SOST

Summary

SOST (sclerostin, HGNC:13771) is a protein-coding gene on chromosome 17q21.31, encoding Sclerostin (Q9BQB4). Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.

Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Loss-of-function mutations in this gene are associated with an autosomal-recessive disorder, sclerosteosis, which causes progressive bone overgrowth. A deletion downstream of this gene, which causes reduced sclerostin expression, is associated with a milder form of the disorder called van Buchem disease.

Source: NCBI Gene 50964 — RefSeq curated summary.

At a glance

• Gene–disease (curated): sclerosteosis 1 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 105 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_025237

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13771
Approved symbol	SOST
Name	sclerostin
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	VBCH, DAND6
Ensembl gene	ENSG00000167941
Ensembl biotype	protein_coding
OMIM	605740
Entrez	50964

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000301691

RefSeq mRNA: 1 — MANE Select: NM_025237 NM_025237

CCDS: CCDS11468

Canonical transcript exons

ENST00000301691 — 2 exons

Exon	Start	End
ENSE00001118564	43753738	43755763
ENSE00001118566	43758522	43758791

Expression profiles

Bgee: expression breadth broad, 73 present calls, max score 91.23.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9510 / max 717.4870, expressed in 210 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166271	6.9192	210
166269	0.0157	10
166268	0.0089	3
166267	0.0071	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	91.23	gold quality
descending thoracic aorta	UBERON:0002345	91.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.52	silver quality
tibia	UBERON:0000979	88.09	gold quality
thoracic aorta	UBERON:0001515	86.59	gold quality
ascending aorta	UBERON:0001496	86.24	gold quality
aorta	UBERON:0000947	83.96	gold quality
popliteal artery	UBERON:0002250	82.00	gold quality
right coronary artery	UBERON:0001625	81.93	gold quality
tibial artery	UBERON:0007610	81.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.21	gold quality
artery	UBERON:0001637	79.53	gold quality
kidney epithelium	UBERON:0004819	74.01	silver quality
adult mammalian kidney	UBERON:0000082	71.76	gold quality
kidney	UBERON:0002113	70.07	gold quality
coronary artery	UBERON:0001621	64.11	gold quality
left coronary artery	UBERON:0001626	63.58	gold quality
secondary oocyte	CL:0000655	61.76	silver quality
metanephros	UBERON:0000081	58.15	gold quality
renal medulla	UBERON:0000362	56.86	gold quality
buccal mucosa cell	CL:0002336	56.28	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
cortex of kidney	UBERON:0001225	53.99	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
bone element	UBERON:0001474	53.39	gold quality
right atrium auricular region	UBERON:0006631	53.09	gold quality
cardiac atrium	UBERON:0002081	53.00	gold quality
epithelial cell of pancreas	CL:0000083	52.91	gold quality
adult organism	UBERON:0007023	52.19	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	2445.80
E-HCAD-10	yes	21.44
E-ANND-3	no	3.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, FOXO3, HEY1, HIF1A, MEF2A, MEF2B, MEF2C, MEF2D, MSX2, PAX6, RUNX2, SMAD9, SP7

miRNA regulators (miRDB)

104 targeting SOST, 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-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AE-3P	99.93	72.66	4867

