GC

Summary

GC (GC vitamin D binding protein, HGNC:4187) is a protein-coding gene on chromosome 4q13.3, encoding Vitamin D-binding protein (P02774). Involved in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5 alpha for neutrophils in inflammation and macrophage activation.

The protein encoded by this gene belongs to the albumin gene family. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2638 — RefSeq curated summary.

At a glance

• GWAS associations: 43
• Clinical variants (ClinVar): 74 total — 1 pathogenic, 8 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000583

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4187
Approved symbol	GC
Name	GC vitamin D binding protein
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	DBP, VDBP, hDBP
Ensembl gene	ENSG00000145321
Ensembl biotype	protein_coding
OMIM	139200
Entrez	2638

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 18 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000273951, ENST00000503364, ENST00000503472, ENST00000504199, ENST00000505234, ENST00000506245, ENST00000509740, ENST00000513476, ENST00000882421, ENST00000882422, ENST00000882423, ENST00000882424, ENST00000882425, ENST00000882426, ENST00000882427, ENST00000882428, ENST00000882429, ENST00000882430, ENST00000882431, ENST00000882432, ENST00000941117, ENST00000941118

RefSeq mRNA: 3 — MANE Select: NM_000583 NM_000583, NM_001204306, NM_001204307

CCDS: CCDS3550, CCDS56332

Canonical transcript exons

ENST00000273951 — 13 exons

Exon	Start	End
ENSE00001138631	71783961	71784079
ENSE00002022228	71741697	71741870
ENSE00003462579	71769331	71769400
ENSE00003493189	71756712	71756914
ENSE00003541072	71768301	71768433
ENSE00003546253	71763408	71763502
ENSE00003555215	71754978	71755107
ENSE00003594208	71746151	71746205
ENSE00003637778	71754411	71754508
ENSE00003647250	71765432	71765643
ENSE00003676874	71763804	71763936
ENSE00003680899	71758042	71758171
ENSE00003692987	71752518	71752650

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 99.79.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 18.8028 / max 7858.0246, expressed in 38 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52457	18.8028	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	99.79	gold quality
right lobe of liver	UBERON:0001114	99.72	gold quality
gall bladder	UBERON:0002110	99.62	gold quality
pancreatic ductal cell	CL:0002079	99.32	gold quality
type B pancreatic cell	CL:0000169	98.64	gold quality
islet of Langerhans	UBERON:0000006	98.45	gold quality
epithelial cell of pancreas	CL:0000083	97.28	gold quality
pancreas	UBERON:0001264	91.66	gold quality
duodenum	UBERON:0002114	89.87	gold quality
body of pancreas	UBERON:0001150	89.54	gold quality
jejunal mucosa	UBERON:0000399	84.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.90	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.95	gold quality
body of stomach	UBERON:0001161	74.71	gold quality
stomach	UBERON:0000945	74.19	gold quality
cardia of stomach	UBERON:0001162	73.94	gold quality
fundus of stomach	UBERON:0001160	73.30	gold quality
adult mammalian kidney	UBERON:0000082	69.24	gold quality
jejunum	UBERON:0002115	67.14	gold quality
colonic epithelium	UBERON:0000397	65.58	silver quality
kidney	UBERON:0002113	64.08	gold quality
nephron tubule	UBERON:0001231	63.92	gold quality
adrenal tissue	UBERON:0018303	62.96	gold quality
kidney epithelium	UBERON:0004819	62.61	silver quality
right coronary artery	UBERON:0001625	60.00	gold quality
metanephric glomerulus	UBERON:0004736	59.44	silver quality
middle frontal gyrus	UBERON:0002702	59.25	gold quality
renal glomerulus	UBERON:0000074	58.82	silver quality
metanephros	UBERON:0000081	58.19	gold quality
metanephros cortex	UBERON:0010533	57.72	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	5201.74
E-MTAB-7407	yes	2459.51
E-CURD-98	yes	1948.37
E-MTAB-5061	yes	1530.54
E-GEOD-81608	yes	1334.71
E-ENAD-27	yes	1110.10
E-GEOD-83139	yes	1092.55
E-HCAD-31	yes	67.76
E-HCAD-9	yes	58.22
E-MTAB-10553	yes	34.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, GCFC2, HIF1A, HNF1A, JUN, KLF5, NFATC3, NR4A1, RELA, SP1, SP3, TBP, TP53, WT1

miRNA regulators (miRDB)

