CCN6

Summary

CCN6 (cellular communication network factor 6, HGNC:12771) is a protein-coding gene on chromosome 6q21, encoding Cellular communication network factor 6 (O95389). Plays a role in mitochondrial electron transport and mitochondrial respiration.

This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. This gene is overexpressed in colon tumors. It may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. Mutations of this gene are associated with progressive pseudorheumatoid dysplasia, an autosomal recessive skeletal disorder, indicating that the gene is essential for normal postnatal skeletal growth and cartilage homeostasis. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8838 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive pseudorheumatoid arthropathy of childhood (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 260 total — 50 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 59
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_198239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12771
Approved symbol	CCN6
Name	cellular communication network factor 6
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	WISP-3
Ensembl gene	ENSG00000112761
Ensembl biotype	protein_coding
OMIM	603400
Entrez	8838

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000230529, ENST00000368664, ENST00000368666, ENST00000454589, ENST00000483439, ENST00000604763, ENST00000613648, ENST00000620524, ENST00000674325

RefSeq mRNA: 2 — MANE Select: NM_198239 NM_003880, NM_198239

CCDS: CCDS5098

Canonical transcript exons

ENST00000368666 — 5 exons

Exon	Start	End
ENSE00000839979	112060991	112061288
ENSE00001835671	112054104	112054405
ENSE00003517217	112068205	112068398
ENSE00003554618	112069339	112069686
ENSE00003556507	112064755	112064997

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 92.73.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1570 / max 25.0672, expressed in 48 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69317	0.1141	41
69318	0.0428	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	92.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.71	gold quality
cartilage tissue	UBERON:0002418	81.94	gold quality
sperm	CL:0000019	78.70	gold quality
male germ cell	CL:0000015	77.19	gold quality
corpus epididymis	UBERON:0004359	73.35	gold quality
cerebellar hemisphere	UBERON:0002245	72.23	gold quality
cerebellar cortex	UBERON:0002129	71.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	70.34	gold quality
right uterine tube	UBERON:0001302	69.85	gold quality
skin of leg	UBERON:0001511	69.63	gold quality
right testis	UBERON:0004534	69.63	gold quality
left testis	UBERON:0004533	68.89	gold quality
cerebellum	UBERON:0002037	68.77	gold quality
renal glomerulus	UBERON:0000074	68.05	silver quality
metanephric glomerulus	UBERON:0004736	67.46	silver quality
testis	UBERON:0000473	67.24	gold quality
diaphragm	UBERON:0001103	66.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.00	gold quality
zone of skin	UBERON:0000014	65.49	gold quality
skin of abdomen	UBERON:0001416	64.42	gold quality
nephron tubule	UBERON:0001231	63.57	gold quality
kidney epithelium	UBERON:0004819	63.09	silver quality
oviduct epithelium	UBERON:0004804	63.01	silver quality
fallopian tube	UBERON:0003889	62.65	gold quality
ectocervix	UBERON:0012249	60.53	gold quality
metanephros	UBERON:0000081	60.15	gold quality
putamen	UBERON:0001874	60.02	gold quality
adult mammalian kidney	UBERON:0000082	59.89	gold quality
vagina	UBERON:0000996	58.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SNAI1, ZEB1

