FRZB

Summary

FRZB (frizzled related protein, HGNC:3959) is a protein-coding gene on chromosome 2q32.1, encoding Secreted frizzled-related protein 3 (Q92765). Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts.

The protein encoded by this gene is a secreted protein that is involved in the regulation of bone development. Defects in this gene are a cause of female-specific osteoarthritis (OA) susceptibility.

Source: NCBI Gene 2487 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 67 total
• Phenotypes (HPO): 2
• MANE Select transcript: NM_001463

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3959
Approved symbol	FRZB
Name	frizzled related protein
Location	2q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FRZB-PEN, FRZB1, SRFP3, FRP-3, SFRP3, FRE, FRITZ, FRZB-1, FZRB, hFIZ
Ensembl gene	ENSG00000162998
Ensembl biotype	protein_coding
OMIM	605083
Entrez	2487

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000295113, ENST00000888345, ENST00000888346, ENST00000957773

RefSeq mRNA: 1 — MANE Select: NM_001463 NM_001463

CCDS: CCDS2286

Canonical transcript exons

ENST00000295113 — 6 exons

Exon	Start	End
ENSE00001070475	182833275	182834965
ENSE00001070476	182838409	182838613
ENSE00001070479	182842478	182842543
ENSE00001156592	182837948	182838011
ENSE00001156606	182858786	182858833
ENSE00001164245	182866075	182866637

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 99.89.

FANTOM5 (CAGE): breadth broad, TPM avg 7.8215 / max 941.1143, expressed in 523 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32757	2.0936	354
32762	2.0655	284
32760	1.5203	330
32759	1.3359	323
32758	0.5456	227
32761	0.1454	70
32756	0.0714	34
202495	0.0437	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.89	gold quality
retina	UBERON:0000966	99.88	gold quality
right coronary artery	UBERON:0001625	98.72	gold quality
blood vessel layer	UBERON:0004797	98.68	gold quality
cartilage tissue	UBERON:0002418	98.58	gold quality
ascending aorta	UBERON:0001496	98.56	gold quality
thoracic aorta	UBERON:0001515	98.54	gold quality
descending thoracic aorta	UBERON:0002345	98.38	gold quality
urethra	UBERON:0000057	97.84	gold quality
calcaneal tendon	UBERON:0003701	97.78	gold quality
aorta	UBERON:0000947	97.63	gold quality
popliteal artery	UBERON:0002250	96.98	gold quality
tibial artery	UBERON:0007610	96.97	gold quality
choroid plexus epithelium	UBERON:0003911	96.81	gold quality
artery	UBERON:0001637	96.76	gold quality
left coronary artery	UBERON:0001626	95.49	gold quality
coronary artery	UBERON:0001621	95.47	gold quality
gall bladder	UBERON:0002110	94.58	gold quality
trachea	UBERON:0003126	94.58	gold quality
tibia	UBERON:0000979	93.45	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.74	gold quality
trigeminal ganglion	UBERON:0001675	92.26	gold quality
placenta	UBERON:0001987	91.96	gold quality
dorsal root ganglion	UBERON:0000044	91.61	gold quality
spleen	UBERON:0002106	91.47	gold quality
superficial temporal artery	UBERON:0001614	90.45	gold quality
hair follicle	UBERON:0002073	90.38	gold quality
trabecular bone tissue	UBERON:0002483	90.30	gold quality
colonic mucosa	UBERON:0000317	89.18	gold quality
body of tongue	UBERON:0011876	89.10	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	6686.29
E-MTAB-7316	yes	5770.28
E-MTAB-9388	yes	4253.40
E-GEOD-135922	yes	3157.03
E-MTAB-7407	yes	2787.26
E-MTAB-8221	yes	2590.41
E-MTAB-9906	yes	2336.11
E-MTAB-10485	yes	2084.45
E-HCAD-11	yes	1096.76
E-HCAD-36	yes	1090.67
E-GEOD-124472	yes	874.83
E-MTAB-6701	yes	788.66
E-ANND-5	yes	699.16
E-MTAB-6911	yes	531.07
E-HCAD-10	yes	62.18

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL11A, CLDN19, CLDN3, CREB1, GLI1, GLI2, MEF2C, TBX2, TBX3

miRNA regulators (miRDB)

106 targeting FRZB, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1297	99.91	73.41	3162

