BGLAP

Summary

BGLAP (bone gamma-carboxyglutamate protein, HGNC:1043) is a protein-coding gene on chromosome 1q22, encoding Osteocalcin (P02818). The carboxylated form is one of the main organic components of the bone matrix, which constitutes 1-2% of the total bone protein.

This gene encodes a highly abundant bone protein secreted by osteoblasts that regulates bone remodeling and energy metabolism. The encoded protein contains a Gla (gamma carboxyglutamate) domain, which functions in binding to calcium and hydroxyapatite, the mineral component of bone. Serum osteocalcin levels may be negatively correlated with metabolic syndrome. Read-through transcription exists between this gene and the neighboring upstream gene, PMF1 (polyamine-modulated factor 1), but the encoded protein only shows sequence identity with the upstream gene product.

Source: NCBI Gene 632 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 22 total
• GTEx eGene: eQTL in 39 tissues, sQTL in 31 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.79 (unconstrained)
• MANE Select transcript: NM_199173
• Interaction hub: 1,986 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1043
Approved symbol	BGLAP
Name	bone gamma-carboxyglutamate protein
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	OCN, BGP
Ensembl gene	ENSG00000242252
Ensembl biotype	protein_coding
OMIM	112260
Entrez	632

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

MANE Select: ENST00000368272

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 5: 1

ENST00000368272, ENST00000471413, ENST00001145634

RefSeq mRNA: 1 — MANE Select: NM_199173 NM_199173

CCDS: CCDS1134

Canonical transcript exons

ENST00000368272 — 4 exons

Exon	Start	End
ENSE00001446742	156242184	156242295
ENSE00003552470	156242762	156242831
ENSE00003590844	156242553	156242591
ENSE00003692422	156243033	156243317

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 90.98.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2000 / max 2351.0940, expressed in 183 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, hemisphere of cerebellum, C1 segment of cervical spinal cord, cerebellar hemisphere.

Genetic regulation across tissues (GTEx eQTL / sQTL)

BGLAP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 39 tissues and its splicing (sQTL) in 31 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 70 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Colon Sigmoid	eqtl	1.7e-26	-0.35	1:156250265:T:C
Thyroid	sqtl	1.3e-24	+0.68	1:156263688:T:C
Heart Atrial Appendage	eqtl	1.5e-23	-0.40	1:156240766:C:T
Artery Tibial	sqtl	2.9e-23	-0.48	1:156257159:T:A
Esophagus Muscularis	eqtl	1.7e-17	-0.31	1:156240766:C:T
Brain Cerebellum	sqtl	7.2e-17	-0.50	1:156240766:C:T
Heart Left Ventricle	eqtl	1.5e-16	-0.36	1:156265244:GGAAGTAAAA:G
Brain Cerebellar Hemisphere	sqtl	1.9e-15	-0.46	1:156263688:T:C
Cells Cultured fibroblasts	eqtl	3.2e-13	-0.34	1:156240766:C:T
Adipose Subcutaneous	sqtl	5.1e-13	-0.32	1:156263688:T:C
Muscle Skeletal	eqtl	5.7e-13	-0.24	1:156240766:C:T
Prostate	sqtl	2.0e-12	-0.52	1:156271044:A:C
Brain Caudate basal ganglia	eqtl	2.6e-12	-0.45	1:156240066:C:T
Brain Hypothalamus	eqtl	2.9e-11	-0.46	1:156257159:T:A
Pancreas	eqtl	4.1e-11	-0.38	1:156240766:C:T
Artery Tibial	eqtl	1.2e-10	-0.25	1:156240766:C:T
Breast Mammary Tissue	sqtl	1.3e-10	-0.42	1:156240766:C:T
Adipose Visceral Omentum	eqtl	1.4e-10	-0.22	1:156240766:C:T
Brain Frontal Cortex BA9	eqtl	2.9e-10	-0.35	1:156265244:GGAAGTAAAA:G
Whole Blood	sqtl	3.6e-10	-0.27	1:156240766:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
5710	2.1631	182
5709	0.0368	17