16 targeting GC, 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-6508-5P	99.92	70.67	2465
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-1-5P	98.70	68.66	1017
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-616-3P	96.82	66.99	784
HSA-MIR-584-5P	95.82	68.05	848
HSA-MIR-675-3P	95.77	69.27	675

Literature-anchored findings (GeneRIF, showing 40)

• GC*IF gene polymorphism of Gc-globulin may be one of the risk factors for chronic obstructive pulmonary disease. However, no association between this polymorphism of Gc-globulin and susceptibility to diffuse panbronchiolitis was found. (PMID:11757623)
• crystal structure in complex with 25-hydroxyvitamin D3, a vitamin D3 metabolite, which reveals the vitamin D-binding site in the N-terminal part of domain I; crystal structure in complex with a vitamin D3 analog (PMID:11799400)
• A polymorphism within the vitamin D-binding protein gene is associated with Graves’ disease but not with Hashimoto’s thyroiditis. (PMID:12050214)
• Although binding of 25-OH-D(3) to DBP might result in discrete conformational changes in the holo-protein to influence actin-binding, these binding processes are largely independent of each other in solution. (PMID:12051678)
• gene and genetic susceptibility to type 2 diabetes mellitus in a Polish population. (PMID:12062854)
• crystal structure of complex with actin (PMID:12119014)
• function in macrophage tumoricidal activity (PMID:12580408)
• Data show that vitamin D-binding protein-macrophage-activating factor (DBP-maf) induces apoptosis in macrophages via a p38 and jun kinase 1/2 pathway. (PMID:12938159)
• The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (PMID:12942785)
• complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis (PMID:12968673)
• Gc-globulin polymorphism is significantly associated with susceptibility to COPD (PMID:14718422)
• Chronic liver patients showed increased levels of Gc globulin following transplantation (PMID:15115254)
• Association was found between frequencies of genotypes SS, 2F and FS, F allele of GC gene with osteoporosis. (PMID:15230135)
• a 20-amino-acid sequence (residues 130-149, 5’-EAFRKDPKEYANQFMWEYST-3’) in domain I of DBP is essential for its C5a chemotactic cofactor function (PMID:15485893)
• single nucleotide polymorphisms (SNPs) within the transcriptional regulatory regions of the VDR and DBP are associated with prostate cancer risk (PMID:15717311)
• The decreased level of DBPE in the peritoneal fluid but not in plasma of women with untreated endometriosis suggests that this molecule may be relevant in the pathogenesis of this disease (PMID:15866120)
• The active form of Vitamin D (1,25(OH)2D3) completely eliminated the chemotactic cofactor function of DBP (Vitamin B binding protein). (PMID:16115686)
• vitamin D binding sites are important for initiating the activities of vitamin D-binding protein on vascular smooth muscle cells (PMID:16269129)
• No major effect of (TAAA)(n)-Alu repeat DBP-polymorphism was demonstrated on BMD, bone turnover markers or body composition. (PMID:16309986)
• Inhibits angiogenesis by blocking critical steps such as endothelial cell proliferation, migration, tube formation and microvessel sprouting. (PMID:16400520)
• A model is proposed in which the DBP gene is independently regulated by dedicated locus control regions. (PMID:16648359)
• These results indicate that fusion of granules with the plasma membrane forms heavy plasma membrane that contains DBP binding sites. (PMID:17113648)
• Polymorphisms of vitamin D-binding protein (DBP) gene were significantly association with human percentage of fat mass, especially in female, suggesting the importance of DBP gene in the pathogenesis of human obesity. (PMID:17342072)
• C5 gene variants and Gc-globulin levels co-define the proinflammatory and profibrogenic effects of C5 in patients at-risk for progression of liver fibrosis (PMID:17428459)
• Free Gc-globulin provides prognostic information in acute liver fafilure. (PMID:17763387)
• A prognostic marker for liver transplantation after acute liver failure. (PMID:17763397)
• *mportance of acute liver failure Gc reductions in the development of multiple organ dysfunction in acute liver failure and cirrhosis. (PMID:17763400)
• These data demonstrate a critical role for elements within intron 1 in the establishment of an autonomous and productive hDBP chromatin locus and suggest that this function is dependent upon C/EBPalpha. (PMID:17785430)
• results provide a direct evidence of cross-talk among the structural domains of DBP (PMID:18035050)
• There was a relationship between DBP Alu genotype and BMD, suggesting that DBP-Alu genotype may influence fracture risk. This effect may be mediated by changes in the circulating concentrations of DBP which influences free concentrations of vitamin D. (PMID:18038108)
• Serum VDBP can be considered a nutritional marker for lipids in cystic fibrosis. (PMID:18303991)
• Serum and peritoneal DBP concentrations are not affected in women with endometriosis. (PMID:18334925)
• the micro-environment of the fatty acid-binding domains of DBP and albumin may be different; and DBP may not replace ALB as a transporter of fatty acids. (PMID:18374965)
• A significantly reduced risk of postmenopausal breast cancer in homozygote carriers of the Gc2 allele in the vitamin D binding protein was observed, independent of serum 25(OH)D. (PMID:18559548)
• SNPs in the DBP are associated with levels of 25(OH)D and 1,25(OH)2D in hispanics and African americans. (PMID:18593774)
• characterization of genotype-dependent glycosylation patterns for the 3 major allele products of DBP (PMID:18686987)
• No evidence that DBP polymorphisms were associated with mammographic breast density among Caucasian premenopausal women of French descent. (PMID:18768522)
• These results support a correlation between the level of DBP and MS. DBP may be a potential useful biomarker for diagnosis or a medicine target for treatment of MS. (PMID:18807170)
• Data show that vitamin D-binding protein (DBP) is elevated in the CSF of temporal lobe epilepsy patients. (PMID:19109932)
• Circulating 25(OH)D concentrations in premenopausal women are strongly related to DBP polymorphisms (PMID:19116321)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gc	ENSDARG00000089310
mus_musculus	Gc	ENSMUSG00000035540
rattus_norvegicus	Gc	ENSRNOG00000003119