Literature-anchored findings (GeneRIF, showing 40)

• functional polymorphisms within FRZB confer susceptibility for hip osteoarthritis in females and implicate the wnt signaling pathway in the pathogenesis of this disease (PMID:15210948)
• methylation silencing of SFRPs may be one of the important mechanisms of aberrant Wnt signaling activation in MM (PMID:15221014)
• The R324G variant of the FRZB gene is involved in osteoarthritis and has a role in several generalized osteoarthritis phenotypes. (PMID:15818669)
• presence of a small degree of differential allelic expression in a low proportion of individuals studied suggests that polymorphism in FRZB cis-acting regulatory elements can be discounted as a major factor influencing development of osteoarthritis (PMID:16889986)
• The FRZB 200Trp allele may be a marker for ‘‘positive’’ bone phenotype after total hip arthroplasty that is characterized by a positive association with the development of heterotopic ossification and a negative association with osteolysis. (PMID:17600823)
• FRZB suppressed gastric cancer cell proliferation and modulated the balance between proliferation and differentiation in gastric cancer. (PMID:17680269)
• In 60 multiple myeloma patients checked, it was found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. (PMID:17702698)
• The expression of FRZB in gastric cancer is correlated with tumor cell differentiation and tumor Lauren classification. (PMID:18344084)
• No association was seen between FRZB, LRP5 and LRP6 variants with radiographic osteoarthritic outcomes in two population-based cohorts (PMID:18406176)
• Usefulness of Frzb in modulating Met signaling as a new treatment strategy for soft tissue sarcomas. (PMID:18451162)
• Study showed no association between the FRZB polymorphisms or haplotypes and the risk of colorectal cancer or adenoma overall. (PMID:19067193)
• Findings do not support the notion that FRZB rs7775 or rs288326 have any sizable genetic effect on osteoarthritis phenotypes. (PMID:19479880)
• Our results suggest that natural variation in FRZB is not a major contributor to the observed variability in peak bone mineral density in either Chinese females or males (PMID:20043861)
• sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells. (PMID:20160027)
• Loss of WNT pathway inhibition due to SFRP3 gene silencing is associated with medulloblastoma. (PMID:20208569)
• SFRP3 functions as a melanoma migration and invasion suppressor by interfering with Wnt5a signaling. (PMID:21494614)
• Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis. (PMID:22544526)
• Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in human. (PMID:23207650)
• The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni’s correction. (PMID:23516639)
• Studied the expression of TCF/LEF and SFRP family members (SFRP1 and SFRP3) to gain a better understanding of biological signaling pathways responsible for epidemiology and clinical parameters of clear cell RCC (cRCC). (PMID:23572277)
• The compound heterozygosity for mutations in the MFRP gene described in the present study should severely affect the function of MFRP by completely removing the cubilin, LDL-A and frizzled-related CRD domains. (PMID:23742260)
• Data indicate an inverse correlation between osteoarthritis and GREM1, FRZB and DKK1 gene expression. (PMID:24286177)
• There is an association between increased sFRP3 expression and adverse outcome in heart failure. (PMID:24330105)
• Promoter hypermethylation of SFRP3 is a common event hepatocellular carcinoma. (PMID:24591760)
• Our results suggest that the sFRP3 c.970C>G and sFRP4 c.958C>A polymorphisms may be genetic factors associated with the prevalence of osteoporosis at the femoral neck in postmenopausal Korean women. (PMID:24662300)
• FRZB knockdown may upregulate the Wnt/betacatenin pathway and promote aggressiveness in gastric cancer. (PMID:24676361)
• These data indicate an important role of methylation-induced gene silencing of the sFRP gene family in human GBM. (PMID:24948145)
• study indicates that increased expression of both SFRP1 and SFRP3 may contribute to the pathogenesis of IUGR placental dysfunction, whereas the loss of these proteins may be involved in the development of human trophoblastic tumors. (PMID:25046226)
• Data suggest secreted FRP3 (frizzled related protein-3) interacts with ADAM17 (A disintegrin/metalloprotease 17) substrate IL6R (interleukin-6 receptor) release; this interaction is down-regulated in osteoarthritis due to rare double variant in FRP3. (PMID:25846075)
• Intermediate levels of sFRP3 were a predictor of all-cause mortality and re-hospitalization in acute coronary syndromes. (PMID:25920031)
• Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3-FOXO1-Positive Alveolar Rhabdomyosarcoma (PMID:26071485)
• Positive expression of FRZB was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. (PMID:26097596)
• Intermediate SFRP3 levels are associated with better survival and fewer cardiovascular events than low or high SFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic Heart Failure of ischemic origin. (PMID:26288364)
• FRZB expression was up-regulated in hepatocellular carcinoma bone metastasis tissue, which suggested that FRZB might play a key role in the HCC bone metastasis. (PMID:26722540)
• This may suggest that SFRP3 acts as an agonist of Wnt signaling and promotes invasive behavior. (PMID:27035837)
• The secreted frizzled-related protein and disheveled protein family members appear to be actively involved in the pathogenesis of primary testicular germ cell tumors. (PMID:27599467)
• endogenous expression of the WNT antagonists DKK1 and FRZB is necessary for multiple steps during chondrogenesis (PMID:27733096)
• this study shows that sFRP3 regulates fibroblast-like synociocyte transformation (PMID:28151034)
• we observed that FRZB regulates integrin beta1D expression, its silencing increasing integrin beta1D expression to levels similar to those in controls. (PMID:28300015)
• active involvement in placental development and important role in pathology of pregnancy (PMID:28738713)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	frzb	ENSDARG00000018383
mus_musculus	Frzb	ENSMUSG00000027004
rattus_norvegicus	Frzb	ENSRNOG00000007765
drosophila_melanogaster	fz	FBGN0001085
drosophila_melanogaster	fz2	FBGN0016797
drosophila_melanogaster	fz3	FBGN0027343
caenorhabditis_elegans		WBGENE00000478
caenorhabditis_elegans	mom-5	WBGENE00003397
caenorhabditis_elegans		WBGENE00022242

