PRG4

Summary

PRG4 (proteoglycan 4, HGNC:9364) is a protein-coding gene on chromosome 1q31.1, encoding Proteoglycan 4 (Q92954). Plays a role in boundary lubrication within articulating joints.

The protein encoded by this gene is a large proteoglycan that is synthesized by chondrocytes located at the surface of articular cartilage and by some synovial lining cells. This protein contains both chondroitin sulfate and keratan sulfate glycosaminoglycans. It functions as a boundary lubricant at the cartilage surface and contributes to the elastic absorption and energy dissipation of synovial fluid. Mutations in this gene result in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10216 — RefSeq curated summary.

At a glance

• Gene–disease (curated): camptodactyly-arthropathy-coxa vara-pericarditis syndrome (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 336 total — 32 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 31
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005807

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9364
Approved symbol	PRG4
Name	proteoglycan 4
Location	1q31.1
Locus type	gene with protein product
Status	Approved
Aliases	JCAP, SZP, MSF, HAPO, bG174L6.2, FLJ32635
Ensembl gene	ENSG00000116690
Ensembl biotype	protein_coding
OMIM	604283
Entrez	10216

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000367482, ENST00000367483, ENST00000367485, ENST00000445192, ENST00000533951, ENST00000635041, ENST00000862630, ENST00000862631, ENST00000862632, ENST00000862633, ENST00000862634, ENST00000862635

RefSeq mRNA: 5 — MANE Select: NM_005807 NM_001127708, NM_001127709, NM_001127710, NM_001303232, NM_005807

CCDS: CCDS1369, CCDS44287, CCDS44288, CCDS81411

Canonical transcript exons

ENST00000445192 — 13 exons

Exon	Start	End
ENSE00000000294	186313681	186314567
ENSE00000790813	186300091	186300213
ENSE00000790814	186301592	186301711
ENSE00000790817	186309793	186309870
ENSE00000790818	186311034	186311170
ENSE00000790821	186312769	186312894
ENSE00000823015	186304108	186304257
ENSE00000823017	186306318	186309140
ENSE00000823018	186311440	186311596
ENSE00000823019	186312175	186312372
ENSE00001030848	186304794	186304922
ENSE00001269472	186296846	186296951
ENSE00003900169	186296279	186296293

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 99.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.6209 / max 1728.7395, expressed in 179 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7298	1.8017	113
7297	0.3144	54
7296	0.2608	73
7300	0.1754	51
7299	0.0380	7
7301	0.0305	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	99.88	gold quality
calcaneal tendon	UBERON:0003701	99.37	gold quality
pericardium	UBERON:0002407	98.38	gold quality
layer of synovial tissue	UBERON:0007616	97.58	gold quality
parietal pleura	UBERON:0002400	96.21	gold quality
right lobe of liver	UBERON:0001114	96.00	gold quality
germinal epithelium of ovary	UBERON:0001304	92.83	gold quality
tendon	UBERON:0000043	91.97	gold quality
liver	UBERON:0002107	89.95	gold quality
islet of Langerhans	UBERON:0000006	89.72	gold quality
omental fat pad	UBERON:0010414	89.72	gold quality
peritoneum	UBERON:0002358	89.59	gold quality
pleura	UBERON:0000977	87.57	gold quality
popliteal artery	UBERON:0002250	87.35	gold quality
tibial artery	UBERON:0007610	87.32	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.15	gold quality
upper lobe of left lung	UBERON:0008952	84.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.00	gold quality
upper lobe of lung	UBERON:0008948	83.52	gold quality
cartilage tissue	UBERON:0002418	82.90	gold quality
right lung	UBERON:0002167	81.69	gold quality
tibial nerve	UBERON:0001323	81.44	gold quality
tendon of biceps brachii	UBERON:0008188	79.69	gold quality
aorta	UBERON:0000947	78.90	gold quality
connective tissue	UBERON:0002384	77.21	gold quality
adipose tissue	UBERON:0001013	76.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.78	silver quality
hindlimb stylopod muscle	UBERON:0004252	75.07	gold quality
visceral pleura	UBERON:0002401	73.63	gold quality
skin of leg	UBERON:0001511	73.16	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	51741.96
E-GEOD-130148	yes	4728.24
E-MTAB-8530	yes	3413.59
E-GEOD-81547	yes	6.57
E-GEOD-81608	yes	6.29
E-ENAD-27	yes	5.06
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DMRT1, DNMT1, FOXO1

miRNA regulators (miRDB)