Paralogs (3): AFM (ENSG00000079557), AFP (ENSG00000081051), ALB (ENSG00000163631)

Protein

Protein identifiers

Vitamin D-binding protein — P02774 (reviewed: P02774)

Alternative names: Gc protein-derived macrophage activating factor, Gc-globulin, Group-specific component, Vitamin D-binding protein-macrophage activating factor

All UniProt accessions (4): D6RBJ7, D6RF20, D6RF35, P02774

UniProt curated annotations — full annotation on UniProt →

Function. Involved in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5 alpha for neutrophils in inflammation and macrophage activation.

Subunit / interactions. Associates with membrane-bound immunoglobulin on the surface of B-lymphocytes and with IgG Fc receptor on the membranes of T-lymphocytes. Interacts with LRP2; the interaction is required for renal uptake of GC in complex with 25-hydroxyvitamin D3.

Subcellular location. Secreted.

Tissue specificity. Expressed in the liver. Found in plasma, ascites, cerebrospinal fluid and urine.

Post-translational modifications. Allele GC*1S is O-glycosylated at Thr-436. The trisaccharide sugar moiety can be modified by the successive removal of neuraminic acid and galactose leaving an O-mceeN-acetyl-galactosamine. This conversion is thought to produce a macrophage-activating factor (Gc-MAF). Only a minor proportion of plasma GC is O-glycosylated. The potential N-glycosylation site predicted at Asn-288 is thought to be nonglycosylated.

Polymorphism. Over 80 variants of human DBP have been identified. The three most common alleles are called GC1F, GC1S, and GC2. The sequence shown is that of the GC1A1 allele.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the ALB/AFP/VDB family.