Top tissues by expression

showing 100 of 133 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.92	gold quality
cerebellar hemisphere	UBERON:0002245	81.64	gold quality
cerebellum	UBERON:0002037	81.49	gold quality
cerebellar cortex	UBERON:0002129	81.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.83	gold quality
putamen	UBERON:0001874	80.77	gold quality
substantia nigra	UBERON:0002038	80.75	gold quality
caudate nucleus	UBERON:0001873	80.50	gold quality
nucleus accumbens	UBERON:0001882	79.75	gold quality
right uterine tube	UBERON:0001302	79.72	gold quality
amygdala	UBERON:0001876	79.53	gold quality
apex of heart	UBERON:0002098	79.52	gold quality
temporal lobe	UBERON:0001871	79.40	gold quality
lower esophagus mucosa	UBERON:0035834	78.51	gold quality
primary visual cortex	UBERON:0002436	78.19	gold quality
mucosa of transverse colon	UBERON:0004991	77.95	gold quality
granulocyte	CL:0000094	77.75	gold quality
right frontal lobe	UBERON:0002810	77.08	gold quality
brain	UBERON:0000955	76.62	gold quality
hypothalamus	UBERON:0001898	76.27	gold quality
anterior cingulate cortex	UBERON:0009835	76.19	gold quality
right lobe of liver	UBERON:0001114	75.93	gold quality
Ammon’s horn	UBERON:0001954	75.81	gold quality
right ovary	UBERON:0002118	75.63	gold quality
left ovary	UBERON:0002119	75.08	gold quality
spleen	UBERON:0002106	74.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.61	gold quality
colon	UBERON:0001155	74.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.58	gold quality
prostate gland	UBERON:0002367	74.45	gold quality
cerebral cortex	UBERON:0000956	73.98	gold quality
ovary	UBERON:0000992	73.89	gold quality
endocervix	UBERON:0000458	73.87	gold quality
pituitary gland	UBERON:0000007	73.70	gold quality
adenohypophysis	UBERON:0002196	73.42	gold quality
transverse colon	UBERON:0001157	73.18	gold quality
frontal cortex	UBERON:0001870	72.74	gold quality
left lobe of thyroid gland	UBERON:0001120	72.57	gold quality
hindlimb stylopod muscle	UBERON:0004252	72.44	gold quality
intestine	UBERON:0000160	72.35	gold quality
right lobe of thyroid gland	UBERON:0001119	72.12	gold quality
thyroid gland	UBERON:0002046	71.67	gold quality
fundus of stomach	UBERON:0001160	71.60	gold quality
body of uterus	UBERON:0009853	71.53	gold quality
cortex of kidney	UBERON:0001225	71.44	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.73	gold quality
right coronary artery	UBERON:0001625	70.63	gold quality
blood	UBERON:0000178	70.59	gold quality
omental fat pad	UBERON:0010414	70.57	gold quality
vagina	UBERON:0000996	70.50	gold quality
myometrium	UBERON:0001296	70.43	gold quality
prefrontal cortex	UBERON:0000451	70.29	gold quality
uterine cervix	UBERON:0000002	69.93	gold quality
small intestine	UBERON:0002108	69.90	gold quality
skin of abdomen	UBERON:0001416	69.70	gold quality
body of stomach	UBERON:0001161	69.19	gold quality
zone of skin	UBERON:0000014	68.91	gold quality
metanephros cortex	UBERON:0010533	68.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	68.85	gold quality
multicellular organism	UBERON:0000468	68.58	gold quality
ectocervix	UBERON:0012249	68.40	gold quality
skin of leg	UBERON:0001511	68.38	gold quality
adipose tissue	UBERON:0001013	68.27	gold quality
tibial nerve	UBERON:0001323	68.01	gold quality
lower esophagus	UBERON:0013473	67.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	67.97	gold quality
thoracic mammary gland	UBERON:0005200	67.93	gold quality
saliva-secreting gland	UBERON:0001044	67.74	gold quality
minor salivary gland	UBERON:0001830	67.74	gold quality
subcutaneous adipose tissue	UBERON:0002190	67.02	gold quality
left uterine tube	UBERON:0001303	66.72	gold quality
esophagus	UBERON:0001043	66.69	gold quality
body of pancreas	UBERON:0001150	66.55	gold quality
stomach	UBERON:0000945	66.36	gold quality
esophagus mucosa	UBERON:0002469	66.27	gold quality
stromal cell of endometrium	CL:0002255	66.25	gold quality
upper lobe of left lung	UBERON:0008952	66.16	gold quality
superior frontal gyrus	UBERON:0002661	66.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.90	gold quality
right atrium auricular region	UBERON:0006631	65.79	gold quality
heart left ventricle	UBERON:0002084	65.66	gold quality
gastrocnemius	UBERON:0001388	65.53	gold quality
mucosa of stomach	UBERON:0001199	65.51	gold quality
right adrenal gland	UBERON:0001233	65.50	gold quality
fallopian tube	UBERON:0003889	65.47	gold quality
lymph node	UBERON:0000029	65.22	gold quality
right lung	UBERON:0002167	65.01	gold quality
liver	UBERON:0002107	64.84	gold quality
muscle of leg	UBERON:0001383	64.71	gold quality
smooth muscle tissue	UBERON:0001135	64.70	gold quality
right adrenal gland cortex	UBERON:0035827	64.08	gold quality
heart	UBERON:0000948	64.03	gold quality
placenta	UBERON:0001987	63.98	gold quality
left adrenal gland	UBERON:0001234	63.91	gold quality
popliteal artery	UBERON:0002250	63.82	gold quality
tibial artery	UBERON:0007610	63.80	gold quality
left adrenal gland cortex	UBERON:0035825	63.76	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.21

