CCN4

Summary

CCN4 (cellular communication network factor 4, HGNC:12769) is a protein-coding gene on chromosome 8q24.22, encoding CCN family member 4 (O95388). Downstream regulator in the Wnt/Frizzled-signaling pathway.

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 may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is expressed at a high level in fibroblast cells, and overexpressed in colon tumors. The encoded protein binds to decorin and biglycan, two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue, and possibly prevents the inhibitory activity of decorin and biglycan in tumor cell proliferation. It also attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. It is 83% identical to the mouse protein at the amino acid level. Multiple alternatively spliced transcript variants have been identified.

Source: NCBI Gene 8840 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 103 total — 1 pathogenic
• MANE Select transcript: NM_003882

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12769
Approved symbol	CCN4
Name	cellular communication network factor 4
Location	8q24.22
Locus type	gene with protein product
Status	Approved
Aliases	WISP-1
Ensembl gene	ENSG00000104415
Ensembl biotype	protein_coding
OMIM	603398
Entrez	8840

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000220856, ENST00000250160, ENST00000377862, ENST00000517423, ENST00000519433

RefSeq mRNA: 4 — MANE Select: NM_003882 NM_001204869, NM_001204870, NM_003882, NM_080838

CCDS: CCDS56555, CCDS56556, CCDS6371, CCDS6372

Canonical transcript exons

ENST00000250160 — 5 exons

Exon	Start	End
ENSE00000704091	133220581	133220841
ENSE00000887866	133212864	133213143
ENSE00002109869	133191039	133191213
ENSE00003325407	133227411	133231690
ENSE00003693904	133225390	133225583

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 96.05.

FANTOM5 (CAGE): breadth broad, TPM avg 7.0908 / max 422.3285, expressed in 694 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91187	6.2336	668
91188	0.8571	330

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	96.05	gold quality
tibia	UBERON:0000979	95.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.88	gold quality
metanephros cortex	UBERON:0010533	83.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.70	gold quality
visceral pleura	UBERON:0002401	82.76	gold quality
smooth muscle tissue	UBERON:0001135	81.85	gold quality
left adrenal gland cortex	UBERON:0035825	81.80	gold quality
myometrium	UBERON:0001296	81.20	gold quality
left adrenal gland	UBERON:0001234	81.00	gold quality
adrenal cortex	UBERON:0001235	80.60	gold quality
body of uterus	UBERON:0009853	80.11	gold quality
saphenous vein	UBERON:0007318	79.93	gold quality
descending thoracic aorta	UBERON:0002345	79.83	gold quality
adrenal gland	UBERON:0002369	79.41	gold quality
right adrenal gland	UBERON:0001233	79.15	gold quality
right adrenal gland cortex	UBERON:0035827	78.97	gold quality
stromal cell of endometrium	CL:0002255	77.92	gold quality
gall bladder	UBERON:0002110	77.66	gold quality
pleura	UBERON:0000977	77.18	gold quality
thoracic aorta	UBERON:0001515	77.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.11	gold quality
tibial artery	UBERON:0007610	77.08	gold quality
ascending aorta	UBERON:0001496	77.07	gold quality
popliteal artery	UBERON:0002250	77.07	gold quality
aorta	UBERON:0000947	76.99	gold quality
endocervix	UBERON:0000458	76.91	gold quality
right ovary	UBERON:0002118	76.87	gold quality
skin of hip	UBERON:0001554	76.79	gold quality
germinal epithelium of ovary	UBERON:0001304	76.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, TBX2

miRNA regulators (miRDB)

132 targeting CCN4, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627

Literature-anchored findings (GeneRIF, showing 40)

• Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. (PMID:11751417)
• Overexpression of WISP1 is associated with breast cancer (PMID:11855747)
• overexpression downregulates motility and invasion of lung cancer cells through inhibition of Rac activation (PMID:12529380)
• WISP1v-mediated signaling is involved in the generation of invasive cellular properties and leads to progression of cholangiocarcinoma. (PMID:12717393)
• Results suggest that disabled-2 functions as a negative regulator of canonical Wnt signaling by stabilizing the beta-catenin degradation complex. (PMID:12805222)
• WISP transcripts may have a role in the development of human hepatocellular carcinoma (PMID:15650268)
• Findings indicate that the WISP1v splicing variant plays a critical role in chondrocyte differentiation, whereas the HCS-2/8-specific splicing variant WISP1vx may be associated with the transformed phenotypes of chondrosarcomas. (PMID:17381509)
• WISP-1 transcripts were found in lower levels in node-positive tumors compared with node negative tumors;were lower in patients with a moderate and poor Nottingham Prognostic Index prognosis compared with good prognostic groups. (PMID:17406949)
• Upregulation of the WISP-1 is associated with lung cancer. (PMID:17579708)
• A genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis. (PMID:17593496)
• Aberrant levels of WISP-1 expression may play a role in rectal tumorigenesis. WISP-1 may be used as a specific clinical diagnosis and prognosis marker in rectal cancer. (PMID:17657846)
• EpCAM is a Wnt-beta-catenin signaling target gene (PMID:18006828)
• These data indicates that full-length WISP-1 and its variant WISP-1va are modulators of proliferation and osteogenic differentiation, and may be novel regulators of TGF-beta1 signaling in osteoblast-like cells. (PMID:18404666)
• These preliminary data suggest that WISP-1 and BGN may functionally interact and control each other’s activity, thus regulating the differentiation and proliferation of osteogenic cells. (PMID:18701807)
• CTGF and WISP-1 could play an important role in the progression of primary lung cancers by either individual gene itself or cointeraction. (PMID:19069651)
• WISP-1 expression is a feature of experimental and human osteoarthritis; WISP-1 regulates chondrocyte and macrophage MMP and aggrecanase expression and induces articular cartilage damage in models of osteoarthritis. (PMID:19180479)
• Results show that NO increases WISP-1 expression, and suggest a new role for iNOS and NO in colitis. (PMID:19238344)
• These results suggest that SORBS1 and GCK are susceptibility loci for hypertension in Japanese women and that WISP1 is such a locus in men. (PMID:19282865)
• expression of WISP1 was increased in alveolar epithelial type II cells in idiopathic pulmonary fibrosis (PMID:19287097)
• A TNF-alpha/WISP1 signaling pathway may contribute to post-infarct cardiac remodeling, a condition characterized by fibrosis and progressive cardiomyocyte loss. (PMID:19339243)
• The CCN4/WISP1 was upregulated in the plexiform neurofibromas. (PMID:20010302)
• WISP1 inhibits doxorubicin-induced p53 activation, p38 MAPK and JNK phosphorylation, Bax translocation to mitochondria, and cytochrome c release into cytoplasm. (PMID:20074638)
• 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)
• WISP-1 expression in human breast cancer increases significantly and may play a key role in invasion and metastasis. (PMID:20506641)
• WISP-1 has a positive influence on bone cell differentiation and function and may work by enhancing the effects of BMP-2 (PMID:20684029)
• WISP1 is mainly expressed during organ development and under diseased conditions, such as fibrosis or cancer. (PMID:21109017)
• IL-18 induces signaling events that result in WISP1-mediated saphenous vein smooth muscle proliferation, survival and MMP induction that are key components of vein graft stenosis. This may be amplified by IL-18 and WISP1 autoregulation/cross-regulation. (PMID:21321938)
• results indicated that WISP-1 enhances the migration of chondrosarcoma cells by increasing MMP-2 expression through the alpha5beta1 integrin receptor, FAK, MEK, ERK, p65 and NF-kappaB signal transduction pathway (PMID:21453685)
• The expression of WISP-1 may play an important role in the progression of esophageal squamous cell carcinoma. (PMID:21498727)
• This study shows that constitutive activation of the Notch1 pathway confers fibroblasts with a suppressive phenotype to melanoma growth, partially through WISP-1. (PMID:21516124)
• Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent (PMID:22715413)
• Prolonged exposure of kidney cells to ochratoxin A, expectable in human kidney due to a normal diet, leads to a marked ERK1/2-dependent upregulation of WISP1 gene expression, which, accompanied by increased ERK1/2- dependent TNF-alpha expression. (PMID:22778029)
• WISP1 is up-regulated by amyloid-beta-protein and can modulate its endogenous expression for the protection of microglia during apoptosis. (PMID:22873724)
• The CCN4-induced VCAM-1 expression promoted monocyte adhesion to human OASFs. (PMID:23313051)
• Beta-catenin-dependent expression of WISP1 and Cyr61 is critical for epithelial repair. (PMID:23316072)
• CCN4 activates signalling pathways in osteoarthritis synovial fibroblasts leading to up-regulation of IL-6 production (PMID:23343403)
• WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease. (PMID:23977121)
• WISP-1 enhances the migration of osteosarcoma cells by increasing MMP-2 and MMP-9 expression through the integrin receptor, Ras, Raf-1, MEK, ERK, and NF-kappaB signal transduction pathway. (PMID:24036215)
• IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision (PMID:24402778)
• WISP-1 has a role in invasive breast cancer oncogenesis and reduced type 1 cell-mediated cytotoxic immunity (PMID:24426833)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccn4a	ENSDARG00000054331
danio_rerio	ccn4b	ENSDARG00000076685
mus_musculus	Ccn4	ENSMUSG00000005124
rattus_norvegicus	Ccn4	ENSRNOG00000007078