Isoforms (3)

UniProt ID	Names	Canonical?
P02774-1	1	yes
P02774-2	2
P02774-3	3

RefSeq proteins (3): NP_000574, NP_001191235, NP_001191236 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000213	VitD-bd	Family
IPR000264	ALB/AFP/VDB	Family
IPR014760	Serum_albumin_N	Domain
IPR015247	VitD-bind_III	Domain
IPR020857	Serum_albumin_CS	Conserved_site
IPR020858	Serum_albumin-like	Homologous_superfamily

Pfam: PF00273, PF09164

UniProt features (59 total): helix 22, disulfide bond 14, strand 5, sequence variant 4, turn 4, domain 3, sequence conflict 3, splice variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1KXP	X-RAY DIFFRACTION	2.1
1KW2	X-RAY DIFFRACTION	2.15
1J78	X-RAY DIFFRACTION	2.31
1MA9	X-RAY DIFFRACTION	2.4
1LOT	X-RAY DIFFRACTION	2.5
1J7E	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02774-F1	92.81	0.89

Functional residue map

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

Disulfide bonds (14): 189–198, 220–266, 265–273, 286–300, 299–311, 335–376, 375–384, 407–453, 452–462, 29–75, 74–83, 96–112, 111–122, 145–190

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196791	Vitamin D (calciferol) metabolism

MSigDB gene sets: 386 (showing top): RNGTGGGC_UNKNOWN, MODULE_93, MODULE_52, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, WANG_CLIM2_TARGETS_UP, MYOGENIN_Q6, RORA1_01, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, HNF1_Q6, MODULE_404, MODULE_503, chr4q13, MODULE_66, MODULE_118, CAIRO_HEPATOBLASTOMA_CLASSES_DN

GO Biological Process (4): response to nutrient levels (GO:0031667), vitamin D metabolic process (GO:0042359), vitamin transport (GO:0051180), vitamin transmembrane transport (GO:0035461)

GO Molecular Function (4): actin binding (GO:0003779), vitamin D binding (GO:0005499), vitamin transmembrane transporter activity (GO:0090482), calcidiol binding (GO:1902118)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of steroids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
response to stimulus	1
steroid metabolic process	1
transport	1
vitamin transport	1
transmembrane transport	1
cytoskeletal protein binding	1
steroid binding	1
vitamin binding	1
transmembrane transporter activity	1
vitamin transmembrane transport	1
D3 vitamins binding	1
cytoplasm	1
lysosome	1
vacuolar lumen	1
extracellular vesicle	1
extracellular region	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GC	LRP2	P98164	988
GC	CUBN	O60494	970
GC	ALB	P02768	936
GC	SLC25A18	Q9H1K4	907
GC	CYP24A1	Q07973	897
GC	CYP2R1	Q6VVX0	895
GC	SCIN	Q9Y6U3	878
GC	AHSG	P02765	870
GC	CYP27B1	O15528	856
GC	HP	P00737	848
GC	GSN	P06396	826
GC	PTH	P01270	798
GC	AZGP1	P25311	797
GC	SERPINA1	P01009	781
GC	ST6GALNAC1	Q9NSC7	746

IntAct

47 interactions, top by confidence:

A	B	Type	Score
GC	POTEF	psi-mi:“MI:0914”(association)	0.530
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
NR2F2	GC	psi-mi:“MI:0914”(association)	0.530
HYCC1	GC	psi-mi:“MI:0914”(association)	0.530
GC	ACTA1	psi-mi:“MI:0407”(direct interaction)	0.440
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
CCND3	GC	psi-mi:“MI:0915”(physical association)	0.370
	GC	psi-mi:“MI:0915”(physical association)	0.370
PPP2R2A	RBM7	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
NSD2	PFKFB2	psi-mi:“MI:0914”(association)	0.350
BUB1B	AP5Z1	psi-mi:“MI:0914”(association)	0.350
RPS6KA4		psi-mi:“MI:0914”(association)	0.350
STRADA		psi-mi:“MI:0914”(association)	0.350
CDK11A	APOA1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
SNX27	IGLL5	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
EGFL8	IGLC7	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (76): GC (Affinity Capture-MS), GC (Affinity Capture-MS), POTEKP (Affinity Capture-MS), POTEF (Affinity Capture-MS), POTEI (Affinity Capture-MS), GC (Affinity Capture-MS), GC (Affinity Capture-MS), ACTB (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), GC (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), GC (Affinity Capture-MS), SERF2 (Two-hybrid), CDC73 (Two-hybrid), LRIF1 (Two-hybrid)

