ_RB1_TARGETS_DN, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_TYPE_II_INTERFERON, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY

GO Biological Process (5): viral process (GO:0016032), response to type II interferon (GO:0034341), xenophagy (GO:0098792), positive regulation of autophagosome maturation (GO:1901098), autophagy (GO:0006914)

GO Molecular Function (4): zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): autophagosome membrane (GO:0000421), nucleus (GO:0005634), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), cytoskeleton (GO:0005856), membrane (GO:0016020), PML body (GO:0016605), cytoplasmic vesicle (GO:0031410), perinuclear region of cytoplasm (GO:0048471)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
biological_process	1
response to cytokine	1
innate immune response	1
macroautophagy	1
defense response to other organism	1
positive regulation of organelle organization	1
positive regulation of macroautophagy	1
positive regulation of protein-containing complex disassembly	1
autophagosome maturation	1
regulation of autophagosome maturation	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
cation binding	1
vacuolar membrane	1
autophagosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
vacuole	1
intracellular membraneless organelle	1
nuclear body	1
intracellular vesicle	1

Protein interactions and networks

STRING

2268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALCOCO2	LGALS8	O00214	996
CALCOCO2	MAP1LC3C	Q9BXW4	994
CALCOCO2	F5GZY7	F5GZY7	992
CALCOCO2	GABARAPL2	P60520	991
CALCOCO2	GABARAP	O95166	991
CALCOCO2	RB1CC1	Q8TDY2	989
CALCOCO2	OPTN	Q96CV9	983
CALCOCO2	SQSTM1	Q13501	973
CALCOCO2	TBKBP1	A7MCY6	944
CALCOCO2	NBR1	Q14596	939
CALCOCO2	PINK1	Q9BXM7	924
CALCOCO2	TBK1	Q9UHD2	921
CALCOCO2	CD300C	Q08708	910
CALCOCO2	MAP1LC3B	Q9GZQ8	905
CALCOCO2	MAP1A	P78559	896

IntAct

671 interactions, top by confidence:

A	B	Type	Score
TCL1A	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.900
CALCOCO2	TCL1A	psi-mi:“MI:0915”(physical association)	0.900
LGALS8	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.890
CALCOCO2	FARS2	psi-mi:“MI:0915”(physical association)	0.780
MOS	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	NAA10	psi-mi:“MI:0915”(physical association)	0.780
GABARAPL2	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	FAM90A1	psi-mi:“MI:0915”(physical association)	0.780
GABARAPL1	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
METTL17	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	LSM4	psi-mi:“MI:0915”(physical association)	0.780
FARS2	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	MOS	psi-mi:“MI:0915”(physical association)	0.780
NAA10	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	METTL17	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	KANSL1	psi-mi:“MI:0915”(physical association)	0.740
CALCOCO2	SRI	psi-mi:“MI:0915”(physical association)	0.740
CALCOCO2	TP53RK	psi-mi:“MI:0915”(physical association)	0.740
CALCOCO2	DUSP12	psi-mi:“MI:0915”(physical association)	0.740
KANSL1	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.740
TP53RK	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (740): CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid), CALCOCO2 (Two-hybrid)

ESM2 similar proteins: A0A1L8ENT6, D2HNY3, G3HKI1, O18737, O60934, O75665, P0C219, P28715, P35689, P97817, Q01850, Q13137, Q13426, Q3B8D4, Q3KNJ2, Q3UKU1, Q3ZBK8, Q4KMA0, Q4R3X1, Q4R914, Q5EAN7, Q5M834, Q5R7H1, Q5RCV3, Q5RD40, Q5ZKM0, Q682V0, Q68F60, Q6AYI4, Q6NV18, Q6TLH3, Q76CY8, Q7L4P6, Q7TN31, Q8BGX7, Q8C6D4, Q8CG73, Q8NA72, Q91VL8, Q924T3

Diamond homologs: A2A6M5, A2BGD5, O18737, Q13137, Q1LWB0, Q2KJ21, Q2KJE0, Q3UKC1, Q4R914, Q5R4U3, Q5R7H1, Q5RD60, Q66HA4, Q66HR5, Q6DD09, Q6DF48, Q6P132, Q6P3P1, Q86VP1, Q8CGU1, Q9DEX1, Q9P1Z2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TBK1	“up-regulates activity”	CALCOCO2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 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
mRNA Splicing	5	10.8×	1e-03
RUNX1 regulates transcription of genes involved in differentiation of HSCs	5	9.3×	1e-03
Processing of Capped Intron-Containing Pre-mRNA	5	8.1×	2e-03
Regulation of expression of SLITs and ROBOs	5	6.8×	4e-03
mRNA Splicing - Major Pathway	6	6.4×	2e-03
Metabolism of RNA	7	5.7×	1e-03
Antigen processing: Ubiquitination & Proteasome degradation	6	4.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1896 predictions. Top by Δscore:

Variant	Effect	Δscore
17:48841886:GA:G	donor_gain	1.0000
17:48841888:G:GG	donor_gain	1.0000
17:48848319:CAGC:C	acceptor_loss	1.0000
17:48848320:A:AG	acceptor_gain	1.0000
17:48848320:A:T	acceptor_loss	1.0000
17:48848321:G:GC	acceptor_gain	1.0000
17:48848321:GC:G	acceptor_gain	1.0000
17:48848321:GCT:G	acceptor_gain	1.0000
17:48848321:GCTT:G	acceptor_gain	1.0000
17:48848321:GCTTA:G	acceptor_gain	1.0000
17:48848429:G:GT	donor_gain	1.0000
17:48848453:CAGG:C	donor_loss	1.0000
17:48848456:G:A	donor_loss	1.0000
17:48849247:TGTA:T	acceptor_loss	1.0000
17:48849249:TA:T	acceptor_loss	1.0000
17:48849250:A:AG	acceptor_gain	1.0000
17:48849250:AG:A	acceptor_gain	1.0000
17:48849250:AGG:A	acceptor_gain	1.0000
17:48849251:G:GT	acceptor_gain	1.0000
17:48849251:GG:G	acceptor_gain	1.0000
17:48849251:GGG:G	acceptor_gain	1.0000
17:48849251:GGGA:G	acceptor_gain	1.0000
17:48849357:GC:G	donor_gain	1.0000
17:48849374:GCAG:G	donor_gain	1.0000
17:48849376:AGGTA:A	donor_loss	1.0000
17:48849377:GGTA:G	donor_loss	1.0000
17:48849379:T:G	donor_loss	1.0000
17:48851080:A:AG	acceptor_gain	1.0000
17:48851084:TATAG:T	acceptor_loss	1.0000
17:48851174:TTCA:T	donor_gain	1.0000

AlphaMissense

3007 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:48848396:A:C	S120R	0.997
17:48848398:T:A	S120R	0.997
17:48848398:T:G	S120R	0.997
17:48848097:T:C	F72L	0.996
17:48848099:C:A	F72L	0.996
17:48848099:C:G	F72L	0.996
17:48848161:T:C	F93S	0.996
17:48848358:T:C	F107S	0.996
17:48848405:T:C	F123L	0.996
17:48848407:C:A	F123L	0.996
17:48848407:C:G	F123L	0.996
17:48841882:T:C	F59L	0.995
17:48841884:T:A	F59L	0.995
17:48841884:T:G	F59L	0.995
17:48848412:T:C	F125S	0.995
17:48841877:G:A	G57D	0.994
17:48848406:T:C	F123S	0.994
17:48848160:T:C	F93L	0.993
17:48848162:C:A	F93L	0.993
17:48848162:C:G	F93L	0.993
17:48848331:T:C	L98P	0.993
17:48848070:T:A	W63R	0.992
17:48848070:T:C	W63R	0.992
17:48841780:T:C	F25L	0.991
17:48841781:T:C	F25S	0.991
17:48841782:T:A	F25L	0.991
17:48841782:T:G	F25L	0.991
17:48841883:T:C	F59S	0.989
17:48841880:T:G	I58S	0.988
17:48848334:C:A	P99H	0.987

dbSNP variants (sampled 300 via entrez): RS1000144760 (17:48831754 A>G), RS1000169292 (17:48861341 C>G), RS1000296774 (17:48855114 A>G), RS1000391302 (17:48854743 A>C), RS1000501392 (17:48844172 C>G,T), RS1000574443 (17:48863217 C>T), RS1000630913 (17:48857097 C>T), RS1000729636 (17:48850893 G>T), RS1001078024 (17:48843018 T>C), RS1001140712 (17:48834442 A>G), RS1001179279 (17:48838256 T>G), RS1001250943 (17:48842393 G>A), RS1001485490 (17:48851825 TAAA>T,TA,TAA,TAAAA,TAAAAA), RS1001706124 (17:48858760 GT>G), RS1001752477 (17:48860808 C>T)

Disease associations

OMIM: gene MIM:604587 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST005414_22	Type 2 diabetes	3.000000e-08
GCST006585_2781	Blood protein levels	1.000000e-08
GCST007517_22	Type 2 diabetes	3.000000e-08
GCST007518_29	Type 2 diabetes (adjusted for BMI)	3.000000e-06
GCST007576_408	Chronotype	2.000000e-08
GCST90000025_596	Appendicular lean mass	2.000000e-10
GCST90011900_149	Serum alkaline phosphatase levels	3.000000e-11
GCST90013406_220	Liver enzyme levels (alkaline phosphatase)	2.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004980	appendicular lean mass
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066361 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.18	Kd	666.9	nM	CHEMBL3752910
6.17	ED50	675.5	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149837: Binding affinity to human CALCOCO2 incubated for 45 mins by Kinobead based pull down assay	kd	0.6669	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
trichostatin A	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
tanshinone	increases expression	1
manganese chloride	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases oxidation, affects cotreatment, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Gallic Acid	increases expression	1
Lead	decreases expression	1
Manganese	increases expression	1
Oxygen	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Urethane	increases expression	1
Cyclosporine	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652879	Binding	Binding affinity to human CALCOCO2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

9 cell lines: 9 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C2VN	HeLa S3 penta KO	Cancer cell line	Female
CVCL_C2VP	HeLa S3 penta KO-ATG13 KO	Cancer cell line	Female
CVCL_C2VQ	HeLa S3 penta KO-ATG14 KO	Cancer cell line	Female
CVCL_C2VR	HeLa S3 penta KO-TBK1 KO	Cancer cell line	Female
CVCL_C2VS	HeLa S3 penta KO-ULK1/ULK2 DKO	Cancer cell line	Female
CVCL_C2VT	HeLa S3 penta KO-TBK1/ULK1/ULK2 TKO	Cancer cell line	Female
CVCL_C8QB	HeLa S3 penta KO-AZI2/TBKBP1 DKO clone 20	Cancer cell line	Female
CVCL_C9DW	HeLa S3 penta KO-ULK1/ULK2 DKO-AZI2/TBKBP1 DKO	Cancer cell line	Female
CVCL_D2Q1	HeLa S3 penta KO-AZI2/TBKBP1 DKO clone 26	Cancer cell line	Female

Clinical trials (associated diseases)

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