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 70 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Corpus callosum	tissue	8.2
Spinal cord	tissue	5.9
Nucleus accumbens	tissue	5.4
Locus coeruleus	tissue	5.3
Hippocampus	tissue	4.6
Medulla oblongata	tissue	4.5
Substantia nigra	tissue	4.5
Midbrain	tissue	4.4
Putamen	tissue	4.1
Ventral forebrain	tissue	4.1
Thalamus	tissue	4.0
Cerebral cortex	tissue	3.9
Superior colliculi	tissue	3.9
Insular cortex	tissue	3.9
Pons	tissue	3.7
Amygdala	tissue	3.6
Periaqueductal gray	tissue	3.5
Septum	tissue	3.5
Somatosensory cortex	tissue	3.4
Retrosplenial cortex	tissue	3.4
Hippocampal formation	tissue	3.3
Entorhinal cortex	tissue	3.3
Hypothalamus	tissue	3.2
Postcentral gyrus	tissue	3.2
Retrosplenial and cingulate cortex	tissue	3.2
Basal ganglia	tissue	2.9
Motor cortex	tissue	2.8
Olfactory bulb	tissue	2.8
Temporal cortex	tissue	2.8
Prefrontal cortex	tissue	2.6
Occipital cortex	tissue	2.5
Choroid plexus	tissue	2.1
Small intestine	tissue	2.1
Colon	tissue	1.8
Rectum	tissue	1.7
Smooth muscle	tissue	1.7
Cerebellum	tissue	1.7
Skin 1	tissue	1.6
Salivary gland	tissue	1.6
Endometrium 1	tissue	1.3
Epididymis	tissue	1.1
Pituitary gland	tissue	0.9
Ovary	tissue	0.8
Bone marrow	tissue	0.8
Stomach 1	tissue	0.6
Seminal vesicle	tissue	0.6
Frontal cortex	tissue	0.6
Gallbladder	tissue	0.6
Duodenum	tissue	0.6
Appendix	tissue	0.6
Skeletal muscle	tissue	0.5
Spleen	tissue	0.5
Vagina	tissue	0.4
Fallopian tube	tissue	0.4
Lymph node	tissue	0.3
Breast	tissue	0.3
Heart muscle	tissue	0.3
Urinary bladder	tissue	0.3
Placenta	tissue	0.3
Lung	tissue	0.3

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Nucleus raphe obscurus (10.3), Dorsal funiculus (white matter) (9.9), Anterior funiculus (white matter) (9.0), Cerebellar white matter (9.0), Cervical spinal cord, ventral horn (9.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ATF4, ATF6, BMP2, BMPR1B, CCL3, CCR1, CEBPB, CEBPD, CEBPG, CREBZF, CREM, CTNNB1, CUX1, DDIT3, DLX3, DLX5, DMTF1, EGR2, ESR1, ESRRA, ESRRG, ETS2, FOS, FOSB, FOSL2, FOXC1, FOXO1, FOXQ1, GLI2, GLIS3, GTF2F1, HDAC3, HES1, HIVEP2, HNF4A, HNRNPK, HR, ID1

miRNA regulators (miRDB)

Targeting BGLAP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

19 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-6779-5P	99.70	65.76	2363
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-516B-5P	99.56	66.33	1495
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-4446-3P	97.91	64.29	991
HSA-MIR-3127-5P	97.52	65.24	786

Functional genomics

gnomAD constraint: pLI 1e-06, LOEUF 1.79, missense Z 0.348 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000368272 — one region, missense o/e 0.89.