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• WISP3 acts as a tumor suppressor gene in the breast. Loss of WISP3 expression contributes to the phenotype of IBC by regulating tumor cell growth, invasion and angiogenesis. (PMID:12082632)
• WISP3 gene expression is higher in rheumatoid arthritis synovium and fibroblast-like synoviocytes compared with osteoarthritis and normal synovial tissue and is further induced by proinflammatory cytokines in vitro. (PMID:15517620)
• the WISP3 gene is essential to skeletal growth or homeostasis in humans but not in mice (PMID:15601861)
• WISP transcripts may have a role in the development of human hepatocellular carcinoma (PMID:15650268)
• stable inhibition of CCN6 expression in human mammary epithelial cells induces epithelial-mesenchymal transition, promotes anchorage-independent growth, motility and invasiveness, and sensitizes mammary epithelial cells to the growth effects of IGF-1 (PMID:16457688)
• WISP-3 may also promote superoxide dismutase expression and activity in chondrocytes (PMID:16480948)
• WISP3 regulates the accumulation of cellular reactive oxygen species, and mutations in WISP3 or loss of expression of WISP3 compromise this function. (PMID:17286957)
• Mutant WISP3 triggers the phenotype shift of articular chondrocytes by promoting sensitivity to IGF1 hypothesis of osteochondrodysplasias. (PMID:17363178)
• WISP-3 showed no statistically significant difference between groups. (PMID:17406949)
• Results show a compound heterozygous mutation of WISP3 and a series of cellular and molecular changes disturbing the endochondral ossification in this PPD patient. (PMID:17483925)
• These results lead to a new hypothesis that Snail and ZEB1 are downstream of CCN6 and play a critical role in CCN6-mediated regulation of E-cadherin in breast cancer. (PMID:18321996)
• novel G46X and C114Y mutations in exon 3 in WISP3 gene are responsible for PPD in Chinese patients (PMID:19064006)
• WISP3 and RhoC genes expression status defines a molecular signature of inflammatory breast cancer (IBC). (PMID:20014943)
• WISPs may play important but contrasting roles in colorectal cancer with WISP-1 appearing to act as a factor stimulating aggressiveness, WISP-2 as a tumour suppressor and WISP-3 having no definable beneficial or detrimental role (PMID:20372786)
• CCN6 (WISP3) blockade activates growth factor-independent survival and resistance to anoikis in human mammary epithelial cells (PMID:20395207)
• The expressions of Cyr61 and/or WISP-3 may be important biological markers in reflecting the progression, biological behaviors, metastatic potential and prognosis of NSCLC. (PMID:21159247)
• our results indicate that CCN6 enhances the migration of chondrosarcoma cells by increasing ICAM-1 expression (PMID:21391218)
• Data define a pathway in which CCN6 attenuates IGF-1 signaling to decrease ZEB1 expression and invasion in breast cancer. (PMID:21525039)
• Homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy. (PMID:21528827)
• KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners (PMID:21628462)
• demonstrated that CCN6 induced the proliferation of lung fibroblasts by binding to integrin beta1, leading to the phosphorylation of FAK(Y397). (PMID:21921419)
• The mutations of the WISP3 gene in Progressive pseudorheumatoid dysplasia are located in the range of exon 2 to exon 5. (PMID:21993478)
• CCN6 was highly expressed in end-stage osteoarthritic cartilage, suggesting a role in cartilage homeostasis. CCN6-induced repression of ADAMTS-5 and regulation of MMP-10 expression suggest complex roles for CCN6 in cartilage biology. (PMID:22294415)
• Results indicate that WNT1-inducible signaling pathway protein 3 (WISP3) mutations are associated with progressive pseudorheumatoid dysplasia (PPD). (PMID:22685593)
• Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases of progressive pseudorheumatoid dysplasia. (PMID:22791401)
• The data presented in this study reveal that CCN6 downregulation disrupts acinar morphogenesis and promotes invasion of mammary epithelial cells (PMID:22805309)
• A report on 11 different homozygous mutations and one instance of compound heterozygosity in the WISP3 gene in patients with progressive pseudorheumatoid dysplasia. (PMID:22987568)
• These results reveal a novel function of the matricellular protein CCN6 and establish a mechanistic link between CCN6 and TbetaRIII in maintaining acinar organization in the breast. (PMID:23226100)
• Results are indicative of an operational WISP3-IGF1 regulatory loop whereby WISP3 preserves cartilage integrity by restricting IGF1-mediated hypertrophic changes in chondrocytes, at least partly, upon interaction with IGF1. (PMID:23424195)
• Suggest WISP3-Wnt/beta-catenin axis may have role in regulating gastric cancer cell proliferation and metastasis. (PMID:25400723)
• This study identified 3 different WISP3 mutations in 2 unrelated Chinese families with spondyloepiphyseal dysplasia tarda with progressive arthropathy. (PMID:25553839)
• A novel mutation c.667T>G (p.Cys223Gly) and the c.857C>G (p.Ser286*) mutation were detected in three Chinese patients with PPD. (PMID:25738435)
• Novel C223G and C252X mutations in exon 4 of the WISP3 gene are responsible for progressive pseudorheumatoid dysplasia in Chinese patients. (PMID:25794430)
• Novel and recurrent mutations in WISP3 and an atypical phenotype have been described in Indian families with progressive pseudorheumatoid dysplasia. (PMID:25988854)
• WISP3 variant leads to the diagnosis of SEDT-PA. (PMID:26493744)
• Studies indicate that the CYR61 CTGF NOV matricellular proteins (CCN family of proteins) comprises the members CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6 and have been identified in various types of cancer. (PMID:26498181)
• These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and tumor initiating cells programs in breast cancer (PMID:26933820)
• two WISP3 mutations have been identified in two affected siblings by targeted NGS, thus permitting the clinical diagnosis of PPD. This case supports the utility of NGS in the genetic characterization of skeletal dysplasias, which in turn may aid their clinical care, permit predictive screening, and to provide genetic counselling to families. (PMID:26991965)
• WISP3 harbored not only frameshift mutation but also mutational intratumoral heterogeneity and loss of expression, which together might play a role in tumorigenesis of GC and CRC with MSI-H by inhibiting tumor suppressor functions of WISP3. (PMID:26997449)
• CCN6 acts as a molecular brake, which is appropriately balanced by Nrf2, in regulating mitochondrial function. (PMID:27252383)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccn6	ENSDARG00000071048
mus_musculus	Ccn6	ENSMUSG00000062074
rattus_norvegicus	Ccn6	ENSRNOG00000000597