Paralogs (15): FZD3 (ENSG00000104290), SFRP1 (ENSG00000104332), SFRP4 (ENSG00000106483), FZD10 (ENSG00000111432), SFRP5 (ENSG00000120057), SMO (ENSG00000128602), SFRP2 (ENSG00000145423), FZD7 (ENSG00000155760), FZD1 (ENSG00000157240), FZD5 (ENSG00000163251), FZD6 (ENSG00000164930), FZD4 (ENSG00000174804), FZD8 (ENSG00000177283), FZD2 (ENSG00000180340), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Secreted frizzled-related protein 3 — Q92765 (reviewed: Q92765)

Alternative names: Frezzled, Fritz, Frizzled-related protein 1, FrzB-1

All UniProt accessions (2): D9ZGF6, Q92765

UniProt curated annotations — full annotation on UniProt →

Function. Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP3/FRZB appears to be involved in limb skeletogenesis. Antagonist of Wnt8 signaling. Regulates chondrocyte maturation and long bone development.

Subunit / interactions. Interacts with MYOC.

Subcellular location. Secreted.

Tissue specificity. Expressed primarily in the cartilaginous cores of the long bone during embryonic and fetal development and in the appendicular skeleton (6-13 weeks). At 13 weeks of gestation, transcripts were present in early chondroblasts of the tarsal bones of the foot, the carpal bones of the hands and the epiphysis of long bones. Highly expressed in placenta and heart, followed by brain, skeletal muscle, kidney and pancreas. Weakly expressed in lung and liver.

Disease relevance. Osteoarthritis 1 (OS1) [MIM:165720] A degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The FZ domain is involved in binding with Wnt ligands.

Similarity. Belongs to the secreted frizzled-related protein (sFRP) family.

RefSeq proteins (1): NP_001454* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001134	Netrin_domain	Domain
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR015526	Frizzled/SFRP	Family
IPR018933	Netrin_module_non-TIMP	Domain
IPR020067	Frizzled_dom	Domain
IPR035813	NTR_Sfrp3	Domain
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR041759	SFRP3_CRD	Domain

Pfam: PF01392, PF01759

UniProt features (17 total): disulfide bond 5, sequence variant 2, sequence conflict 2, domain 2, compositionally biased region 2, signal peptide 1, chain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92765-F1	81.00	0.54

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 (5): 80–119, 108–147, 112–136, 35–96, 43–89

Glycosylation sites (1): 49

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 261 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, MACLACHLAN_BRCA1_TARGETS_DN, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, MODULE_64