ESM2 similar proteins: A2V9Z4, A6YF56, G3MYZ3, O01454, O35090, O89020, P02768, P02769, P02770, P02771, P02772, P02773, P02774, P04276, P07724, P08759, P08835, P14639, P14872, P19121, P21614, P21847, P21848, P28050, P35747, P36953, P43652, P49064, P49065, P49066, P49822, P53789, P83632, P84407, Q03156, Q17077, Q25513, Q27388, Q28522, Q28789

Diamond homologs: P02774, P04276, P21614, P53789, Q3MHN5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GC	“up-regulates quantity”	“vitamin D”	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	8
Uncertain significance	44
Likely benign	7
Benign	9

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
3242552	NM_000583.4(GC):c.1366A>T (p.Asn456Tyr)	Pathogenic
3336641	NM_000583.4(GC):c.1368C>A (p.Asn456Lys)	Likely pathogenic
3336642	NM_000583.4(GC):c.1322_1323insTG (p.Val442fs)	Likely pathogenic
3336643	NM_000583.4(GC):c.1328del (p.Asn443fs)	Likely pathogenic
3336644	NM_000583.4(GC):c.1349C>G (p.Ser450Cys)	Likely pathogenic
3336646	NM_000583.4(GC):c.1364T>C (p.Ile455Thr)	Likely pathogenic
3336647	NM_000583.4(GC):c.1330A>T (p.Lys444Ter)	Likely pathogenic
3336648	NM_000583.4(GC):c.1324dup (p.Val442fs)	Likely pathogenic
3336649	NM_000583.4(GC):c.1327_1328insT (p.Asn443fs)	Likely pathogenic

SpliceAI

1362 predictions. Top by Δscore:

Variant	Effect	Δscore
4:71754407:TTA:T	donor_loss	1.0000
4:71754409:A:AC	donor_gain	1.0000
4:71754409:AC:A	donor_loss	1.0000
4:71754410:C:CT	donor_gain	1.0000
4:71754504:GGGCC:G	acceptor_gain	1.0000
4:71754506:GCC:G	acceptor_gain	1.0000
4:71754506:GCCCT:G	acceptor_loss	1.0000
4:71754507:CC:C	acceptor_gain	1.0000
4:71754507:CCC:C	acceptor_gain	1.0000
4:71754507:CCCT:C	acceptor_loss	1.0000
4:71754508:CC:C	acceptor_gain	1.0000
4:71754509:C:CC	acceptor_gain	1.0000
4:71754509:CTGT:C	acceptor_loss	1.0000
4:71754510:T:A	acceptor_loss	1.0000
4:71754982:G:C	donor_gain	1.0000
4:71756710:A:AC	donor_gain	1.0000
4:71756711:C:CC	donor_gain	1.0000
4:71756711:CTTAT:C	donor_gain	1.0000
4:71756714:AT:A	donor_gain	1.0000
4:71756715:T:C	donor_gain	1.0000
4:71756872:T:C	acceptor_gain	1.0000
4:71756911:GCAG:G	acceptor_gain	1.0000
4:71756912:CAG:C	acceptor_gain	1.0000
4:71756912:CAGC:C	acceptor_gain	1.0000
4:71756913:AG:A	acceptor_gain	1.0000
4:71756915:C:CA	acceptor_loss	1.0000
4:71756915:C:CC	acceptor_gain	1.0000
4:71756916:T:G	acceptor_loss	1.0000
4:71758037:CTTA:C	donor_loss	1.0000
4:71758038:TTA:T	donor_loss	1.0000