Paralogs (5): CCN5 (ENSG00000064205), CCN4 (ENSG00000104415), CCN2 (ENSG00000118523), CCN3 (ENSG00000136999), CCN1 (ENSG00000142871)

Protein

Protein identifiers

Cellular communication network factor 6 — O95389 (reviewed: O95389)

Alternative names: CCN family member 6, WNT1-inducible-signaling pathway protein 3

All UniProt accessions (5): A0A384NYW3, A0A6I8PRG4, O95389, F8WC24, G3V0J1

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in mitochondrial electron transport and mitochondrial respiration. Through its regulation of the mitochondrial function may play a role in normal postnatal skeletal growth and cartilage homeostasis.

Subcellular location. Secreted. Mitochondrion.

Tissue specificity. Predominant expression in adult kidney and testis and fetal kidney. Weaker expression found in placenta, ovary, prostate and small intestine. Also expressed in skeletally-derived cells such as synoviocytes and articular cartilage chondrocytes.

Disease relevance. Progressive pseudorheumatoid dysplasia (PPRD) [MIM:208230] An autosomal recessive disorder characterized by stiffness and swelling of joints, motor weakness and joint contractures. Signs and symptoms of the disease develop typically between three and eight years of age. This progressive disease is a primary disorder of articular cartilage with continued cartilage loss and destructive bone changes with aging. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CCN family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95389-1	1	yes
O95389-2	2

RefSeq proteins (2): NP_003871, NP_937882* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR000884	TSP1_rpt	Repeat
IPR006207	Cys_knot_C	Domain
IPR006208	Glyco_hormone_CN	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR012395	IGFBP_CNN	Family
IPR017891	Insulin_GF-bd_Cys-rich_CS	Conserved_site
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR043973	TSP1_CCN	Domain
IPR050941	CCN	Family

Pfam: PF00007, PF00219, PF19035

UniProt features (44 total): sequence variant 24, disulfide bond 11, domain 3, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95389-F1	74.30	0.24

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 (11): 61–78, 86–100, 92–114, 268–305, 285–319, 296–335, 299–337, 304–341, 48–72, 52–74, 54–75

Glycosylation sites (2): 178, 308

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GOMF_GROWTH_FACTOR_ACTIVITY, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, GOBP_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, FREAC3_01, MORF_CTSB, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, MORF_IL4, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOBP_REGULATION_OF_MITOCHONDRIAL_MEMBRANE_POTENTIAL, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS

GO Biological Process (9): cell adhesion (GO:0007155), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), negative regulation of cell population proliferation (GO:0008285), negative regulation of angiogenesis (GO:0016525), positive regulation of cell differentiation (GO:0045597), regulation of mitochondrial membrane potential (GO:0051881), regulation of reactive oxygen species biosynthetic process (GO:1903426), regulation of developmental process (GO:0050793)