Paralogs (5): CCN5 (ENSG00000064205), CCN6 (ENSG00000112761), CCN2 (ENSG00000118523), CCN3 (ENSG00000136999), CCN1 (ENSG00000142871)

Protein

Protein identifiers

CCN family member 4 — O95388 (reviewed: O95388)

Alternative names: WNT1-inducible-signaling pathway protein 1, Wnt-1-induced secreted protein

All UniProt accessions (2): O95388, E5RG88

UniProt curated annotations — full annotation on UniProt →

Function. Downstream regulator in the Wnt/Frizzled-signaling pathway. Associated with cell survival. Attenuates p53-mediated apoptosis in response to DNA damage through activation of AKT kinase. Up-regulates the anti-apoptotic Bcl-X(L) protein. Adheres to skin and melanoma fibroblasts. In vitro binding to skin fibroblasts occurs through the proteoglycans, decorin and biglycan.

Subcellular location. Secreted.

Tissue specificity. Expressed in heart, kidney, lung, pancreas, placenta, ovary, small intestine and spleen. Isoform 2 is expressed predominantly in scirrhous gastric carcinoma and, weakly in placenta. Overexpression is associated with several cancers including breast cancer and colon tumors. Isoform 2 is overexpressed in scirrhous gastric carcinoma.

Similarity. Belongs to the CCN family.

Isoforms (5)

UniProt ID	Names	Canonical?
O95388-1	1	yes
O95388-2	2, WISP1v
O95388-3	3
O95388-4	4
O95388-5	5

RefSeq proteins (4): NP_001191798, NP_001191799, NP_003873, NP_543028 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR000884	TSP1_rpt	Repeat
IPR001007	VWF_dom	Domain
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, PF00093, PF00219, PF19035

UniProt features (31 total): disulfide bond 11, splice variant 7, domain 4, glycosylation site 4, sequence conflict 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95388-F1	77.16	0.39

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): 49–73, 53–75, 55–76, 62–79, 87–101, 93–115, 273–310, 290–324, 301–340, 304–342, 309–346

Glycosylation sites (4): 86, 143, 284, 343

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 226 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, ATF_B, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, WALLACE_PROSTATE_CANCER_RACE_UP, TSENG_IRS1_TARGETS_UP, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_OSTEOBLAST_DIFFERENTIATION

GO Biological Process (20): osteoblast differentiation (GO:0001649), regulation of cytokine production (GO:0001817), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), positive regulation of smooth muscle cell migration (GO:0014911), Wnt signaling pathway (GO:0016055), positive regulation of Wnt signaling pathway (GO:0030177), osteoclast differentiation (GO:0030316), negative regulation of chondrocyte differentiation (GO:0032331), glucose homeostasis (GO:0042593), positive regulation of cell differentiation (GO:0045597), negative regulation of fat cell differentiation (GO:0045599), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of smooth muscle cell proliferation (GO:0048661), positive regulation of inflammatory response (GO:0050729), bone development (GO:0060348), positive regulation of wound healing (GO:0090303), regulation of cell differentiation (GO:0045595), regulation of multicellular organismal process (GO:0051239)