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A 52 kb deletion has been identified downstream of the SOST gene in patients with van Buchem disease. (PMID:11836356)
• Decreases BMP signaling and suppresses mineralization of osteoblastic cells. (PMID:14633986)
• The regulation of SOST expression by Cbfa1 suggests a potential role for the sclerosteosis gene in homeostatic regulation of osteoblast differentiation and function. (PMID:14739291)
• The ability of sclerostin to interact with important growth factors such as bone morphogenetic proteins likely serves as the basis by which it modulates the survival of osteoblasts (PMID:15454089)
• sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces (PMID:16123173)
• Heterozygous carriers of sclerosteosis have bone mineral density consistently higher than mean of healthy subjects without any bone complications encountered in homozygotes. Of obvious significance for the development of new therapeutics for osteoporosis. (PMID:16189254)
• functional interactions between Sost or Wise and LRP5 have the potential to regulate bone deposition by modulating Wnt signaling (PMID:17002572)
• SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases (PMID:17052975)
• Van Buchem disease and sclerosteosis are confirmed to be allelic disorders as both are shown to be due to loss of function of sclerostin protein. (PMID:17185822)
• high bone mass in sclerosteosis and Van Buchem disease may result from increased Wnt signaling due to the absence of or insensitivity to sclerostin. (PMID:18292354)
• the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer. (PMID:18931653)
• mutation analysis of the SOST gene showing a homozygous nonsense mutation (Trp124X) in two cases of sclerosteosis (PMID:19072561)
• S1P induces osteoblast precursor recruitment and promotes mature cell survival. Wnt10b and BMP6 also were significantly increased in mature osteoclasts, whereas sclerostin levels decreased during differentiation. (PMID:19075223)
• Data show that the conserved N- and C-terminal arms of sclerostin are unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins. (PMID:19208630)
• These data suggest a mechanistic link between rs1230399 and bone mineral density through estrogen ERalpha/FOXA1 signaling pathways driven by long-distance enhancers. (PMID:19371798)
• Expression of sclerostin was demonstrated in osteocytes of mouse and human alveolar bone. Distinct immunolocalization in cementocytes was shown. In periodontal ligament cultures, following mineralization treatment, increasing levels of SOST was verified. (PMID:19778325)
• The amino-terminal (IgG 2aK) and carboxy-terminal (IgG 2bK) antibodies bound bioactive sclerostin that was expressed in an insect-cell expression system with dissociation constants in the nanomolar range (PMID:19857121)
• Sclerostin expression is impaired in patients with ankylosing spondylitis, suggesting a specific alteration of osteocyte function in this disease. (PMID:19877044)
• results suggest that SNP in SOST is not associated with bone mineral density in the Slovenian population (PMID:19898734)
• Lrp4 is a novel osteoblast expressed Dkk1 and sclerostin receptor with a physiological role in the regulation of bone growth and turnover (PMID:19936252)
• The data show that sclerostin binds to and influences the activity of Cyr61. (PMID:20043874)
• Our findings suggest that serum sclerostin levels are regulated by both estrogens and parathyroid hormone in postmenopausal women (PMID:20156921)
• Sclerostin appears to be a strong determinant of whether osteoblasts actively produce bone. (PMID:20200987)
• Long-term immobilized patients present hypersclerostinemia associated with reduced bone formation, suggesting that sclerostin may be a link between mechanical unloading and disuse osteoporosis in humans. (PMID:20305005)
• data suggest that hypoxia inhibits sclerostin expression, through enhanced antagonism of BMP signaling independent of VEGF (PMID:20336693)
• Overexpression of SOST leads to loss of posterior structures of the zeugopod and autopod by perturbing anterior-posterior and proximal-distal signaling centers in the developing limb in transgenic mice. (PMID:20359476)
• Circulating sclerostin levels are reduced by estrogen but not by testosterone. (PMID:20499362)
• Study identified a missense mutation (c.499T>C; p.Cys167Arg) in exon 2 of the SOST gene in sclerosteosiss patients. (PMID:20583295)
• circulating sclerostin levels depend on age, gender and bone mass (PMID:20721932)
• Circulating SOST levels are lower in patients with chronic hyperparathyroidism compared to parathyroidectomy controls, a negative correlation that may demonstrate the downregulation of SOST by parathyroid hormone in humans. (PMID:20817762)
• The data demonstrate that sclerostin functions in part, by modulating the activity of erbB-3. (PMID:20951118)
• when both proteins are expressed in the same cell, sclerostin can antagonize BMP signaling directly by inhibiting BMP7 secretion (PMID:20952383)
• TWEAK and TNF regulation of sclerostin: a novel pathway for the regulation of bone remodelling (PMID:21153337)
• Sclerostin was superior to intact parathyroid hormone for the positive prediction of high bone turnover and number of osteoblasts (PMID:21164019)
• craniodiaphyseal dysplasia, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. (PMID:21221996)
• Sclerostin acts through regulation of the PHEX/MEPE axis at the preosteocyte stage and serves as a master regulator of physiologic bone mineralization. (PMID:21312267)
• an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing (PMID:21347301)
• Increased bone mass in Lrp5-high bone mass patients seems to be caused primarily by changes in trabecular and cortical bone mass and structure. (PMID:21351148)
• polymorphisms in the 5’ region of the SOST gene are associated with bone mineral density in postmenopausal women. (PMID:21441835)
• the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone. (PMID:21471202)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sost	ENSDARG00000061259
mus_musculus	Sost	ENSMUSG00000001494
rattus_norvegicus	Sost	ENSRNOG00000071073

Paralogs (1): SOSTDC1 (ENSG00000171243)

Protein

Protein identifiers

Sclerostin — Q9BQB4 (reviewed: Q9BQB4)

All UniProt accessions (1): Q9BQB4

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.