GO Molecular Function (3): integrin binding (GO:0005178), growth factor activity (GO:0008083), heparin binding (GO:0008201)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), mitochondrion (GO:0005739), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cell communication	2
signaling	2
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
regulation of membrane potential	1
regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species metabolic process	1
developmental process	1
regulation of biological process	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCN6	WNT1	P04628	708
CCN6	VWF	P04275	620
CCN6	COL10A1	Q03692	615
CCN6	BMP4	P12644	549
CCN6	LRP6	O75581	534
CCN6	SPARC	P09486	507
CCN6	RHOC	P08134	479
CCN6	WNT4	P56705	472
CCN6	CDH1	P12830	371
CCN6	EBLN2	Q6P2I7	352
CCN6	ACAN	P16112	330
CCN6	MMP10	P09238	325
CCN6	CTNNB1	P35222	309
CCN6	THBS1	P07996	307
CCN6	IGF1	P01343	298

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CCN6	AKT1	psi-mi:“MI:2364”(proximity)	0.470
CCN6	BRAF	psi-mi:“MI:2364”(proximity)	0.470
CCN6	AKT1	psi-mi:“MI:0915”(physical association)	0.470
BRAF	CCN6	psi-mi:“MI:0915”(physical association)	0.470
CCN6	CRELD2	psi-mi:“MI:0914”(association)	0.350
CCN6	LRP6	psi-mi:“MI:0914”(association)	0.350
FBXW7	CCN6	psi-mi:“MI:2364”(proximity)	0.270
CCN6	FBXW7	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	CCN6	psi-mi:“MI:2364”(proximity)	0.270
CCN6	SMAD4	psi-mi:“MI:2364”(proximity)	0.270
CCN6	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SPOP	CCN6	psi-mi:“MI:2364”(proximity)	0.270
CCN6	SPOP	psi-mi:“MI:2364”(proximity)	0.270
EGFR	CCN6	psi-mi:“MI:2364”(proximity)	0.270
CCN6	PTEN	psi-mi:“MI:2364”(proximity)	0.270
CCN6	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
CCN6	TP53	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (29): APBB2 (Affinity Capture-MS), CRELD2 (Affinity Capture-MS), DDX47 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), APBB2 (Affinity Capture-MS), DDX47 (Affinity Capture-MS), CRELD2 (Affinity Capture-MS), POLR2D (Affinity Capture-MS), WISP3 (Positive Genetic), APBB2 (Affinity Capture-MS), CRELD2 (Affinity Capture-MS), DDX47 (Affinity Capture-MS), NMU (Affinity Capture-MS), NOTCH1 (Affinity Capture-MS)

ESM2 similar proteins: A4IIA2, A5A6L1, D3Z5L9, O00622, O43184, O54775, O95388, O95389, P08833, P15473, P17936, P18406, P19336, P21743, P21744, P24591, P24593, P24594, P47876, P47878, P47879, P48745, P51609, P59384, P59511, P97857, Q05717, Q07079, Q28985, Q501P1, Q5XHC5, Q61824, Q64299, Q68SA9, Q6Q484, Q76HP2, Q76HP3, Q8BNJ2, Q8TE58, Q90WV8