Literature-anchored findings (GeneRIF, showing 40)

• Osteocalcin was not localized extracellularly within the collagen-rich dentin matrix (predentin or intertubular dentin), but was found in the mature enamel. (PMID:11856645)
• data support the BGP gene as a quantitative trait locus(QTL)underlying hip bone mineral density variation variation (PMID:11918225)
• exists in osteoblasts and suppresses excess calcification (PMID:11979972)
• Differential regulation of Cbfa1/Runx2 and osteocalcin gene expression by vitamin-D3, dexamethasone, and local growth factors in primary human osteoblasts (PMID:12112004)
• Expression is regulated by a novel Ku antigen transcription factor complex (PMID:12145306)
• TWIST inactivation reduces CBFA1/RUNX2 expression and DNA binding to its promoter in osteoblasts (PMID:12270142)
• This protein is regulated by human basic fibroblast growth factor. (PMID:12393937)
• Telomerase accelerates osteogenesis of bone marrow stromal stem cells by upregulation of CBFA1, osterix, and osteocalcin. (PMID:12674332)
• osteocalcin genes are susceptibility loci for reduced bone mineral density in postmenopausal women (PMID:12843190)
• relationship between increase in undercarboxylated osteocalcin levels and low bone mineral density in elderly women with type II diabetes mellitus (PMID:15108065)
• HindIII RFLP of the BGP gene may be limited as a genetic marker to discern women susceptible to low BMD and thus osteoporosis in Chinese (PMID:15108070)
• Low serum level in osteochondrodysplasia. (PMID:15562030)
• the osteocalcin sequences of Neanderthals, modern human, chimpanzee, and orangutan are unusual among mammals in that the ninth amino acid is proline (Pro-9), whereas most species have hydroxyproline (Hyp-9) (PMID:15753298)
• May be a biological markers of bone disease in multiple myeloma. (PMID:16263577)
• mRNA and protein are expressed in c-KIT positive neoplastic stem cells in hematological malignancies. (PMID:16387359)
• The transcription axis of osteocalcin is crucial in maintaining equilibrium of bone formation and resorption. Heparin affects expression in osteoblast culture. (PMID:17000892)
• Serum osteocalcin showed no significant difference with the control healthy subjects. (PMID:17242729)
• Data show that simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. (PMID:17252541)
• local 1,25D synthesis has paracrine effects in the bone microenvironment implying that vitamin D metabolism in human osteoblasts represents a physiologically important pathway (PMID:17254772)
• Our data do not support the BGP gene having a major effect on BMD variation in pre-menopausal Chinese women. (PMID:17627084)
• Combined use of osteocalcin and beta-CTX could be useful in early detection of bone metastatic breast cancer which might improve the outcome of the disease. (PMID:17889845)
• BGLAP is expressed in pancreatic cancer cells and increases their growth and invasion (PMID:18163903)
• TFIIA gamma together with ATF4 and Runx2 stimulates osteocalcin promoter activity and endogenous mRNA expression. (PMID:18171674)
• In cotransfection experiments with an osteocalcin (OC) promoter construct, we confirmed that only RUNX2wt and RUNX2Delta7 could upregulate the OC promoter activity in the osteosarcoma cell line. (PMID:18321663)
• There is a potential role of osteocalcin in regulating blood glucose levels in postmenopausal women (PMID:18657532)
• Exposure of odontoblast-like cells to LPS decreases osteocalcin gene expression. (PMID:19031822)
• Plasma osteocalcin is inversely related to fat mass and plasma glucose. (PMID:19063687)
• serum osteocalcin concentration was inversely associated with markers of dysmetabolic phenotype & measures of adiposity; results provide support for important role of osteocalcin to regulate glucose tolerance, insulin sensitivity & systemic inflammation (PMID:19088165)
• Protein levels and mRNA expression of osteocalcin were greater in calcified compared to noncalcified plaques. (PMID:19136823)
• strain enhance expression of osteocalcin, type I collagen gene and Cbfa1/Runx2 in human osteoblas (PMID:19595020)
• The OC/BAP ratio could be clinically useful for assessing the risk of vertebral fractures independent of BMD in diabetic men. (PMID:19641839)
• Data suggest taht serial measurements of osteocalcin could be useful in the detection of bone metastases from differentiated thyroid carcinoma. (PMID:19732762)
• Relationship between bone formation markers osteocalcin and bone-specific alkaline phosphatase and age in postmenopausal women. (PMID:19751416)
• Prevalence of osteopenia and relationships between osteocalcin, bone alkaline phosphatase, and bone mineral density in patients with insulin-dependent diabetes mellitus. (PMID:19751417)
• not associated with dental fluorosis (PMID:19767102)
• Data show that the gradual process of osteogenesis can be followed by different proteins being expressed at various time points, comprising early bone-specific alkaline phosphatase (bALP)) and late gene osteocalcin. (PMID:19856264)
• Elevated plasma osteocalcin is associated with improved glucose tolerance. Elevated uncarboxylated osteocalcin is associated with enhanced beta-cell function; elevated carboxylated osteocalcin is associated with improved insulin sensitivity. (PMID:19877133)
• A positive association is found between serum level of osteocalcin and severity of hand osteoarthritis, in a cross-sectional population-based study. (PMID:20157712)
• Polymorphisms in and around the osteocalcin locus are significantly associated with serum-TotalOC and fracture. (PMID:20200947)
• These results indicate that older age, a greater number of prevalent fractures and higher undercarboxylated osteocalcin levels, and lower lumbar bone mineral density are risks for incident fractures despite use of amino-bisphosphonates. (PMID:20221651)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bglap	ENSDARG00000058414
mus_musculus	Bglap	ENSMUSG00000074483
mus_musculus	Bglap2	ENSMUSG00000074486
mus_musculus	Bglap3	ENSMUSG00000074489
rattus_norvegicus	Bglap	ENSRNOG00000019607