84 targeting PRG4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-579-3P	99.86	71.66	3628

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Mrna present in tendons from tennis elbow. PRG4 may also be expressed as alternatively spliced form lacking exons which encode part of the N-terminal matrix-binding and cell-proliferative domain. (PMID:12475643)
• Megakaryocyte stimulating factor (msf) is linked to prosthetic loosening. (PMID:12783322)
• data suggest that HAPO is a novel growth factor acting on the primitive cells of both hematopoietic and endothelial cell lineages [HAPO] (PMID:14976050)
• hemangiopoietin is encoded by HAPO, also known as CACP, MSF, SZP, and PRG4 [editorial] (PMID:15710563)
• Results describe the production of antibodies against human lubricin to determine the consequence of disease-causing mutations at the protein level and to study the protein’s normal post-translational processing. (PMID:16000300)
• PRG4 mutations may have a role camptodactyly-arthropathy-coxa vara-pericarditis in Saudi families (PMID:16429407)
• In the human knee, cartilaginous deposits and osteoarthritic cartilage contained PRG4 in patients with advanced knee osteoarthritis. (PMID:17343281)
• Lubricin provides synovial fluid with an ability to dissipate strain energy induced by mammalian locomotion, which is a chondroprotective feature that is distinct from boundary lubrication. (PMID:17404241)
• synovial fluid lubricin concentrations were significantly reduced at an early stage following anterior cruciate ligament injury when compared with those in the contralateral joint. (PMID:18512776)
• These findings demonstrate that HAPO induces endothelial cell proliferation through the PI-3K/Akt pathway. (PMID:18769058)
• findings point to two distinct mechanisms by which rh-lubricin lubricates, one mechanism involving lubricin bound to the tissue surface and the other involving lubricin in solution (PMID:19058183)
• HAPO enhanced total adherence of HUVEC in a concentration-dependent manner. (PMID:19900364)
• O-linked oligosaccharides NeuAc alpha2-3Gal beta1-3GalNAc and NeuAc alpha2-3Gal beta1-3(NeuAc alpha2-6)GalNAc were the dominating structures on lubricin. The latter was more prevalent in rheumatoid arthritis, indicating that sialylation is up-regulated. (PMID:20443780)
• We described a 2-bp novel deletion mutation in PRG4 gene in a Pakistani family with camptodactyly-arthropathy-coxa-vara-pericarditis syndrome (PMID:21565623)
• The surface layer of lubricin coating torn edges of anterior cruciate ligaments and menisci may interfere with the integrative healing process needed for repair. (PMID:21647956)
• lubricin is expressed in the TMJ disc bilaminar zone; lubricin may have a role in normal disc posterior attachment physiology through the prevention of cellular adhesion as well as providing lubrication during normal bilaminar zone function (PMID:21955422)
• Lubricin is expressed in chondrocytes derived from osteoarthritic cartilage encapsulated in poly (ethylene glycol) diacrylate scaffold. (PMID:22073377)
• Production and accumulation of the superficial zone protein (SZP), also known as lubricin, by the surface zone is a characteristic feature of articular cartilage. (PMID:22490392)
• the identification of a novel null mutation in PRG4 confirming the genetic homogeneity of Camptodactyly-arthropathy-coxa vara-pericarditis syndrome . (PMID:22678705)
• Lubricin in human breast tissue expander capsules (PMID:22865664)