Diamond homologs: A5A6L1, D3Z5L9, D3ZKF5, O00622, O18739, O19113, O54775, O76076, O95388, O95389, P18406, P19336, P28686, P29268, P29279, P42642, P48745, P51609, Q64299, Q99PP0, Q9ES72, Q9JHC6, Q9QZQ5, Q9R1E9, Q9Z0G4, E1BJW1, Q98UI9, Q9NQ30, A2RT60, A4IIA2, A9JRB3, P12843, P47877, Q5XHC5, Q9JLL0, Q9NZV1, Q80T14, P97682, Q9QYY7, Q7T3Q2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	8
Uncertain significance	73
Likely benign	89
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071874	NM_198239.2(CCN6):c.624dup (p.Cys209fs)	Pathogenic
1072578	NM_198239.2(CCN6):c.342T>G (p.Cys114Trp)	Pathogenic
1323771	NM_198239.2(CCN6):c.626_627del (p.Cys209fs)	Pathogenic
1680467	NM_198239.2(CCN6):c.587del (p.Pro196fs)	Pathogenic
1680470	NM_198239.2(CCN6):c.622A>T (p.Lys208Ter)	Pathogenic
1683480	NM_198239.2(CCN6):c.1011_1014delinsATT (p.Cys337_Gln338delinsTer)	Pathogenic
1685603	NM_198239.2(CCN6):c.149G>A (p.Trp50Ter)	Pathogenic
1687519	NM_198239.2(CCN6):c.80T>A (p.Leu27Ter)	Pathogenic
1804751	NM_198239.2(CCN6):c.667T>G (p.Cys223Gly)	Pathogenic
1806291	NM_198239.2(CCN6):c.737del (p.Leu246fs)	Pathogenic
2044417	NM_198239.2(CCN6):c.646_647dup (p.Trp216fs)	Pathogenic
2136454	NM_198239.2(CCN6):c.197G>A (p.Ser66Asn)	Pathogenic
252451	NM_198239.2(CCN6):c.589+1G>A	Pathogenic
2636177	NM_198239.2(CCN6):c.621_622delinsT (p.Lys207fs)	Pathogenic
2693488	NM_198239.2(CCN6):c.473dup (p.Leu160fs)	Pathogenic
2734927	NM_198239.2(CCN6):c.185del (p.Pro62fs)	Pathogenic
2734928	NM_198239.2(CCN6):c.327C>A (p.Tyr109Ter)	Pathogenic
2734930	NM_198239.2(CCN6):c.624del (p.Lys208fs)	Pathogenic
2734931	NM_198239.2(CCN6):c.725_726del (p.Lys242fs)	Pathogenic
2734932	NM_198239.2(CCN6):c.756C>A (p.Cys252Ter)	Pathogenic
2734933	NM_198239.2(CCN6):c.857C>G (p.Ser286Ter)	Pathogenic
2734934	NM_198239.2(CCN6):c.866dup (p.Ser290fs)	Pathogenic
2793088	NM_198239.2(CCN6):c.2T>A (p.Met1Lys)	Pathogenic
2803165	NM_198239.2(CCN6):c.2T>C (p.Met1Thr)	Pathogenic
2838170	NM_198239.2(CCN6):c.111del (p.Val38fs)	Pathogenic
2839235	NM_198239.2(CCN6):c.629_630del (p.Leu210fs)	Pathogenic
2860288	NM_198239.2(CCN6):c.641_642del (p.Thr214fs)	Pathogenic
2902108	NM_198239.2(CCN6):c.3G>T (p.Met1Ile)	Pathogenic
2965678	NM_198239.2(CCN6):c.116C>A (p.Ser39Ter)	Pathogenic
3644487	NM_198239.2(CCN6):c.726dup (p.Glu243fs)	Pathogenic

SpliceAI

764 predictions. Top by Δscore:

Variant	Effect	Δscore
6:112054834:T:G	donor_gain	1.0000
6:112054992:G:GT	donor_gain	1.0000
6:112068203:A:AG	acceptor_gain	1.0000
6:112068204:G:GA	acceptor_gain	1.0000
6:112068204:GC:G	acceptor_gain	1.0000
6:112068204:GCT:G	acceptor_gain	1.0000
6:112068204:GCTT:G	acceptor_gain	1.0000
6:112068204:GCTTA:G	acceptor_gain	1.0000
6:112068395:AAAGG:A	donor_loss	1.0000
6:112068397:AGG:A	donor_loss	1.0000
6:112068398:GGTAA:G	donor_loss	1.0000
6:112068399:GTAA:G	donor_loss	1.0000
6:112068400:T:G	donor_loss	1.0000
6:112069337:A:AG	acceptor_gain	1.0000
6:112069338:G:GG	acceptor_gain	1.0000
6:112054403:CAGG:C	donor_loss	0.9900
6:112054405:GGTA:G	donor_loss	0.9900
6:112054406:G:GC	donor_loss	0.9900
6:112054407:T:G	donor_loss	0.9900
6:112065005:G:GT	donor_gain	0.9900
6:112065038:G:GA	donor_gain	0.9900
6:112068197:T:TA	acceptor_gain	0.9900
6:112068399:G:GG	donor_gain	0.9900
6:112069335:TCAG:T	acceptor_loss	0.9900
6:112069337:A:C	acceptor_loss	0.9900
6:112069338:G:A	acceptor_loss	0.9900
6:112069338:GA:G	acceptor_gain	0.9900
6:112069338:GATT:G	acceptor_gain	0.9900
6:112054992:G:T	donor_gain	0.9800
6:112069338:GATTC:G	acceptor_gain	0.9800