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88156) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
small testis	1
oligozoospermia	1
decreased circulating testosterone level	1
decreased testis weight	1
decreased seminal vesicle weight	1
decreased epididymis weight	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Ateles geoffroyi	A2D4U1	100.0%	Diamond
Macaca mulatta	A2D670	100.0%	Diamond
Macaca nemestrina	A2T6K4	100.0%	Diamond
Macaca fascicularis	P02819	100.0%	Diamond
Bos taurus	P02820	100.0%	Diamond
Capra hircus	P0C225	100.0%	Diamond
Notamacropus eugenii	P0C226	100.0%	Diamond
Dromaius novaehollandiae	P15504	100.0%	Diamond
Xenopus laevis	P40147	100.0%	Diamond
Sparus aurata	P40148	100.0%	Diamond
Equus caballus	P83005	100.0%	Diamond
Bison priscus	P83489	100.0%	Diamond
Pan troglodytes	P84348	100.0%	Diamond
Gorilla gorilla gorilla	P84349	100.0%	Diamond
Pongo pygmaeus	P84350	100.0%	Diamond
Homo sapiens neanderthalensis	P84351	100.0%	Diamond
Camelus dromedarius	P86313	100.0%	Diamond
Camelus bactrianus	P86314	100.0%	Diamond
Lama guanicoe	P86315	100.0%	Diamond
Diplodus sargus	P86867	100.0%	Diamond
Xenopus tropicalis	Q6DJ00	100.0%	Diamond
Sus scrofa	Q8HYY9	100.0%	Diamond
Canis lupus familiaris	P81455	91.8%	Diamond
Felis catus	P02821	91.7%	Diamond
Gallus gallus	P02822	91.7%	Diamond
Oryctolagus cuniculus	P39056	88.4%	Diamond
Camelops hesternus	P86312	85.7%	Diamond
Solea senegalensis	Q1EG28	82.2%	Diamond
Xiphias gladius	P02823	80.9%	Diamond
Argyrosomus regius	Q800Y1	73.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PMF1	protein-coding	11243
GLMP	protein-coding	112770
SMG5	protein-coding	23381
PAQR6	protein-coding	79957
TMEM79	protein-coding	84283
SLC25A44	protein-coding	9673
PMF1-BGLAP	protein-coding	100527963
VHLL	protein-coding	391104
SEMA4A	protein-coding	64218

Protein

Protein identifiers

Osteocalcin — P02818 (reviewed: P02818)

Alternative names: Bone Gla protein, Gamma-carboxyglutamic acid-containing protein

All UniProt accessions (1): P02818

UniProt curated annotations — full annotation on UniProt →

Function. The carboxylated form is one of the main organic components of the bone matrix, which constitutes 1-2% of the total bone protein. Acts as a negative regulator of bone formation and is required to limit bone formation without impairing bone resorption or mineralization. Binds strongly to apatite and calcium upon gamma-carboxylation; this modification is essential for bone metabolism. The uncarboxylated form acts as a hormone secreted by osteoblasts, which regulates different cellular processes, such as energy metabolism, male fertility and brain development. Regulates of energy metabolism by acting as a hormone favoring pancreatic beta-cell proliferation, insulin secretion and sensitivity and energy expenditure. Uncarboxylated osteocalcin hormone also promotes testosterone production in the testes: acts as a ligand for G protein-coupled receptor GPRC6A at the surface of Leydig cells, initiating a signaling response that promotes the expression of enzymes required for testosterone synthesis in a CREB-dependent manner. Also acts as a regulator of brain development: osteocalcin hormone crosses the blood-brain barrier and acts as a ligand for GPR158 on neurons, initiating a signaling response that prevents neuronal apoptosis in the hippocampus, favors the synthesis of all monoamine neurotransmitters and inhibits that of gamma-aminobutyric acid (GABA). Osteocalcin also crosses the placenta during pregnancy and maternal osteocalcin is required for fetal brain development.

Subcellular location. Secreted.

Post-translational modifications. Carboxylated by vitamin K-dependent GGCX to form gamma-carboxyglutamate; these residues are essential for the binding of calcium. Decarboxylation promotes the hormone activity.