AlphaMissense

3098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:71763814:A:C	F199C	0.993
4:71765471:C:G	C145S	0.991
4:71765472:A:T	C145S	0.991
4:71765471:C:T	C145Y	0.990
4:71768340:G:C	C74W	0.990
4:71763840:A:C	C190W	0.989
4:71763841:C:T	C190Y	0.989
4:71768341:C:T	C74Y	0.989
4:71769373:C:G	C29S	0.989
4:71769374:A:T	C29S	0.989
4:71763843:G:C	C189W	0.988
4:71765540:C:G	C122S	0.988
4:71765541:A:T	C122S	0.988
4:71765618:C:T	C96Y	0.988
4:71768338:C:T	C75Y	0.988
4:71763844:C:T	C189Y	0.987
4:71765618:C:G	C96S	0.987
4:71765619:A:T	C96S	0.987
4:71768415:A:C	S49R	0.987
4:71768415:A:T	S49R	0.987
4:71768417:T:G	S49R	0.987
4:71763841:C:G	C190S	0.986
4:71763842:A:T	C190S	0.986
4:71768337:A:C	C75W	0.986
4:71765471:C:A	C145F	0.985
4:71765573:C:G	C111S	0.985
4:71765574:A:T	C111S	0.985
4:71765470:A:C	C145W	0.984
4:71765472:A:G	C145R	0.984
4:71768342:A:G	C74R	0.984

dbSNP variants (sampled 300 via entrez): RS1000138805 (4:71791736 A>G), RS1000169255 (4:71782510 G>T), RS1000221924 (4:71741451 T>A), RS1000228788 (4:71804296 C>T), RS1000276997 (4:71787325 C>T), RS1000282396 (4:71788976 TATA>T), RS1000304607 (4:71782119 A>C), RS1000383039 (4:71746886 A>C), RS1000397465 (4:71769588 A>G), RS1000424223 (4:71751817 G>A), RS1000455705 (4:71793220 G>C,T), RS1000509388 (4:71774502 G>T), RS1000657537 (4:71741268 C>A), RS1000725907 (4:71745433 G>A), RS1000736981 (4:71788739 A>G)

Disease associations

OMIM: gene MIM:139200 | disease phenotypes: MIM:606963

GenCC curated gene-disease

Mondo (2): periodontitis (MONDO:0005076), chronic obstructive pulmonary disease (MONDO:0005002)

Orphanet (0):

HPO phenotypes

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

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST000664_1	Vitamin D levels	2.000000e-49
GCST000697_2	Vitamin D insufficiency	2.000000e-109
GCST001560_1	Vitamin D levels	2.000000e-14
GCST001639_31	Metabolite levels	1.000000e-14
GCST001766_4	Non-alcoholic fatty liver disease histology (other)	1.000000e-06
GCST002414_1	Serum vitamin D-binding protein levels	1.000000e-246
GCST002414_3	Serum vitamin D-binding protein levels	5.000000e-91
GCST002602_10	Vitamin D levels	4.000000e-09
GCST002602_8	Vitamin D levels	4.000000e-09
GCST004610_68	White blood cell count	2.000000e-11
GCST004613_106	Sum neutrophil eosinophil counts	2.000000e-10
GCST004614_148	Granulocyte count	1.000000e-10
GCST004620_143	Sum basophil neutrophil counts	1.000000e-10
GCST004626_36	Myeloid white cell count	5.000000e-11
GCST004629_60	Neutrophil count	2.000000e-10
GCST005366_1	Vitamin D levels (dietary vitamin D intake interaction)	1.000000e-187
GCST005367_3	Vitamin D levels	0.000000e+00
GCST005729_1	Serum 25-Hydroxyvitamin D levels	5.000000e-38
GCST005782_1	Serum 25-Hydroxyvitamin D levels	1.000000e-12
GCST005782_10	Serum 25-Hydroxyvitamin D levels	3.000000e-06
GCST005782_11	Serum 25-Hydroxyvitamin D levels	4.000000e-62
GCST005782_14	Serum 25-Hydroxyvitamin D levels	8.000000e-10
GCST005782_15	Serum 25-Hydroxyvitamin D levels	6.000000e-13
GCST005782_3	Serum 25-Hydroxyvitamin D levels	3.000000e-10
GCST005782_4	Serum 25-Hydroxyvitamin D levels	4.000000e-63
GCST005782_8	Serum 25-Hydroxyvitamin D levels	1.000000e-06
GCST005782_9	Serum 25-Hydroxyvitamin D levels	1.000000e-07
GCST009240_166	Serum metabolite levels (CMS)	3.000000e-12
GCST009242_342	Serum metabolite levels	7.000000e-07
GCST009671_1	Serum 25-Hydroxyvitamin D levels	1.000000e-11