• lubricin is able to bind to PMN via an L-selectin-dependent and -independent manner and may play a role in PMN-mediated inflammation. (PMID:22930755)
• The objective was to evaluate the presence and distribution of the lubricating and anti-adhesion glycoprotein lubricin and cells containing the contractile isoform smooth muscle alpha-actin (SMA) in pseudomembranes around loose hip prostheses. (PMID:23174700)
• Lubricin is transcribed, translated, and expressed by ocular surface epithelia. Lubricin presence significantly reduces friction between the cornea and conjunctiva. (PMID:23599181)
• 5 novel PRG4 mutations and the first case of CACP syndrome resulting from uniparental disomy of chromosome 1. (PMID:23756439)
• We speculate that an important role of lubricin in mediating interactions at the cartilage surface is to attach to the cartilage surface and provide a protective coating that maintains the contacting surfaces in a sterically repulsive state. (PMID:24406099)
• Lubricin (Prg4) plays a role in preventing damage to the superficial zone and preservation of chondrocytes. [Review] (PMID:25172828)
• The O-glycomap of lubricin, a novel mucin responsible for joint lubrication, has been identified by site-specific glycopeptide analysis. (PMID:25187573)
• PRG4 is a novel putative ligand for CD44 and may control synoviocyte overgrowth in inflammatory arthropathies via a CD44-mediated mechanism. (PMID:25708025)
• The finding that rhPRG4 can increase the viscosity of low concentration HA solutions suggests that supplementation with rhPRG4 may help mitigate the loss in synovial fluid viscosity experienced with decreased HA concentration in osteoarthritis. (PMID:25818000)
• no synovial fluid level differences detected between healthy knees and injured knees (PMID:26037740)
• PRG4 binds to TLR2 and TLR4 and this binding mediates a novel anti-inflammatory role for PRG4. (PMID:26643105)
• Cartilage derived from MSCs expressed lubricin protein both in vitro and in vivo (PMID:26867127)
• lubricin expression may typify adaptive and neoplastic changes along a pathway toward fibroblast-like synoviocytes (PMID:26924731)
• adult talar cartilage increases both PRG4 release and biosynthetic activity as immediate cellular response to injury (PMID:27551813)
• Double knockdown of PRG4 and IL-24 did not inhibit myxoid liposarcoma (MLS)- cell growth, and single knockdown of PRG4 remarkably increased IL-24 expression. These results suggest that the growth inhibitory effect of PRG4 knockdown is caused by induction of IL-24 expression, and PRG4 may contribute to maintain MLS cell growth through repression of IL-24 expression. (PMID:28192118)
• PRG4 plays an important anti-inflammatory role in regulating osteoarthritis synoviocyte proliferation. (PMID:28482921)
• Intra-articular injection of human PRG4 in vivo in Prg4-/- mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction. (PMID:28604608)
• IL6 and PRG4 represent potential novel tissue biomarkers of disease severity and prognosis in conjunctival fibrosis after glaucoma surgery. (PMID:28975281)
• FoxO play a key role in postnatal cartilage development, maturation, and modulate autophagy and proteoglycan 4 in osteoarthritis. (PMID:29444976)
• Inflammatory Biomarker Profiling in Total Joint Arthroplasty and Its Relevance to Circulating Levels of Lubricin, a Novel Proteoglycan. (PMID:29683034)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	prg4a	ENSDARG00000010482
danio_rerio	prg4b	ENSDARG00000028163
mus_musculus	Prg4	ENSMUSG00000006014
rattus_norvegicus	Prg4	ENSRNOG00000002385