Similarity. Belongs to the osteocalcin/matrix Gla protein family.

RefSeq proteins (1): NP_954642* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000294	GLA_domain	Domain
IPR002384	Osteocalcin/MGP	Family
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR039176	Osteocalcin	Family
IPR058704	BGLAP-like_C	Domain

Pfam: PF25890

UniProt features (20 total): binding site 5, modified residue 3, strand 2, signal peptide 1, propeptide 1, disulfide bond 1, sequence variant 1, sequence conflict 1, turn 1, helix 1, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

9 structures by resolution:

PDB	Title	Method	Resolution (Å)
8XS1	Crystal structure of Fab fragment of anti-osteocalcin antibody KTM219 complexed with …	X-RAY DIFFRACTION	2.3
9L23	cryo-EM structure of Vitamin K-dependent gamma-carboxylase complexed with Osteocalcin	ELECTRON MICROSCOPY	2.62
13IB	Structure of GGCX-BGP-Anisindione complex	ELECTRON MICROSCOPY	2.68
9WF2	Cryo-EM structure of GGCX-BGP complex	ELECTRON MICROSCOPY	2.94
9BUR	Structure of GGCX-BGP complex	ELECTRON MICROSCOPY	2.95
9BUX	Structure of GGCX-BGP-menaquinone-4 epoxide complex	ELECTRON MICROSCOPY	3.06
9MQC	Vitamin K-dependent gamma-carboxylase with Osteocalcin (mutant) and vitamin K hydroquinone	ELECTRON MICROSCOPY	3.13
9MQB	Vitamin K-dependent gamma-carboxylase with Osteocalcin (mutant) and vitamin K …	ELECTRON MICROSCOPY	3.37
9MQE	Vitamin K-dependent gamma-carboxylase with Osteocalcin and vitamin K hydroquinone	ELECTRON MICROSCOPY	3.56

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02818-F1	76.66	0.39

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 8XS1

Human Protein Atlas

Protein class: Predicted secreted proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Functional residue map

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

Catalytic / active sites (1)

Position	Role
60	not hydroxylated

Ligand- & substrate-binding residues (5)

Position	Role
68	Ca(2+)
72	Ca(2+)
75	Ca(2+)
81	Ca(2+)

Post-translational modifications (3)

Type	Positions
4-carboxyglutamate	68, 72, 75

Disulfide bonds (1)

Type	Positions
Disulfide bond	74–80

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 13; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

13 pathways:

ID	Pathway	Evidence
R-HSA-159740	Gamma-carboxylation of protein precursors	curated
R-HSA-159782	Removal of aminoterminal propeptides from gamma-carboxylated proteins	curated
R-HSA-159763	Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	curated
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	—
R-HSA-159854	Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-8941326	RUNX2 regulates bone development	—
R-HSA-8940973	RUNX2 regulates osteoblast differentiation	electronic
R-HSA-8878166	Transcriptional regulation by RUNX2	—

MSigDB gene sets: 209 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_COGNITION, GOBP_RESPONSE_TO_ZINC_ION, GOBP_BEHAVIOR, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, PID_REG_GR_PATHWAY

GO Biological Process (41): skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), positive regulation of neurotransmitter secretion (GO:0001956), cell adhesion (GO:0007155), brain development (GO:0007420), learning or memory (GO:0007611), response to xenobiotic stimulus (GO:0009410), response to mechanical stimulus (GO:0009612), response to gravity (GO:0009629), response to zinc ion (GO:0010043), response to activity (GO:0014823), bone mineralization (GO:0030282), regulation of bone mineralization (GO:0030500), response to vitamin K (GO:0032571), cellular response to insulin stimulus (GO:0032869), response to vitamin D (GO:0033280), response to testosterone (GO:0033574), response to hydroxyisoflavone (GO:0033594), cellular response to zinc ion starvation (GO:0034224), response to macrophage colony-stimulating factor (GO:0036005), glucose homeostasis (GO:0042593), response to estrogen (GO:0043627), type B pancreatic cell proliferation (GO:0044342), regulation of bone resorption (GO:0045124), response to ethanol (GO:0045471), regulation of osteoclast differentiation (GO:0045670), stem cell differentiation (GO:0048863), cognition (GO:0050890), response to glucocorticoid (GO:0051384), bone development (GO:0060348), cellular response to vitamin D (GO:0071305), cellular response to growth factor stimulus (GO:0071363), regulation of cellular response to insulin stimulus (GO:1900076), negative regulation of bone development (GO:1903011), regulation of testosterone biosynthetic process (GO:2000224), ossification (GO:0001503), signal transduction (GO:0007165), biomineral tissue development (GO:0031214), response to nutrient levels (GO:0031667), response to insulin (GO:0032868), system development (GO:0048731)