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0003762	vitamin D deficiency
EFO:0004723	coronary artery calcification
EFO:0005675	vitamin D-binding protein measurement
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0008539	vitamin D dietary intake measurement
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010518	Periodontitis	C07.465.714.533
D029424	Pulmonary Disease, Chronic Obstructive	C08.381.495.389; C23.550.291.500.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2259 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 29,522 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL846	CALCITRIOL	4	29,522

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7041	Efficacy	3	deferasirox	Beta-thalassemia and related diseases

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4588	GC		0.00	0
rs7041	GC	3	2.00	1	deferasirox

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.62	Kd	24	nM	CALCITRIOL

PubChem BioAssay actives

1 with measured affinity, of 57 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
Calcitriol	472017: Binding affinity to human vitamin D binding protein	kd	0.0240	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Calcitriol	affects transport, affects binding, affects abundance	3
25-hydroxyvitamin D	affects abundance	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Vitamin D	affects binding	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
methyleugenol	decreases expression	1
bisphenol A	affects binding	1
potassium persulfate	increases expression	1
terbufos	affects response to substance	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Olanzapine	affects phosphorylation	1
Zoledronic Acid	increases expression	1
Ethanol	decreases expression	1
Vehicle Emissions	decreases methylation	1
Cadmium	affects binding	1
Carbon	affects response to substance	1
Copper	affects binding	1
Lead	affects binding	1
Lipopolysaccharides	affects cotreatment, increases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Nickel	affects binding	1
Ouabain	affects expression	1
Parathion	affects response to substance	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1014566	Binding	Binding affinity to human DBP at EC50 in 4 degC relative to 1-alpha,25-(OH)2D3	Synthesis and biological activity of previtamin D(3) analogues with A-ring modifications. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00296881	PHASE4	UNKNOWN	SRP in Combination With PERIOWAVE in Comparison to SRP Alone in Chronic Periodontitis
NCT00297518	PHASE4	COMPLETED	Study of Scaling and Root Planing (SRP) With PerioWave vs. SRP Alone in Chronic Periodontitis
NCT00297531	PHASE4	UNKNOWN	Study of Scaling and Root Planing With PerioWave Versus Scaling and Root Planing Alone in Chronic Periodontitis
NCT00668746	PHASE4	COMPLETED	Long-term Safety of Minocycline in Patients With Gum Disease
NCT00707369	PHASE4	COMPLETED	Adjunctive Antimicrobial Therapy of Periodontitis: Long-Term Effects on Disease Progression and Oral Microbiological Colonization
NCT01030666	PHASE4	TERMINATED	Effect of Postsurgical Systemic Doxycycline After Regenerative Periodontal Therapy
NCT01538927	PHASE4	COMPLETED	Effect of Fibrin Sealant on Early Wound Healing
NCT01548469	PHASE4	COMPLETED	Study to Evaluate Clinical Efficacy and Safety of Bio Mineral Toothpaste in Patients With Mild Periodontitis
NCT01593540	PHASE4	COMPLETED	Clinical Examination of Metal Free Interdental Brushes