GO Molecular Function (3): integrin binding (GO:0005178), heparin binding (GO:0008201), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), cytosol (GO:0005829), extracellular matrix (GO:0031012), extracellular region (GO:0005576), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	3
cellular anatomical structure	3
cellular process	2
cell communication	2
signaling	2
regulation of cellular process	2
negative regulation of cell differentiation	2
ossification	1
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
cellular response to stimulus	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
positive regulation of cell migration	1
cell surface receptor signaling pathway	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
myeloid leukocyte differentiation	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cartilage development	1
carbohydrate homeostasis	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
fat cell differentiation	1
regulation of fat cell differentiation	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
positive regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
skeletal system development	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCN4	BGN	P13247	951
CCN4	WNT1	P04628	814
CCN4	NDRG1	Q92597	802
CCN4	DCN	P07585	726
CCN4	WNT4	P56705	622
CCN4	HNF4A	P41235	606
CCN4	BMP2	P12643	603
CCN4	VWF	P04275	598
CCN4	CTNNB1	P35222	593
CCN4	IGFBP5	P24593	525
CCN4	TGFB3	P10600	525
CCN4	RHOU	Q7L0Q8	524
CCN4	DKK1	O94907	520
CCN4	FRZB	Q92765	491
CCN4	WNT5A	P41221	484

IntAct

11 interactions, top by confidence:

A	B	Type	Score
CCN4	OTX1	psi-mi:“MI:0915”(physical association)	0.560
CCN4	HOXA1	psi-mi:“MI:0915”(physical association)	0.560
CCN4		psi-mi:“MI:0915”(physical association)	0.370
CCN4	UGGT1	psi-mi:“MI:0915”(physical association)	0.000
OTX1	CCN4	psi-mi:“MI:0915”(physical association)	0.000
CCN4	HOXA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): UGGT1 (Affinity Capture-MS), WISP1 (Affinity Capture-MS), HOXA1 (Two-hybrid), OTX1 (Two-hybrid)

ESM2 similar proteins: A5A6L1, B3F211, D3Z5L9, O00622, O15072, O54775, O95388, O95450, P08833, P18406, P19336, P24593, P24594, P47876, P51609, P59384, P59510, P59511, P79331, P97857, Q05717, Q07079, Q1EHB3, Q28985, Q4VC17, Q5XHC5, Q64299, Q68SA9, Q69Z28, Q7T3Q2, Q8AWW5, Q8C9W3, Q8CJ69, Q8N8U9, Q8TE57, Q8TE58, Q8TE60, Q8WXS8, Q90WV8, Q91713

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

2 interactions.

A	Effect	B	Mechanism
CCN4	“up-regulates activity”	AKT	phosphorylation
CTNNB1	“up-regulates quantity”	CCN4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	83
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2425511	NC_000008.10:g.(?134107268)(134296554_?)del	Pathogenic

SpliceAI

779 predictions. Top by Δscore:

Variant	Effect	Δscore
8:133191210:CACGG:C	donor_loss	1.0000
8:133191211:ACGG:A	donor_loss	1.0000
8:133191212:CGG:C	donor_loss	1.0000
8:133191213:GGT:G	donor_loss	1.0000
8:133191214:G:GG	donor_gain	1.0000
8:133191214:GTG:G	donor_loss	1.0000
8:133191215:T:A	donor_loss	1.0000
8:133227410:GGCA:G	acceptor_gain	1.0000
8:133191212:CG:C	donor_gain	0.9900
8:133191213:GG:G	donor_gain	0.9900
8:133220579:A:AG	acceptor_gain	0.9900
8:133220580:G:GG	acceptor_gain	0.9900
8:133227407:TCA:T	acceptor_loss	0.9900
8:133227409:A:AG	acceptor_gain	0.9900
8:133227409:AG:A	acceptor_gain	0.9900
8:133227410:G:GG	acceptor_gain	0.9900
8:133227410:GG:G	acceptor_gain	0.9900
8:133227410:GGC:G	acceptor_gain	0.9900
8:133191209:CCACG:C	donor_gain	0.9800
8:133191211:ACG:A	donor_gain	0.9800
8:133212859:CGCA:C	acceptor_loss	0.9800
8:133212860:GCAG:G	acceptor_loss	0.9800
8:133212861:CA:C	acceptor_loss	0.9800
8:133212862:A:AT	acceptor_loss	0.9800
8:133212863:GGCC:G	acceptor_gain	0.9800
8:133220578:CAG:C	acceptor_gain	0.9800
8:133220579:AGA:A	acceptor_gain	0.9800
8:133220580:GAG:G	acceptor_gain	0.9800
8:133220580:GAGGT:G	acceptor_gain	0.9800
8:133223130:A:T	donor_gain	0.9800