Paralogs (1): VTN (ENSG00000109072)

Protein

Protein identifiers

Proteoglycan 4 — Q92954 (reviewed: Q92954)

Alternative names: Lubricin, Megakaryocyte-stimulating factor, Superficial zone proteoglycan

All UniProt accessions (3): Q92954, E9PLR3, J3KP74

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in boundary lubrication within articulating joints. Prevents protein deposition onto cartilage from synovial fluid by controlling adhesion-dependent synovial growth and inhibiting the adhesion of synovial cells to the cartilage surface. Isoform F plays a role as a growth factor acting on the primitive cells of both hematopoietic and endothelial cell lineages.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in synovial tissue, cartilage and liver and weakly in heart and lung. Isoform B is expressed in kidney, lung, liver, heart and brain. Isoform C and isoform D are widely expressed.

Post-translational modifications. N-glycosylated. O-glycosylated; contains glycosaminoglycan chondroitin sulfate and keratan sulfate. O-glycosylated with sialylated oligosaccharides which are predominantly represented by the monosialylated core type I structure, NeuNAcalpha2-3Galbeta1-3GalNAc, with smaller amounts of disialylated O-glycans. The disulfide bond between Cys-1146 and Cys-1403 is essential for protein cleavage. Proteolytically cleaved by cathepsin CTSG.

Disease relevance. Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) [MIM:208250] An autosomal recessive disorder characterized by the association of congenital or early-onset camptodactyly and non-inflammatory arthropathy with synovial hyperplasia. Individuals with CACP have normal appearing joints at birth but with advancing age develop joint failure, non-inflammatory synoviocyte hyperplasia and subintimal fibrosis of the synovial capsule. Some patients also manifest progressive coxa vara deformity and/or non-inflammatory pericardial or pleural effusions. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Different forms varying in molecular weight have been observed. Such forms are possibly due to different levels of glycosylation and protein cleavage.

Isoforms (6)

UniProt ID	Names	Canonical?
Q92954-1	A	yes
Q92954-2	B
Q92954-3	C
Q92954-4	D
Q92954-5	E
Q92954-6	F, Hemangiopoietin, HAPO

RefSeq proteins (5): NP_001121180, NP_001121181, NP_001121182, NP_001290161, NP_005798* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000585	Hemopexin-like_dom	Domain
IPR001212	Somatomedin_B_dom	Domain
IPR018486	Hemopexin_CS	Conserved_site
IPR018487	Hemopexin-like_repeat	Repeat
IPR020436	SMB_chordata	Domain
IPR036024	Somatomedin_B-like_dom_sf	Homologous_superfamily
IPR036375	Hemopexin-like_dom_sf	Homologous_superfamily
IPR051298	Heme_transport/Cell_adhesion	Family

Pfam: PF00045, PF01033

UniProt features (230 total): glycosylation site 103, repeat 61, compositionally biased region 30, disulfide bond 15, splice variant 4, sequence variant 4, sequence conflict 4, region of interest 3, chain 2, domain 2, signal peptide 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92954-F1	48.76	0.14

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): 1306–1307 (cleavage; by subtilisin-like proprotein convertase 4)

Disulfide bonds (15): 30–46, 30–34, 34–64, 44–57, 44–46, 50–56, 57–64, 70–86, 70–74, 74–104, 84–97, 84–86, 90–96, 97–104, 1146–1403

Glycosylation sites (103): 123, 136, 206, 240, 253, 277, 291, 305, 306, 310, 317, 324, 332, 338, 367, 373, 376, 384, 385, 388 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 263 (showing top): ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, TAL1ALPHAE47_01, KONG_E2F1_TARGETS, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, RIGGI_EWING_SARCOMA_PROGENITOR_DN, TCF11_01, CAIRO_HEPATOBLASTOMA_DN, GRE_C, MODULE_99, HNF4_01, PITX2_Q2, TAL1BETAE47_01, FOX_Q2, MODULE_112

GO Biological Process (3): immune response (GO:0006955), vesicle-mediated transport (GO:0016192), electron transport chain (GO:0022900)

GO Molecular Function (3): scavenger receptor activity (GO:0005044), polysaccharide binding (GO:0030247), extracellular matrix structural constituent conferring compression resistance (GO:0030021)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
immune system process	1
response to stimulus	1
transport	1
cellular process	1
generation of precursor metabolites and energy	1
cargo receptor activity	1
carbohydrate binding	1
extracellular matrix structural constituent	1
external encapsulating structure	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRG4	ACAN	P16112	901
PRG4	HPX	P02790	855
PRG4	CD44	P16070	793
PRG4	TLR2	O60603	773
PRG4	TLR4	O00206	717
PRG4	COMP	P49747	709
PRG4	CSPG4	Q6UVK1	633
PRG4	FN1	P02751	623
PRG4	ALB	P02768	607
PRG4	BGN	P13247	594
PRG4	HSPG2	P98160	590
PRG4	COL2A1	P02458	588
PRG4	SOX9	P48436	571
PRG4	MMP13	P45452	549
PRG4	COL10A1	Q03692	543