NCT01806974	PHASE4	TERMINATED	Consequences of Anti-interleukin 6 Immunotherapy Treatment for Rheumatoid Arthritis on Periodontium
NCT02030470	PHASE4	COMPLETED	Evaluation of Photodynamic Treatment FOTOSAN® Efficacy in Periodontology
NCT02062047	PHASE4	COMPLETED	Full-mouth and Partial-mouth Scaling and Root Planing in Type 2 Diabetic Subjects
NCT02124655	PHASE4	COMPLETED	Antiplaque Effect of Essential Oils and 0.2% Chlorhexidine on an in Situ Model of Oral Biofilm Growth.
NCT02135952	PHASE4	UNKNOWN	Metronidazole and Amoxicillin for the Treatment of Type 2 Diabetic Subjects With Periodontitis
NCT02149758	PHASE4	COMPLETED	EFFECT OF SELECTIVE COX-2 INHIBITOR (ETORICOXIB) ALONG WITH SCALING AND ROOT PLANING (SRP) ON CLINICAL PARAMETERS AND SALIVARY LEVEL OF SUPEROXIDE DISMUTASE IN CHRONIC GENERALIZED PERIODONTITIS A DOUBLE-BLIND, PLACEBO-CONTROLLED, DOUBLE-MASKED RANDOMIZED CONTROLLED TRIAL (RCT).
NCT02215460	PHASE4	COMPLETED	Treatment of Periodontitis by Conventional 4 Weekly Sections or Within 24 Hours
NCT02215473	PHASE4	COMPLETED	Bacteremia in Periodontal Patients
NCT02267239	PHASE4	UNKNOWN	Methodology Antiseptic Application, Influence on Oral Biofilm.
NCT02359721	PHASE4	COMPLETED	Clarithromycin is an Adjunct to Scaling and Root Planing
NCT02470611	PHASE4	COMPLETED	Sodium Alendronate in Non Surgical Periodontal Therapy
NCT02794506	PHASE4	COMPLETED	Propolis Improves Glycemic Control in Subjects With Type 2 Diabetes and Chronic Periodontitis
NCT02921165	PHASE4	COMPLETED	Comparison of Topical Analgesic With Saline Rinses in Post Extraction Healing
NCT02946801	PHASE4	UNKNOWN	Antiplaque Effect of Essential Oils With and Without Alcochol on an in Situ Model of Oral Biofilm Growth
NCT03103204	PHASE4	COMPLETED	Treatment of Periodontitis in Obese Individuals
NCT03146390	PHASE4	UNKNOWN	Essential Oils With and Without Alcohol: Substantivity and Antiplaque Effect
NCT03176537	PHASE4	WITHDRAWN	Periodontal Profile of Hypogonadic Men
NCT03311906	PHASE4	COMPLETED	Evaluation of the Efficacy of 0.8% Hyaluronic Acid Gel
NCT03354312	PHASE4	COMPLETED	Acceptance and Preference of Lidocaine Gel Compared to Injection Anesthesia After Non Surgical Periodontal Treatment
NCT04027179	PHASE4	UNKNOWN	Tongue Dysbiosis Effects on Arterial Pressure of Periodontitis Patients
NCT04032132	PHASE4	COMPLETED	Curcumin Paste as an Adjunctive Therapy in Periodontitis
NCT04036890	PHASE4	COMPLETED	Local Minocycline in Patients Under Supportive Periodontal Therapy
NCT04044417	PHASE4	COMPLETED	Curcumin-Simvastatin-EDTA in the Treatment of Periodontitis
NCT04149405	PHASE4	COMPLETED	Alterations of GCF Levels of Sclerostin and DKK-1 in Postmenopausal Osteoporosis
NCT04178590	PHASE4	COMPLETED	Effect of Injectable Platelet-Rich Fibrin (i-PRF) in Initial Treatment of Chronic Periodontitis
NCT04223076	PHASE4	UNKNOWN	Clinical Effect of Chlorhexidine Mouthwash After Periodontal Surgery
NCT04353362	PHASE4	COMPLETED	Alternative Antibiotic Regimen in Periodontitis Treatment
NCT04964167	PHASE4	COMPLETED	Indocyanine-green Mediated Photosensitizer VS Aloe Vera Gel: Adjunct Therapy to Scaling and Root Planing in Patients With Chronic Periodontitis
NCT04983849	PHASE4	COMPLETED	Evaluation of Metronidazole Hydrogel 25% in Stage II and III Periodontitis
NCT05530252	PHASE4	COMPLETED	Effects of AMP Application After Non-surgical Periodontal Therapy on Treatment of Periodontitis
NCT05657015	PHASE4	COMPLETED	Lepidium Sativum Extract Versus Simvastatin as an Adjunctive Local Delivery Agents to Non-Surgical Periodontal Therapy