Subunit / interactions. Interacts with LRP4 (via the extracellular domain); the interaction facilitates the inhibition of Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains); the interaction inhibits Wnt-mediated signaling. Interacts with LRP6.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Widely expressed at low levels with highest levels in bone, cartilage, kidney, liver, bone marrow and primary osteoblasts differentiated for 21 days. Detected in the subendothelial layer of the aortic intima (at protein level).

Disease relevance. Sclerosteosis 1 (SOST1) [MIM:269500] An autosomal recessive sclerosing bone dysplasia characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. The disease is caused by variants affecting the gene represented in this entry. Van Buchem disease (VBCH) [MIM:239100] VBCH is an autosomal recessive sclerosing bone dysplasia characterized by endosteal hyperostosis of the mandible, skull, ribs, clavicles, and diaphyses of the long bones. Affected patients present a symmetrically increased thickness of bones, most frequently found as an enlarged jawbone, but also an enlargement of the skull, ribs, diaphysis of long bones, as well as tubular bones of hands and feet. The clinical consequence of increased thickness of the skull include facial nerve palsy causing hearing loss, visual problems, neurological pain, and, very rarely, blindness as a consequence of optic atrophy. Serum alkaline phosphatase levels are elevated. The disease is caused by variants affecting the gene represented in this entry. A 52 kb deletion downstream of SOST results in SOST transcription suppression causing van Buchem disease. Craniodiaphyseal dysplasia autosomal dominant (CDD) [MIM:122860] A severe bone dysplasia characterized by massive generalized hyperostosis and sclerosis, especially involving the skull and facial bones. The sclerosis is so severe that the resulting facial distortion is referred to as ’leontiasis ossea’ (leonine faces) and the bone deposition results in progressive stenosis of craniofacial foramina. Respiratory obstruction due to choanal stenosis compromises the clinical outcomes of affected patients. The disease is caused by variants affecting the gene represented in this entry. Heterozygous mutations located in the secretion signal of the SOST gene prevent sclerostin secretion and can be responsible for craniodiaphyseal dysplasia.

Similarity. Belongs to the sclerostin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BQB4-1	1	yes
Q9BQB4-2	2

RefSeq proteins (1): NP_079513* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006207	Cys_knot_C	Domain
IPR008835	Sclerostin/SOSTDC1	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF05463

UniProt features (22 total): strand 6, disulfide bond 4, sequence variant 3, region of interest 2, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3SOV	X-RAY DIFFRACTION	1.27
6L6R	X-RAY DIFFRACTION	3.8
2K8P	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQB4-F1	70.73	0.25

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 (4): 105–165, 109–167, 80–134, 94–148

Glycosylation sites (2): 53, 175

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-3772470	Negative regulation of TCF-dependent signaling by WNT ligand antagonists
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT

MSigDB gene sets: 276 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, MYAATNNNNNNNGGC_UNKNOWN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, MYOGENIN_Q6, GCANCTGNY_MYOD_Q6, AP4_Q6, RACCACAR_AML_Q6, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, CCANNAGRKGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MYOD_01

GO Biological Process (12): ossification (GO:0001503), response to mechanical stimulus (GO:0009612), negative regulation of Wnt signaling pathway (GO:0030178), negative regulation of ossification (GO:0030279), BMP signaling pathway (GO:0030509), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of DNA-templated transcription (GO:0045893), canonical Wnt signaling pathway (GO:0060070), cellular response to parathyroid hormone stimulus (GO:0071374), negative regulation of canonical Wnt signaling pathway (GO:0090090), Wnt signaling pathway (GO:0016055)

GO Molecular Function (6): heparin binding (GO:0008201), carbohydrate binding (GO:0030246), BMP binding (GO:0036122), DNA-binding transcription factor binding (GO:0140297), molecular function inhibitor activity (GO:0140678), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by WNT	1
TCF dependent signaling in response to WNT	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	2
binding	2
multicellular organismal process	1
response to external stimulus	1
response to abiotic stimulus	1
negative regulation of signal transduction	1
regulation of Wnt signaling pathway	1
ossification	1
regulation of ossification	1
negative regulation of multicellular organismal process	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cellular response to hormone stimulus	1
response to parathyroid hormone	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
cell surface receptor signaling pathway	1
glycosaminoglycan binding	1
sulfur compound binding	1
cytokine binding	1
transcription factor binding	1
molecular function regulator activity	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular_component	1