GO Biological Process (22): skeletal system development (GO:0001501), epithelial cell development (GO:0002064), negative regulation of cell population proliferation (GO:0008285), negative regulation of cell development (GO:0010721), neural crest cell differentiation (GO:0014033), negative regulation of Wnt signaling pathway (GO:0030178), negative regulation of cell growth (GO:0030308), non-canonical Wnt signaling pathway (GO:0035567), positive regulation of apoptotic process (GO:0043065), positive regulation of fat cell differentiation (GO:0045600), convergent extension involved in organogenesis (GO:0060029), canonical Wnt signaling pathway (GO:0060070), negative regulation of cartilage development (GO:0061037), somite development (GO:0061053), hepatocyte differentiation (GO:0070365), negative regulation of hepatocyte differentiation (GO:0070367), negative regulation of canonical Wnt signaling pathway (GO:0090090), cochlea morphogenesis (GO:0090103), Wnt signaling pathway (GO:0016055), cell differentiation (GO:0030154), inner ear morphogenesis (GO:0042472), regulation of cell differentiation (GO:0045595)

GO Molecular Function (2): Wnt-protein binding (GO:0017147), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), membrane (GO:0016020), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	3
cellular anatomical structure	3
epithelial cell differentiation	2
cell development	2
negative regulation of cellular process	2
negative regulation of multicellular organismal process	2
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cell differentiation	1
regulation of cell development	1
mesenchymal cell differentiation	1
stem cell differentiation	1
negative regulation of signal transduction	1
regulation of Wnt signaling pathway	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
animal organ development	1
convergent extension	1
negative regulation of developmental process	1
cartilage development	1
regulation of cartilage development	1
embryo development	1
epithelium development	1
liver development	1
negative regulation of epithelial cell differentiation	1
hepatocyte differentiation	1
regulation of hepatocyte differentiation	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
inner ear morphogenesis	1
embryonic morphogenesis	1

Protein interactions and networks

STRING

1838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRZB	MATN3	O15232	953
FRZB	WIF1	Q9Y5W5	894
FRZB	ASPN	Q9BXN1	890
FRZB	CTDSP2	O14595	886
FRZB	DKK1	O94907	869
FRZB	DKK2	Q9UBU2	827
FRZB	DKK4	Q9UBT3	823
FRZB	CTNNB1	P35222	809
FRZB	LRP5	O75197	785
FRZB	GDF5	P43026	764
FRZB	WNT1	P04628	752
FRZB	WNT5A	P41221	739
FRZB	TNFAIP6	P98066	714
FRZB	GSK3B	P49841	688
FRZB	ANKRD42	Q8N9B4	650

IntAct

14 interactions, top by confidence:

A	B	Type	Score
CYSRT1	FRZB	psi-mi:“MI:0915”(physical association)	0.560
FRZB	SMC3	psi-mi:“MI:0915”(physical association)	0.400
BBS10	FRZB	psi-mi:“MI:0915”(physical association)	0.370
FRZB	EHF	psi-mi:“MI:0915”(physical association)	0.370
FRZB	ELF5	psi-mi:“MI:0915”(physical association)	0.370
PNO1	FRZB	psi-mi:“MI:0915”(physical association)	0.370
POLA2	FRZB	psi-mi:“MI:0915”(physical association)	0.370
RBX1	FRZB	psi-mi:“MI:0915”(physical association)	0.370
FRZB	SMAD1	psi-mi:“MI:0915”(physical association)	0.370
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
FRZB	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
FRZB	metE	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): CYSRT1 (Two-hybrid), SMC3 (Proximity Label-MS), FRZB (Negative Genetic), FRZB (Affinity Capture-MS), HSP90AB1 (Cross-Linking-MS (XL-MS)), MANF (Cross-Linking-MS (XL-MS)), POLA2 (Two-hybrid), BBS10 (Two-hybrid), EHF (Two-hybrid), SMAD1 (Two-hybrid), RBX1 (Two-hybrid), PNO1 (Two-hybrid), ELF5 (Two-hybrid)

ESM2 similar proteins: A0MTF4, A4Q9F4, M3X9S6, O15520, O35565, O43189, O43320, O54693, O54769, O73754, O95750, P05524, P08620, P11487, P12034, P15656, P31371, P36364, P36386, P48801, P48802, P48803, P48804, P48807, P54130, P70492, P97401, P98172, Q20FD0, Q2HXK8, Q3ZFI5, Q5RF67, Q5T6S3, Q5XI70, Q91875, Q92765, Q92838, Q95117, Q95L12, Q96GD3