GO Molecular Function (7): hormone activity (GO:0005179), structural molecule activity (GO:0005198), calcium ion binding (GO:0005509), structural constituent of bone (GO:0008147), hydroxyapatite binding (GO:0046848), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): extracellular region (GO:0005576), cytoplasm (GO:0005737), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), dendrite (GO:0030425), vesicle (GO:0031982), perikaryon (GO:0043204)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
RUNX2 regulates bone development	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Post-translational protein modification	1
RNA Polymerase II Transcription	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX2	1

GO top-level categories

50 GO namespaces:

Category	Terms
response to ketone	3
cellular anatomical structure	3
animal gross anatomical part developmental process	2
ossification	2
response to abiotic stimulus	2
response to vitamin	2
response to lipid	2
intracellular organelle lumen	2
system development	1
cell differentiation	1
neurotransmitter secretion	1
regulation of neurotransmitter secretion	1
positive regulation of synaptic transmission	1
positive regulation of neurotransmitter transport	1
positive regulation of secretion by cell	1
cellular process	1
central nervous system development	1
animal organ development	1
head development	1
behavior	1
cognition	1
response to chemical	1
response to external stimulus	1
response to metal ion	1
response to stimulus	1
biomineral tissue development	1
regulation of ossification	1
bone mineralization	1
regulation of biomineral tissue development	1
response to insulin	1
cellular response to peptide hormone stimulus	1
response to oxygen-containing compound	1
response to phenylpropanoid	1
cellular response to starvation	1
response to zinc ion starvation	1
response to cytokine	1
receptor ligand activity	1
molecular_function	1
metal ion binding	1
structural molecule activity	1
small molecule binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
endoplasmic reticulum	1
Golgi apparatus	1
neuron projection	1
dendritic tree	1
membrane-bounded organelle	1
neuronal cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 56 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
osteoblast differentiation	BP	expression pattern
response to vitamin D	BP	expression pattern
cytoplasm	CC	direct assay

Protein interactions and networks

STRING

showing 16 of 1,986 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BGLAP	RUNX2	Q13950	977
BGLAP	IBSP	P21815	953
BGLAP	SPP1	P10451	947
BGLAP	PTH	P01270	930
BGLAP	BMP2	P12643	930
BGLAP	ALPL	P05186	924
BGLAP	TNFSF11	O14788	916
BGLAP	MGP	P08493	890
BGLAP	TNFRSF11B	O00300	887
BGLAP	SP7	Q8TDD2	884
BGLAP	ACP5	P13686	881
BGLAP	COL1A1	P02452	876
BGLAP	SPARC	P09486	869
BGLAP	GGCX	P38435	866
BGLAP	MSX2	P35548	861
BGLAP	SOST	Q9BQB4	861

IntAct

Human interaction partners of BGLAP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
ASPH	physical association	0.560	3
HSPA5	association	0.350	1

BioGRID (10 interactions; top human partners by supporting records): ASPH (Two-hybrid), CBX5 (Affinity Capture-MS), GRN (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), POC1A (Affinity Capture-MS), POLI (Reconstituted Complex), RUNX2 (Co-localization), SEH1L (Affinity Capture-MS), SPPL3 (Positive Genetic)

SIGNOR signaling

showing 12 of 16 signaling interactions:

A	Effect	B	Mechanism
RUNX2	“up-regulates quantity by expression”	BGLAP	“transcriptional regulation”
TGFB1	“down-regulates quantity by repression”	BGLAP	“transcriptional regulation”
SMOC1	“up-regulates quantity by expression”	BGLAP	“transcriptional regulation”
GGCX	“up-regulates activity”	BGLAP	carboxylation
SP7	“up-regulates quantity by expression”	BGLAP	“transcriptional regulation”
ETS2	“up-regulates quantity by expression”	BGLAP	“transcriptional regulation”
RUNX2/EP300	“up-regulates quantity by expression”	BGLAP	“transcriptional regulation”
CTSB	“down-regulates quantity by destabilization”	BGLAP	cleavage
CTSD	“down-regulates quantity by destabilization”	BGLAP	cleavage
CTSL	“down-regulates quantity by destabilization”	BGLAP	cleavage
CTSS	“down-regulates quantity by destabilization”	BGLAP	cleavage
CTSH	“down-regulates quantity by destabilization”	BGLAP	cleavage

Disease & clinical

Genetic variants

Variant evidence for BGLAP: 22 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 18 predictions of 222):