Protein interactions and networks

STRING

2228 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOST	LRP5	O75197	999
SOST	LRP6	O75581	998
SOST	DKK1	O94907	958
SOST	TNFSF11	O14788	928
SOST	PTH	P01270	887
SOST	BMP4	P12644	872
SOST	BGLAP	P02818	871
SOST	SP7	Q8TDD2	857
SOST	BMP6	P22004	851
SOST	PTH1R	Q03431	851
SOST	CTNNB1	P35222	842
SOST	DKK2	Q9UBU2	832
SOST	NOG	Q13253	822
SOST	FGF23	Q9GZV9	819
SOST	BMP7	P18075	814

IntAct

22 interactions, top by confidence:

A	B	Type	Score
LRP6	SOST	psi-mi:“MI:0407”(direct interaction)	0.890
SOST	LRP6	psi-mi:“MI:0914”(association)	0.890
SOST	LRP6	psi-mi:“MI:0915”(physical association)	0.890
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
SOST	LRP4	psi-mi:“MI:0914”(association)	0.790
LRP4	SOST	psi-mi:“MI:0407”(direct interaction)	0.790
SOST	LRP4	psi-mi:“MI:0407”(direct interaction)	0.790
SOST	LRP4	psi-mi:“MI:0915”(physical association)	0.790
SOST	LRP5	psi-mi:“MI:0915”(physical association)	0.740
SOST	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
SOST	KPNA4	psi-mi:“MI:0914”(association)	0.530
SOST	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
SOST		psi-mi:“MI:0914”(association)	0.350
CTAG2	LAMB2	psi-mi:“MI:0914”(association)	0.350
TMEM98	PDGFRB	psi-mi:“MI:0914”(association)	0.350
SOST	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (167): LRP6 (Affinity Capture-MS), CSH2 (Affinity Capture-MS), LRP5 (Affinity Capture-MS), SPOP (Affinity Capture-MS), SRRT (Affinity Capture-MS), SIRT1 (Affinity Capture-MS), GTF2I (Affinity Capture-MS), PSMG2 (Affinity Capture-MS), DCAF5 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), GLDC (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), LRP4 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), IMPDH1 (Affinity Capture-MS)

ESM2 similar proteins: B0VXV3, B0VXV4, C0K3N1, E1ZVK1, F1QCY8, O35485, P0DW98, P15304, P26342, P35054, P43027, P49764, P49765, P49766, P67861, P67862, P67863, P85315, P98153, P98154, Q05469, Q1RMT9, Q28H35, Q2TAL6, Q330K6, Q56A20, Q5BIR3, Q5R7R7, Q5RCS3, Q5RD34, Q5VUB5, Q63434, Q6J936, Q800X4, Q8C8N3, Q90X23, Q90X24, Q91ZV2, Q92563, Q96FE7

Diamond homologs: Q5R5D2, Q642G2, Q6VYA3, Q6X4U4, Q99P67, Q99P68, Q9BG78, Q9BG79, Q9BQB4, Q9CQN4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
BMPR1A	up-regulates	SOST
SOST	down-regulates	WNT3A
PTH1R	“down-regulates quantity”	SOST

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	57
Likely benign	22
Benign	7

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1342991	NM_025237.3(SOST):c.87dup (p.Lys30fs)	Pathogenic
31593	NM_025237.3(SOST):c.61G>T (p.Val21Leu)	Pathogenic
4783	NM_025237.3(SOST):c.70C>T (p.Gln24Ter)	Pathogenic
4785	NM_025237.3(SOST):c.372G>A (p.Trp124Ter)	Pathogenic
4786	NM_025237.3(SOST):c.376C>T (p.Arg126Ter)	Pathogenic
2583091	NM_025237.3(SOST):c.327C>A (p.Cys109Ter)	Likely pathogenic
31592	NM_025237.3(SOST):c.61G>A (p.Val21Met)	Likely pathogenic

SpliceAI

188 predictions. Top by Δscore:

Variant	Effect	Δscore
17:43755759:CACGT:C	acceptor_gain	1.0000
17:43755760:ACGT:A	acceptor_gain	1.0000
17:43755761:CGT:C	acceptor_gain	1.0000
17:43755761:CGTC:C	acceptor_gain	1.0000
17:43755762:GT:G	acceptor_gain	1.0000
17:43755763:TC:T	acceptor_loss	1.0000
17:43755764:C:CC	acceptor_gain	1.0000
17:43755764:C:T	acceptor_loss	1.0000
17:43755765:T:G	acceptor_loss	1.0000
17:43758516:CCATA:C	donor_loss	1.0000
17:43758517:CATAC:C	donor_loss	1.0000
17:43758518:ATAC:A	donor_loss	1.0000
17:43758519:TA:T	donor_loss	1.0000
17:43758520:A:C	donor_loss	1.0000
17:43758521:C:G	donor_loss	1.0000
17:43758556:T:TA	donor_gain	0.9900
17:43755766:G:C	acceptor_gain	0.9800
17:43755766:G:GC	acceptor_gain	0.9700
17:43758553:C:CA	donor_gain	0.9700
17:43755760:ACGTC:A	acceptor_gain	0.9600
17:43755761:CGTCT:C	acceptor_gain	0.9600
17:43755762:GTCT:G	acceptor_gain	0.9600
17:43755763:TCTGT:T	acceptor_gain	0.9600
17:43755764:CTGT:C	acceptor_gain	0.9400
17:43758520:A:AC	donor_gain	0.9300
17:43758521:C:CC	donor_gain	0.9300
17:43757199:T:TA	donor_gain	0.8900
17:43755765:T:A	acceptor_gain	0.8800
17:43758619:T:A	donor_gain	0.8600
17:43758521:CCT:C	donor_gain	0.8400

AlphaMissense

1367 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:43755480:C:A	K168N	0.998
17:43755480:C:G	K168N	0.998
17:43755484:C:G	C167S	0.998
17:43755485:A:T	C167S	0.998
17:43755583:C:G	C134S	0.998
17:43755584:A:T	C134S	0.998
17:43755670:C:G	C105S	0.998
17:43755671:A:T	C105S	0.998
17:43755490:C:G	C165S	0.997
17:43755490:C:T	C165Y	0.997
17:43755491:A:T	C165S	0.997
17:43755584:A:G	C134R	0.997
17:43755670:C:T	C105Y	0.997
17:43755671:A:G	C105R	0.997
17:43755489:G:C	C165W	0.996
17:43755582:G:C	C134W	0.996
17:43755583:C:T	C134Y	0.996
17:43755658:C:G	C109S	0.996
17:43755659:A:T	C109S	0.996
17:43755669:G:C	C105W	0.996
17:43755696:G:C	S96R	0.996
17:43755696:G:T	S96R	0.996
17:43755698:T:G	S96R	0.996
17:43755745:C:G	C80S	0.996
17:43755745:C:T	C80Y	0.996
17:43755746:A:T	C80S	0.996
17:43755485:A:G	C167R	0.995
17:43755491:A:G	C165R	0.995
17:43755490:C:A	C165F	0.994
17:43755583:C:A	C134F	0.994

dbSNP variants (sampled 300 via entrez): RS1000004963 (17:43755941 C>G), RS1000772545 (17:43759348 T>C), RS1000807536 (17:43760711 T>C), RS1001415547 (17:43754409 C>G), RS1001975810 (17:43754386 G>A,C), RS1002054418 (17:43760645 A>C,T), RS1002080063 (17:43757630 G>A), RS1002572283 (17:43760374 C>T), RS1002600993 (17:43757246 G>T), RS1003061696 (17:43757460 C>A,T), RS1003605850 (17:43755506 G>A,T), RS1004221324 (17:43755470 G>A,T), RS1004222814 (17:43758837 A>G), RS1005179768 (17:43755796 C>T), RS1006003802 (17:43756856 A>G)

Disease associations

OMIM: gene MIM:605740 | disease phenotypes: MIM:269500, MIM:122860

GenCC curated gene-disease

Disease	Classification	Inheritance
sclerosteosis 1	Strong	Autosomal recessive
craniodiaphyseal dysplasia	Supportive	Autosomal dominant
sclerosteosis	Supportive	Autosomal recessive
hyperostosis corticalis generalisata	Supportive	Autosomal dominant
craniodiaphyseal dysplasia, autosomal dominant	Limited	Unknown