Diamond homologs: A0A0K3AWM6, B3DIG4, G5ECQ2, O00144, O19116, O42579, O57328, O57329, O60353, O70421, O75084, O93274, P18537, P58421, P97299, P97401, Q08463, Q08464, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RCN4, Q5RF67, Q5T4F7, Q61086, Q61088, Q61089, Q61090, Q61091, Q6FHJ7, Q7YRN1, Q80YN4, Q863H1, Q8AVJ9, Q8BKG4, Q8C4U3, Q8CHL0, Q8K4C8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FRZB	down-regulates	WNT1	binding
FRZB	down-regulates	WNT8A	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

874 predictions. Top by Δscore:

Variant	Effect	Δscore
2:182834964:CG:C	acceptor_gain	1.0000
2:182834968:G:C	acceptor_gain	1.0000
2:182837032:T:C	acceptor_gain	1.0000
2:182837943:CTTA:C	donor_loss	1.0000
2:182837944:TTA:T	donor_loss	1.0000
2:182837945:TA:T	donor_loss	1.0000
2:182837946:A:C	donor_loss	1.0000
2:182837947:C:CT	donor_loss	1.0000
2:182838011:TC:T	acceptor_loss	1.0000
2:182838012:C:CA	acceptor_loss	1.0000
2:182838012:C:CC	acceptor_gain	1.0000
2:182838017:T:TC	acceptor_gain	1.0000
2:182838018:T:C	acceptor_gain	1.0000
2:182838020:T:C	acceptor_gain	1.0000
2:182838020:T:TC	acceptor_gain	1.0000
2:182838404:ATTAC:A	donor_loss	1.0000
2:182838405:TTA:T	donor_loss	1.0000
2:182838406:TAC:T	donor_loss	1.0000
2:182838407:ACCT:A	donor_loss	1.0000
2:182838408:C:A	donor_loss	1.0000
2:182838610:ATGA:A	acceptor_gain	1.0000
2:182838611:TGA:T	acceptor_gain	1.0000
2:182838611:TGAC:T	acceptor_loss	1.0000
2:182838612:GA:G	acceptor_gain	1.0000
2:182838613:AC:A	acceptor_loss	1.0000
2:182838614:C:A	acceptor_loss	1.0000
2:182838614:C:CC	acceptor_gain	1.0000
2:182838615:T:C	acceptor_loss	1.0000
2:182866070:CTCA:C	donor_loss	1.0000
2:182866071:TCACC:T	donor_loss	1.0000

AlphaMissense

2135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:182866112:G:C	C147W	1.000
2:182866113:C:A	C147F	1.000
2:182866113:C:G	C147S	1.000
2:182866113:C:T	C147Y	1.000
2:182866114:A:G	C147R	1.000
2:182866114:A:T	C147S	1.000
2:182866163:C:A	W130C	1.000
2:182866163:C:G	W130C	1.000
2:182866165:A:G	W130R	1.000
2:182866165:A:T	W130R	1.000
2:182866197:C:G	C119S	1.000
2:182866197:C:T	C119Y	1.000
2:182866198:A:G	C119R	1.000
2:182866198:A:T	C119S	1.000
2:182866217:G:C	C112W	1.000
2:182866218:C:G	C112S	1.000
2:182866218:C:T	C112Y	1.000
2:182866219:A:G	C112R	1.000
2:182866219:A:T	C112S	1.000
2:182866229:A:C	C108W	1.000
2:182866230:C:A	C108F	1.000
2:182866230:C:G	C108S	1.000
2:182866230:C:T	C108Y	1.000
2:182866231:A:G	C108R	1.000
2:182866231:A:T	C108S	1.000
2:182866254:A:C	F100C	1.000
2:182866265:G:C	C96W	1.000
2:182866266:C:G	C96S	1.000
2:182866266:C:T	C96Y	1.000
2:182866267:A:G	C96R	1.000

dbSNP variants (sampled 300 via entrez): RS1000005869 (2:182864390 G>A), RS1000021508 (2:182856574 A>T), RS1000077816 (2:182850267 T>C), RS1000112570 (2:182841065 T>C), RS1000197545 (2:182836837 A>C,G), RS1000282041 (2:182837339 G>A), RS1000282436 (2:182843916 G>A), RS1000397829 (2:182837562 A>G), RS1000432372 (2:182839572 CA>C), RS1000700396 (2:182867810 T>A,C), RS1000710745 (2:182861293 C>A), RS1000715988 (2:182843687 C>A), RS1000817260 (2:182861902 G>A,T), RS1000932399 (2:182854822 A>G), RS1000986962 (2:182851611 G>A,C)