AlphaMissense

2447 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:112068263:G:C	W216C	0.999
6:112068263:G:T	W216C	0.999
6:112068261:T:A	W216R	0.996
6:112068261:T:C	W216R	0.996
6:112061216:T:A	C92S	0.995
6:112061217:G:C	C92S	0.995
6:112061198:T:A	C86S	0.993
6:112061199:G:C	C86S	0.993
6:112061240:T:A	C100S	0.993
6:112061241:G:C	C100S	0.993
6:112064812:T:G	F135C	0.993
6:112061282:T:A	C114S	0.992
6:112061283:G:C	C114S	0.992
6:112064772:T:A	C122S	0.990
6:112064773:G:C	C122S	0.990
6:112064841:T:A	C145S	0.990
6:112064842:G:C	C145S	0.990
6:112061217:G:A	C92Y	0.989
6:112061241:G:A	C100Y	0.989
6:112061284:T:G	C114W	0.989
6:112061216:T:C	C92R	0.988
6:112061199:G:A	C86Y	0.987
6:112061282:T:C	C114R	0.987
6:112061283:G:A	C114Y	0.987
6:112064862:T:A	C152S	0.987
6:112064863:G:C	C152S	0.987
6:112061217:G:T	C92F	0.986
6:112064841:T:C	C145R	0.986
6:112064843:T:G	C145W	0.986
6:112068356:T:G	C247W	0.986

dbSNP variants (sampled 300 via entrez): RS1000187096 (6:112057436 G>A), RS1000384656 (6:112057596 T>C), RS1000491470 (6:112062306 T>C), RS1000948381 (6:112055956 T>C), RS1001010724 (6:112068979 T>C,G), RS1001183892 (6:112065401 C>T), RS1001389167 (6:112058851 C>G), RS1001698785 (6:112065019 T>C), RS1001748789 (6:112064552 T>C), RS1001778735 (6:112051813 A>T), RS1002140771 (6:112070181 C>G,T), RS1002958044 (6:112055874 G>A,T), RS1003157852 (6:112066392 A>C), RS1003701794 (6:112054547 A>G), RS1004394857 (6:112057066 T>C)

Disease associations

OMIM: gene MIM:603400 | disease phenotypes: MIM:208230

GenCC curated gene-disease

Disease	Classification	Inheritance
progressive pseudorheumatoid arthropathy of childhood	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
progressive pseudorheumatoid arthropathy of childhood	Definitive	AR

Mondo (1): progressive pseudorheumatoid arthropathy of childhood (MONDO:0008827)

Orphanet (1): Progressive pseudorheumatoid dysplasia (Orphanet:1159)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000464	Abnormality of the neck
HP:0000926	Platyspondyly
HP:0000939	Osteoporosis
HP:0001225	Wrist swelling
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001376	Limitation of joint mobility
HP:0001384	Abnormal hip joint morphology
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001760	Abnormal foot morphology
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002655	Spondyloepiphyseal dysplasia
HP:0002751	Kyphoscoliosis
HP:0002758	Osteoarthritis
HP:0002812	Coxa vara
HP:0002815	Abnormality of the knee
HP:0002829	Arthralgia
HP:0002857	Genu valgum
HP:0002867	Abnormal ilium morphology
HP:0002923	Rheumatoid factor positive
HP:0002970	Genu varum
HP:0003016	Metaphyseal widening
HP:0003040	Arthropathy
HP:0003043	Abnormal shoulder morphology
HP:0003071	Flattened epiphysis
HP:0003301	Irregular vertebral endplates
HP:0003307	Hyperlordosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_367	Height	4.000000e-08

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535387	Arthropathy, progressive pseudorheumatoid, of childhood (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
terbufos	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	decreases expression	1
Aflatoxin B1	increases methylation	1

Cellosaurus cell lines

4 cell lines: 3 induced pluripotent stem cell, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D1GU	H9-WISP3KO	Embryonic stem cell	Female
CVCL_D1GV	PPAC1-iPSCs	Induced pluripotent stem cell	Female
CVCL_D1GW	PPAC1-C-iPSCs	Induced pluripotent stem cell	Female
CVCL_D1GX	PPAC4-iPSCs	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03228394	PHASE2	COMPLETED	A Clinical Trial of Intravenous (IV) Ganaxolone in Women With Postpartum Depression
NCT03460756	PHASE2	COMPLETED	A Clinical Trial of Oral Ganaxolone in Women With Postpartum Depression