Mondo (5): sclerosteosis 1 (MONDO:0010016), craniodiaphyseal dysplasia, autosomal dominant (MONDO:0021021), craniodiaphyseal dysplasia (MONDO:0009031), sclerosteosis (MONDO:0017838), hyperostosis corticalis generalisata (MONDO:0009395)

Orphanet (2): Sclerosteosis (Orphanet:3152), Craniodiaphyseal dysplasia (Orphanet:1513)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000098	Tall stature
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000336	Prominent supraorbital ridges
HP:0000365	Hearing impairment
HP:0000366	Abnormality of the nose
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000452	Choanal stenosis
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000529	Progressive visual loss
HP:0000565	Esotropia
HP:0000572	Visual loss
HP:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000689	Dental malocclusion
HP:0000692	Tooth malposition
HP:0000772	Abnormal rib morphology
HP:0000858	Irregular menstruation
HP:0000885	Broad ribs
HP:0000889	Abnormal clavicle morphology

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000297_1	Bone mineral density (hip)	2.000000e-08
GCST002897_7	Triglycerides	8.000000e-13
GCST002899_38	HDL cholesterol	1.000000e-14
GCST003388_4	Bone mineral density (spine)	6.000000e-09
GCST003388_7	Bone mineral density (spine)	3.000000e-06
GCST003389_1	Bone mineral density (hip)	5.000000e-10
GCST003389_5	Bone mineral density (hip)	4.000000e-08
GCST003389_6	Bone mineral density (hip)	1.000000e-06
GCST003389_7	Bone mineral density (hip)	1.000000e-06
GCST003660_18	HDL cholesterol	1.000000e-11
GCST004606_33	Eosinophil count	2.000000e-10
GCST004624_14	Sum eosinophil basophil counts	8.000000e-10
GCST005795_7	Femoral neck bone mineral density	3.000000e-11
GCST005796_30	Lumbar spine bone mineral density	5.000000e-09
GCST006288_288	Heel bone mineral density	2.000000e-36
GCST006288_289	Heel bone mineral density	1.000000e-26
GCST006288_357	Heel bone mineral density	8.000000e-13
GCST006288_358	Heel bone mineral density	2.000000e-08
GCST006288_55	Heel bone mineral density	2.000000e-24
GCST006288_56	Heel bone mineral density	1.000000e-18
GCST006423_13	Fracture	3.000000e-25
GCST006979_819	Heel bone mineral density	1.000000e-29
GCST006979_820	Heel bone mineral density	3.000000e-60
GCST006980_12	Fracture	5.000000e-41
GCST007691_17	Femoral neck bone mineral density	2.000000e-11
GCST011348_50	High density lipoprotein cholesterol levels	2.000000e-41

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007701	spine bone mineral density
EFO:0007702	hip bone mineral density
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0007785	femoral neck bone mineral density
EFO:0009270	heel bone mineral density

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C562940	Craniodiaphyseal Dysplasia (supp.)
C567275	Craniodiaphyseal Dysplasia, Autosomal Dominant (supp.)
C537525	Sclerosteosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3580487 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 262,520 (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
CHEMBL311498	CIANIDANOL	4	59,647
CHEMBL6466	COUMARIN	4	202,873

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs865429	SOST		0.00	0
rs1234612	SOST		0.00	0