IntAct

10 interactions, top by confidence:

A	B	Type	Score
Dlg4	PRG4	psi-mi:“MI:0407”(direct interaction)	0.440
GRB2	PRG4	psi-mi:“MI:0915”(physical association)	0.400
PRG4	NCL	psi-mi:“MI:0915”(physical association)	0.400
MAP1B	PRG4	psi-mi:“MI:0915”(physical association)	0.400
PRG4	H2AC12	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
MYC		psi-mi:“MI:0914”(association)	0.350

BioGRID (9): PRG4 (Affinity Capture-MS), PRG4 (Affinity Capture-MS), HIST1H2AH (Proximity Label-MS), PRG4 (Proximity Label-MS), PRG4 (Proximity Label-MS), PRG4 (Affinity Capture-MS), TRDN (Cross-Linking-MS (XL-MS)), PRPF40A (Cross-Linking-MS (XL-MS)), PRG4 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0U1RQI7, A0A494C071, A6QL64, A6ZXT5, A7XUY5, E2RYF6, E2RYF7, O60732, O88799, P06916, P12021, P18583, P41809, P43537, P47179, P53353, Q00130, Q02496, Q02505, Q04893, Q05049, Q12459, Q14242, Q32KG4, Q4ZJY7, Q4ZJZ0, Q54QZ8, Q5H9R4, Q5H9T9, Q5JPF3, Q5SSG8, Q5XHX6, Q60528, Q63661, Q685J3, Q6P902, Q86VQ3, Q8JZM8, Q8N307, Q8NET4

Diamond homologs: A1L237, A6QLQ8, A8E624, A8E627, B1H3D5, B1WBB4, P21128, Q1LUM3, Q21109, Q3V188, Q503V9, Q8JFY9, Q92954, Q9JM99, Q9PTU6, Q9VF14, Q9VZ49, D0EM77, G5EBU3, O04529, O13065, O18767, O18927, O23507, O35548, O44836, O54732, O55123, O55761, O60882, O62806, O70138, O75900, O77656, O88272, O88676, O88766, P02790, P03956, P03957