Disease associations

OMIM: gene MIM:605083 | disease phenotypes: MIM:613251, MIM:165720

GenCC curated gene-disease

Mondo (3): hypertrophic cardiomyopathy 14 (MONDO:0013197), osteoarthritis susceptibility 1 (MONDO:0008143), osteoarthritis (MONDO:0005178)

Orphanet (0):

HPO phenotypes

2 total (3 of 2 shown, HPO-id order):

HPO	Term
HP:0001426	Non-Mendelian inheritance
HP:0008843	Hip osteoarthritis
HP:0002758	Osteoarthritis

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003542_73	Night sleep phenotypes	5.000000e-06
GCST004582_3	Waist-to-hip circumference ratio (dietary energy interaction)	9.000000e-06
GCST006288_237	Heel bone mineral density	3.000000e-06
GCST006288_500	Heel bone mineral density	8.000000e-10
GCST006585_992	Blood protein levels	2.000000e-19
GCST006979_48	Heel bone mineral density	8.000000e-19
GCST008478_6	Neurological blood protein biomarker levels	8.000000e-19
GCST008478_8	Neurological blood protein biomarker levels	2.000000e-13
GCST008892_2	Working memory	5.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007827	nighttime rest measurement
EFO:0004343	waist-hip ratio
EFO:0008111	diet measurement
EFO:0009270	heel bone mineral density
EFO:0004335	short-term memory