ChEMBL bioactivities

40 potent at pChembl≥5 of 41 total, top 40 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.81	Kd	15.4	nM	CHEMBL5558704
7.71	Kd	19.6	nM	CHEMBL5558704
7.70	IC50	20	nM	CHEMBL4448674
7.70	IC50	20	nM	CHEMBL4475291
7.70	IC50	20	nM	CHEMBL4455231
7.70	IC50	20	nM	CHEMBL4544777
7.70	IC50	20	nM	CHEMBL4459781
7.70	IC50	20	nM	CHEMBL4448063
7.47	EC50	34.2	nM	CHEMBL4546624
7.42	Kd	37.66	nM	CHEMBL2021342
7.37	Kd	42.43	nM	CHEMBL2021342
7.28	EC50	52.7	nM	CHEMBL4570369
7.22	EC50	60.7	nM	CHEMBL4554919
7.05	EC50	88.3	nM	CHEMBL4454661
6.98	EC50	104	nM	CHEMBL4573551
6.80	EC50	156.7	nM	CHEMBL4458856
6.79	EC50	162.3	nM	CHEMBL4462045
6.67	Kd	211.2	nM	CHEMBL455364
6.64	Kd	230.8	nM	COUMARIN
6.63	Kd	233.7	nM	CHEMBL5531992
6.56	Kd	273.3	nM	COUMARIN
6.40	Kd	397.1	nM	CHEMBL5531959
6.34	Kd	453.6	nM	CHEMBL5531959
6.28	EC50	529	nM	CHEMBL4456989
6.27	Kd	531.9	nM	CHEMBL455364
6.10	EC50	802	nM	CHEMBL4450022
6.07	EC50	861	nM	CHEMBL4545471
6.02	Kd	960	nM	CHEMBL5531992
5.93	Kd	1180	nM	CHEMBL5531992
5.82	IC50	1500	nM	CHEMBL4462260
5.82	IC50	1500	nM	OCOTEINE
5.82	IC50	1500	nM	CHEMBL1560685
5.82	IC50	1500	nM	CHEMBL464955
5.80	Kd	1579	nM	CIANIDANOL
5.79	EC50	1620	nM	CHEMBL4444758
5.73	Kd	1845	nM	CIANIDANOL
5.58	Kd	2632	nM	(+)-EPITAXIFOLIN
5.41	Kd	3900	nM	CHEMBL5559172
5.32	Kd	4782	nM	CHEMBL5559172
5.30	IC50	5000	nM	BOLDINE

PubChem BioAssay actives

18 with measured affinity, of 33 total; 9 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
2-[[4-(3-acetamidoprop-1-ynyl)benzoyl]amino]acetic acid	2063313: Binding affinity to SOST loop3 (unknown origin) by SPR analysis	kd	0.0154	uM
(2S)-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid	2063311: Binding affinity to SOST (unknown origin) by SPR analysis	kd	0.0377	uM
1,3,6,7-tetrahydroxy-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyxanthen-9-one	2063311: Binding affinity to SOST (unknown origin) by SPR analysis	kd	0.2112	uM
Coumarin	2063312: Binding affinity to SOST loop2 (unknown origin) by SPR analysis	kd	0.2308	uM
N-[(4-methyl-3-pyridinyl)methyl]-2-azabicyclo[2.2.2]octane-2-carboxamide	2063311: Binding affinity to SOST (unknown origin) by SPR analysis	kd	0.2337	uM
3-fluoro-N-[2-[1-(oxolan-3-yl)triazol-4-yl]ethyl]benzenesulfonamide	2063311: Binding affinity to SOST (unknown origin) by SPR analysis	kd	0.3971	uM
cianidanol	2063311: Binding affinity to SOST (unknown origin) by SPR analysis	kd	1.5790	uM
(2S,3R)-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-2,3-dihydrochromen-4-one	2063311: Binding affinity to SOST (unknown origin) by SPR analysis	kd	2.6320	uM
(2S,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one	2063312: Binding affinity to SOST loop2 (unknown origin) by SPR analysis	kd	3.9000	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation	2
Valproic Acid	increases expression	2
terbufos	increases methylation	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation, decreases methylation	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
MT19c compound	decreases expression	1
Panobinostat	affects cotreatment, increases expression	1
Bilirubin	decreases expression	1
Calcitriol	increases expression, increases reaction	1
Carbamazepine	affects expression	1
Dexamethasone	increases expression, decreases reaction	1
Diethylhexyl Phthalate	decreases expression	1
Fonofos	increases methylation	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Plant Oils	increases expression	1
Tretinoin	increases expression, increases reaction	1
Triclosan	decreases expression	1
Cadmium Chloride	decreases reaction, increases expression	1
Okadaic Acid	decreases expression	1
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418051	Binding	Inhibition of human sclerostin in MC3T3E1/TetON-Wnt1/STF-Luc#5 cells assessed as sclerostin neutralizing activity by Wnt1-induced TCF/LEF luciferase reporter gene assay	Inhibitory polypeptides specific to WNT inhibitors

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1RQ	HyCyte MDA-MB-231 KO-hSOST	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03861871	PHASE2	COMPLETED	Fenfluramine in CDKL5 Deficiency Disorder (CDD)
NCT05558371	Not specified	RECRUITING	International CDKL5 Clinical Research Network