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	10
Uncertain significance	215
Likely benign	51
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1176527	NM_005807.6(PRG4):c.2998_3001del (p.Lys1000fs)	Pathogenic
1176528	NM_005807.6(PRG4):c.3848del (p.Gly1283fs)	Pathogenic
1323494	NM_005807.6(PRG4):c.4064C>G (p.Ser1355Ter)	Pathogenic
1323495	NM_005807.6(PRG4):c.3486dup (p.Val1163fs)	Pathogenic
1323496	NM_005807.6(PRG4):c.1935del (p.Glu646fs)	Pathogenic
1333348	NM_005807.6(PRG4):c.2894_2898del (p.Thr965fs)	Pathogenic
1526151	NM_005807.6(PRG4):c.301G>T (p.Glu101Ter)	Pathogenic
2127928	NM_005807.6(PRG4):c.3850del (p.Arg1284fs)	Pathogenic
2570744	NM_005807.6(PRG4):c.3560_3561del (p.Glu1187fs)	Pathogenic
2577870	NM_005807.6(PRG4):c.1134dup (p.Lys379fs)	Pathogenic
2577871	NM_005807.6(PRG4):c.1699del (p.Glu567fs)	Pathogenic
2577874	NM_005807.6(PRG4):c.2816_2817del (p.Lys939fs)	Pathogenic
4293731	NM_005807.6(PRG4):c.6_7dup (p.Trp3fs)	Pathogenic
5651	NM_005807.6(PRG4):c.2806_2810del (p.Lys936fs)	Pathogenic
5653	PRG4, 2-BP DEL, NT3023	Pathogenic
5655	NM_005807.6(PRG4):c.4190_4191delinsAG (p.Ser1397Ter)	Pathogenic
5656	PRG4, IVS6, 41-BP INS	Pathogenic
599362	NC_000001.10:g.(?186265850)(186266785_?)del	Pathogenic
684664	NM_005807.6(PRG4):c.1194del (p.Thr399fs)	Pathogenic
684665	NM_005807.6(PRG4):c.3917_3934del (p.Arg1306_Ser1311del)	Pathogenic
684666	NM_005807.6(PRG4):c.3277_3278del (p.Lys1093fs)	Pathogenic
684667	NM_005807.6(PRG4):c.4101C>G (p.Tyr1367Ter)	Pathogenic
684668	NM_005807.6(PRG4):c.2215A>T (p.Lys739Ter)	Pathogenic
684669	NM_005807.6(PRG4):c.1911del (p.Glu638fs)	Pathogenic
684670	NM_005807.6(PRG4):c.1910_1911del (p.Pro637fs)	Pathogenic
684671	NM_005807.6(PRG4):c.2841_2842del (p.Lys947fs)	Pathogenic
684672	NM_005807.6(PRG4):c.849del (p.Val284fs)	Pathogenic
800914	NM_005807.6(PRG4):c.3139_3140del (p.Lys1047fs)	Pathogenic
986018	NM_005807.6(PRG4):c.3023_3024del (p.Lys1008fs)	Pathogenic
986019	NM_005807.6(PRG4):c.3660del (p.Asn1221fs)	Pathogenic

SpliceAI

1437 predictions. Top by Δscore:

Variant	Effect	Δscore
1:186296843:CA:C	acceptor_loss	1.0000
1:186296845:GC:G	acceptor_gain	1.0000
1:186296845:GCAA:G	acceptor_gain	1.0000
1:186296947:TCAAG:T	donor_loss	1.0000
1:186296948:CAAG:C	donor_loss	1.0000
1:186296949:AAGG:A	donor_loss	1.0000
1:186296950:AG:A	donor_loss	1.0000
1:186296951:GG:G	donor_loss	1.0000
1:186296952:G:A	donor_loss	1.0000
1:186296953:T:G	donor_loss	1.0000
1:186301707:AGAAG:A	donor_loss	1.0000
1:186301709:AAGG:A	donor_loss	1.0000
1:186301713:T:A	donor_loss	1.0000
1:186304792:A:AG	acceptor_gain	1.0000
1:186304793:G:GG	acceptor_gain	1.0000
1:186304793:GAAC:G	acceptor_gain	1.0000
1:186305177:A:G	donor_gain	1.0000
1:186306316:A:AG	acceptor_gain	1.0000
1:186306317:G:GG	acceptor_gain	1.0000
1:186311430:A:AG	acceptor_gain	1.0000
1:186311552:C:G	donor_gain	1.0000
1:186311592:GAGAG:G	donor_gain	1.0000
1:186312151:ATGT:A	acceptor_gain	1.0000
1:186312152:T:G	acceptor_gain	1.0000
1:186312163:A:AG	acceptor_gain	1.0000
1:186312369:AAAG:A	donor_loss	1.0000
1:186312370:AAGG:A	donor_loss	1.0000
1:186312371:AGGTA:A	donor_loss	1.0000
1:186312373:GTA:G	donor_loss	1.0000
1:186312374:T:A	donor_loss	1.0000