AlphaMissense

2415 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:133225448:G:C	W223C	0.999
8:133225448:G:T	W223C	0.999
8:133213071:T:A	C93S	0.997
8:133213072:G:C	C93S	0.997
8:133220638:T:G	F136C	0.997
8:133227571:T:G	F322C	0.997
8:133213095:T:A	C101S	0.996
8:133213096:G:C	C101S	0.996
8:133225539:T:A	C254S	0.996
8:133225540:G:C	C254S	0.996
8:133227480:A:C	S292R	0.996
8:133227482:C:A	S292R	0.996
8:133227482:C:G	S292R	0.996
8:133227626:C:G	C340W	0.996
8:133213053:T:A	C87S	0.995
8:133213054:G:C	C87S	0.995
8:133213072:G:A	C93Y	0.995
8:133213137:T:A	C115S	0.995
8:133213138:G:C	C115S	0.995
8:133220598:T:A	C123S	0.995
8:133220599:G:C	C123S	0.995
8:133225446:T:A	W223R	0.995
8:133225446:T:C	W223R	0.995
8:133225489:G:C	R237P	0.995
8:133227423:T:A	C273S	0.995
8:133227424:G:C	C273S	0.995
8:133227625:G:A	C340Y	0.995
8:133227630:T:A	C342S	0.995
8:133227631:G:C	C342S	0.995
8:133213055:C:G	C87W	0.994

dbSNP variants (sampled 300 via entrez): RS1000043982 (8:133212155 G>A), RS1000066079 (8:133201247 G>A), RS1000182209 (8:133201623 C>T), RS1000198946 (8:133209497 T>C), RS1000208188 (8:133214948 T>C), RS1000254389 (8:133196152 G>T), RS1000332660 (8:133204159 T>C), RS1000335276 (8:133207094 C>G), RS1000386475 (8:133203817 A>C,G), RS1000411788 (8:133229434 C>G,T), RS1000424337 (8:133190626 C>A,G,T), RS1000536171 (8:133220358 A>G), RS1000540465 (8:133190786 G>A), RS1000601504 (8:133223301 G>A), RS1000607171 (8:133198482 C>T)

Disease associations

OMIM: gene MIM:603398 | disease phenotypes: MIM:121200

GenCC curated gene-disease

Mondo (2): Charcot-Marie-Tooth disease type 4 (MONDO:0018995), benign neonatal seizures (MONDO:0016027)

Orphanet (2): Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Self-limited neonatal epilepsy (Orphanet:1949)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001809_5	Type 2 diabetes	2.000000e-06
GCST001984_1	Graves’ disease	8.000000e-09
GCST003649_3	Pneumococcal bacteremia	5.000000e-06
GCST004785_46	Vitiligo	2.000000e-13
GCST006585_1105	Blood protein levels	1.000000e-163
GCST007932_11	Medication use (thyroid preparations)	1.000000e-11
GCST012490_461	Femur bone mineral density x serum urate levels interaction	5.000000e-10
GCST90014325_38	Asthma	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:1001925	pneumococcal bacteremia
EFO:0009933	Thyroid preparation use measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2929973	CCN4		0.00	0
rs2977551	CCN4		0.00	0
rs2977549	CCN4		0.00	0
rs10956697	CCN4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
ochratoxin A	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
2,2’-(hydroxynitrosohydrazono)bis-ethanamine	increases expression, decreases reaction	1
U 0126	increases expression	1
abrine	decreases expression	1
PKF115-584	affects expression	1
bisphenol S	decreases expression	1
Temozolomide	affects response to substance	1
Arsenic Trioxide	decreases expression	1
Troglitazone	decreases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	increases expression, affects response to substance	1
Calcitriol	decreases expression	1
Carmustine	affects response to substance	1
Cycloheximide	decreases reaction, increases expression	1
Dactinomycin	decreases reaction, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Folic Acid	affects expression	1
Homocysteine	decreases expression	1
Indomethacin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Methotrexate	decreases expression	1
Nitroprusside	increases expression	1
Paraquat	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

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