Position(s)	Effect	Δscore	Sites
1:156242296	donor_loss	1.0000
1:156242552	acceptor_loss	1.0000
1:156242296–156242297	donor_loss	0.9900	3
1:156242551	acceptor_loss	0.9900
1:156242293	donor_gain	0.9800
1:156242551–156242552	acceptor_loss	0.9800	3
1:156242297	donor_loss	0.9700
1:156242592–156242593	donor_loss	0.9500	4
1:156243032	acceptor_gain	0.9500
1:156242592–156242593	donor_loss	0.9400	2

AlphaMissense

149 missense substitutions predicted likely pathogenic (of 636 scored), across 38 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D81	8	0.900	0.966
C74	7	0.989	0.996
C80	7	0.989	0.996
E75	7	0.929	0.968
E72	7	0.916	0.954
F96	7	0.888	0.974
F89	7	0.841	0.988
E68	7	0.815	0.915
G88	6	0.881	0.984
A92	6	0.833	0.974
F36	6	0.823	0.942
E82	6	0.636	0.728
Y93	5	0.937	0.977
R71	5	0.855	0.927
Y97	5	0.830	0.929
D85	5	0.813	0.894
A84	4	0.946	0.988
G98	4	0.881	0.950
L83	4	0.867	0.969
R48	4	0.755	0.837

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Ovary Serous Cystadenocarcinoma (TCGA)	favorable	0.000182

Disease associations

OMIM: gene MIM:112260 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST009067_23	Mosaic loss of chromosome Y (Y chromosome dosage)	3e-88
GCST000582_7	Mean corpuscular hemoglobin concentration	3e-9
GCST007344_129	Estimated glomerular filtration rate	1e-8
GCST003013_36	White matter hyperintensity burden	2e-8

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0005665	white matter hyperintensity measurement
EFO:0007783	mosaic loss of chromosome Y measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1800247	dexamethasone	Toxicity	Genotypes CT + TT are not associated with increased risk of Osteonecrosis when treated with dexamethasone in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC.	PMID:18285546

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Calcitriol	increases reaction, increases secretion, affects cotreatment, affects binding, decreases reaction (+1 more)	8
Dexamethasone	increases expression, decreases secretion, increases secretion, affects cotreatment, decreases reaction	6
beta-glycerophosphoric acid	increases secretion, affects cotreatment, decreases reaction, increases expression	5
Simvastatin	increases expression, increases secretion	5
Resveratrol	decreases reaction, increases expression, affects cotreatment	4
ascorbate-2-phosphate	increases secretion, affects cotreatment, decreases reaction, increases expression	3
Ascorbic Acid	affects cotreatment, increases expression, decreases reaction	3
Beclomethasone	decreases expression	3
Cadmium	decreases expression, decreases secretion, increases expression, decreases reaction	3
Sodium Fluoride	affects reaction, increases expression, decreases expression	3
Valproic Acid	affects cotreatment, decreases expression, affects expression	3
cobaltiprotoporphyrin	affects cotreatment, increases expression, decreases reaction, decreases secretion	2
fucoxanthin	increases secretion, decreases reaction, decreases secretion	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression, decreases expression	2
U 0126	decreases reaction, decreases expression	2
dorsomorphin	increases expression, decreases expression, affects cotreatment, decreases reaction	2
neohesperidin	increases expression, decreases reaction	2
CRT 0066101	decreases reaction, increases expression, decreases expression	2
Fulvestrant	decreases reaction, increases expression	2
Cholecalciferol	affects cotreatment, increases expression, increases secretion	2
Estradiol	affects cotreatment, increases expression, decreases reaction	2
Hydrogen Peroxide	decreases reaction, decreases expression, increases expression	2
Lead	decreases reaction, decreases secretion	2
Quercetin	decreases reaction, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	affects expression	2
Vitamin K 2	decreases expression, decreases reaction	2
protosappanin B	increases expression	1
kuntai capsule	affects cotreatment, affects expression	1
daidzein	affects cotreatment, increases expression	1
naringin	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

5 trials:

NCT	Phase	Status	Title
NCT02096965	Phase 1	COMPLETED	Use of Tolvaptan to Reduce Urinary Supersaturation: a Pilot Proof of Principle Study
NCT00381849	Phase 1/2	COMPLETED	Use of an Herbal Preparation to Prevent and Dissolve Kidney Stones
NCT06330246	Not specified	RECRUITING	O. Formigenes Colonization in Calcium Oxalate Kidney Stone Disease
NCT06331546	Not specified	RECRUITING	Gut Oxalate Absorption in Calcium Oxalate Stone Disease
NCT06989320	Not specified	RECRUITING	Endogenous Oxalate Synthesis in Idiopathic Calcium Oxalate Kidney Stone Disease