AlphaMissense

8986 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:186301600:T:A	C70S	0.999
1:186301601:G:C	C70S	0.999
1:186301660:T:A	C90S	0.999
1:186301661:G:C	C90S	0.999
1:186300164:T:G	C50W	0.998
1:186300204:T:A	C64S	0.998
1:186300204:T:C	C64R	0.998
1:186300205:G:C	C64S	0.998
1:186300206:C:G	C64W	0.998
1:186301600:T:C	C70R	0.998
1:186301601:G:A	C70Y	0.998
1:186301602:T:G	C70W	0.998
1:186301610:G:C	R73P	0.998
1:186301612:T:A	C74S	0.998
1:186301613:G:C	C74S	0.998
1:186301642:T:A	C84S	0.998
1:186301642:T:C	C84R	0.998
1:186301643:G:C	C84S	0.998
1:186301648:T:A	C86S	0.998
1:186301649:G:C	C86S	0.998
1:186301660:T:C	C90R	0.998
1:186301678:T:A	C96S	0.998
1:186301679:G:C	C96S	0.998
1:186301681:T:A	C97S	0.998
1:186301681:T:C	C97R	0.998
1:186301682:G:C	C97S	0.998
1:186311099:T:A	W1189R	0.998
1:186311099:T:C	W1189R	0.998
1:186311101:G:C	W1189C	0.998
1:186311101:G:T	W1189C	0.998

dbSNP variants (sampled 300 via entrez): RS1000075687 (1:186304973 G>T), RS1000369554 (1:186298374 T>C,G), RS1000826948 (1:186296205 A>C), RS1000899197 (1:186296384 T>G), RS1000995992 (1:186312063 T>C), RS1001106904 (1:186301826 A>G), RS1001527962 (1:186298847 C>T), RS1001697581 (1:186311917 C>T), RS1001827683 (1:186297546 A>G), RS1001896227 (1:186297864 G>A,C), RS1001946465 (1:186310800 C>T), RS1002001751 (1:186310496 T>C), RS1002137077 (1:186304651 A>C), RS1002313183 (1:186296964 T>C,G), RS1002400476 (1:186310515 C>A,G,T)

Disease associations

OMIM: gene MIM:604283 | disease phenotypes: MIM:208250, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
camptodactyly-arthropathy-coxa vara-pericarditis syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
camptodactyly-arthropathy-coxa vara-pericarditis syndrome	Definitive	AR

Mondo (3): camptodactyly-arthropathy-coxa vara-pericarditis syndrome (MONDO:0008828), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (3): Camptodactyly-arthropathy-coxa-vara-pericarditis syndrome (Orphanet:2848), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000939	Osteoporosis
HP:0001225	Wrist swelling
HP:0001239	Wrist flexion contracture
HP:0001369	Arthritis
HP:0001541	Ascites
HP:0001634	Mitral valve prolapse
HP:0001653	Mitral regurgitation
HP:0001701	Pericarditis
HP:0001836	Camptodactyly of toe
HP:0002102	Pleuritis
HP:0002563	Constrictive pericarditis
HP:0002812	Coxa vara
HP:0002938	Lumbar hyperlordosis
HP:0002960	Autoimmunity
HP:0003040	Arthropathy
HP:0003940	Osteoarthritis of the elbow
HP:0005086	Knee osteoarthritis
HP:0005186	Synovial lining hyperplasia
HP:0005194	Flattened metatarsal heads
HP:0005195	Polyarticular arthropathy
HP:0005197	Generalized morning stiffness
HP:0005879	Congenital finger flexion contractures
HP:0008610	Infantile sensorineural hearing impairment
HP:0008812	Flattened femoral head
HP:0011909	Flattened metacarpal heads
HP:0012062	Bone cyst
HP:0033331	Acute phase response
HP:0100018	Nuclear cataract
HP:0100490	Camptodactyly of finger

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002777_14	Clozapine-induced cytotoxicity	2.000000e-06
GCST002777_15	Clozapine-induced cytotoxicity	3.000000e-06
GCST002777_16	Clozapine-induced cytotoxicity	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537560	Jacobs syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	2
Cadmium	decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
hydroxyhydroquinone	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
incobotulinumtoxinA	increases expression	1
Rosiglitazone	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Berberine	decreases expression	1
Doxorubicin	decreases expression	1
Lovastatin	increases expression	1
Phenobarbital	affects expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Valproic Acid	decreases methylation, increases expression	1
Cyclosporine	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3