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010003	Osteoarthritis	C05.550.114.606; C05.799.613
C567684	Cardiomyopathy, Familial Hypertrophic, 14 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression	3
methylmercuric chloride	decreases expression	2
(+)-JQ1 compound	decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	decreases expression	2
Aflatoxin B1	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
propionaldehyde	increases expression	1
N(4)-hydroxycytidine	decreases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
ochratoxin A	increases expression	1
mercuric bromide	affects cotreatment, decreases expression	1
deguelin	increases expression	1
rofecoxib	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
licochalcone B	increases expression	1
incobotulinumtoxinA	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00130468	PHASE4	COMPLETED	TREAD-20: Trial of Hyalgan Three Injection-Regimen for the Treatment of Knee Pain Due to Osteoarthritis
NCT00138892	PHASE4	UNKNOWN	A Randomized Controlled Trial of Long Versus Short Wait For Primary Total Hip and Knee Arthroplasty
NCT00140972	PHASE4	COMPLETED	A Study to Assess Etoricoxib Versus Diclofenac in Chinese Patients With Osteoarthritis of the Knee or Hip (0663-080)(COMPLETED)
NCT00141102	PHASE4	COMPLETED	Study Of Celecoxib Or Diclofenac And Omeprazole For Gastrointestinal (GI) Safety In High GI Risk Patients With Arthritis
NCT00208364	PHASE4	TERMINATED	A Two Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Metal-on-Metal Bearing in Primary Total Hip Replacement
NCT00208377	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00208390	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the Summit™ Hip in Primary Total Hip Replacement
NCT00208403	PHASE4	TERMINATED	A Randomised Single Centre Study to Compare the Long-term Performance of Acryloc™ and Palacos® R Bone Cements in Primary Total Hip Replacement
NCT00208416	PHASE4	TERMINATED	A Randomised Multi-centre Study to Compare the Short-term Outcomes of Minimally Invasive and Conventional Surgery in Primary Total Hip Replacement
NCT00208429	PHASE4	WITHDRAWN	A Multi-centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Polyethylene-on-metal Bearing in Primary Total Hip Replacement
NCT00208442	PHASE4	COMPLETED	A Randomised Single Centre Study to Compare the Long-term Wear Characteristics of Marathon™ and Enduron™ Polyethylene Cup Liners in Primary Total Hip Replacement
NCT00208455	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT00236366	PHASE4	COMPLETED	A Study of the Effect on Pain Control of Treatment With Fentanyl, Administered Through the Skin, Compared With Placebo in Patients With Osteoarthritis
NCT00251069	PHASE4	COMPLETED	Glucosamine Sulphate and Increased Level of Blood Cholesterol
NCT00253851	PHASE4	COMPLETED	Does Thinning the Blood During Surgery Prevent Blood Clots Following Total Knee Replacement Surgery
NCT00267176	PHASE4	COMPLETED	Safety and Efficacy of Lumiracoxib in Patients With Osteoarthritis and With Controlled Hypertension
NCT00270322	PHASE4	TERMINATED	Pain Treatment After Total Knee Replacement - Continuous Epidural Versus Intravenous Patient Controlled Analgesia With Morphine
NCT00279838	PHASE4	COMPLETED	Computer Assisted Total Knee Replacement
NCT00294801	PHASE4	UNKNOWN	Effect of Flex-a-New on Osteoarthritis of the Knee
NCT00324038	PHASE4	COMPLETED	Buprenorphine in the Treatment of Osteoarthritis (OA) in the Elderly
NCT00346788	PHASE4	COMPLETED	The Subvastus Approach in Total Knee Arthroplasty
NCT00359151	PHASE4	TERMINATED	Celebrex Total Knee Arthroplasty Study
NCT00373685	PHASE4	COMPLETED	GI-Reasons- A Trial Of GI Safety Of Celecoxib Compared With Non-Selective Nonsteroidal Antiinflammatory Drugs (NSAIDS)
NCT00393393	PHASE4	UNKNOWN	Effectiveness Study of Hylan G-F 20 to Preserve Cartilage in Osteoarthritis of the Knee
NCT00399178	PHASE4	COMPLETED	A Randomised Open Controlled Parallel Group Study Comparing Norspan and Tramadol
NCT00426647	PHASE4	COMPLETED	Norspan® Patches Versus Tramadol in Subjects With Chronic, Moderate to Severe Osteoarthritis Pain in the Hip Knee and/or Lumbar Spine
NCT00431509	PHASE4	UNKNOWN	Trial Comparing Navigated and Conventional Implantation Techniques in Knee Replacement Surgery
NCT00440661	PHASE4	COMPLETED	Exploration of the Synovial Fluid Inflammation Mediators Under Diacerhein in Knee Osteoarthritis
NCT00443092	PHASE4	COMPLETED	Efficacy of Proprietary Cherry Juice Blend in Osteoarthritis of the Knee
NCT00447759	PHASE4	COMPLETED	The Standard Care Versus Celecoxib Outcome Trial
NCT00484718	PHASE4	TERMINATED	Measuring Gait And Self-Reported Pain In Patients With Osteoarthritis Of The Knee Using Placebo/Oxycodone/Celecoxib.
NCT00524160	PHASE4	COMPLETED	A Study of the Effect on Pain Control of Treatment With Fentanyl, Administered Through the Skin, in Patients With Rheumatoid Arthritis or Osteoarthritis
NCT00542139	PHASE4	COMPLETED	Evaluation of Diprospan Injection to the Knee on Rehabilitation of Patients After TKR of the Contralateral Knee
NCT00546598	PHASE4	TERMINATED	Post-approval Study of the DURALOC® Option Ceramic-on-Ceramic Hip Prosthesis System
NCT00565500	PHASE4	COMPLETED	Celecoxib, Ibuprofen and the Antiplatelet Effect of Aspirin
NCT00598234	PHASE4	COMPLETED	Perioperative Pain Control With Celecoxib (Celebrex) in Total Knee Arthroplasty
NCT00609557	PHASE4	COMPLETED	A Single-Blind Placebo Run-in Study of Duloxetine for Activity-Limiting Osteoarthritis Pain
NCT00611676	PHASE4	COMPLETED	A Single-Blind Placebo Run-In Study of Venlafaxine for Activity-Limiting Osteoarthritis Pain
NCT00620828	PHASE4	COMPLETED	The Role of Intra-Operative Intracapsular Blocks in Post-Operative Pain Management Following Total Knee Arthroplasty
NCT00635349	PHASE4	COMPLETED	A Comparative Study of Tramadol Hydrochloride Plus Acetaminophen Tablets Maintenance Versus Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Maintenance in Participants With Knee Osteoarthritis