CCN4

Chr 8

cellular communication network factor 4

Also known as: WISP1, WISP1-OT1, WISP1-UT1, WISP1c, WISP1i, WISP1tc

NCBI Gene: 8840 ENSG00000104415 UniProt: O95388 OMIM: 603398

The CCN4 protein is a downstream regulator in the Wnt signaling pathway that promotes cell survival by attenuating p53-mediated apoptosis and upregulating anti-apoptotic proteins. Mutations in CCN4 cause autosomal recessive spondylomegaepiphyseal dysplasia with upper limb mesomelia, joint laxity, and distinctive facies, a skeletal dysplasia syndrome affecting bone and cartilage development. The gene shows low constraint to loss-of-function variation (pLI near 0), consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Mar 2011]

OMIM ResearchGenerating clinical summary…

LOEUF 1.13

Clinical Summary— CCN4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 77 VUS of 97 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.13LOEUF

pLI 0.000

Z-score 1.18

OE 0.69 (0.44–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.22Z-score

OE missense 0.96 (0.86–1.07)

236 obs / 245.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.44–1.13)

0≤0.351.4

Missense OE?0.96 (0.86–1.07)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 12 / 17.3Missense obs/exp: 236 / 245.5Syn Z: -1.11

ClinVar Variant Classifications

97 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS77

Likely Benign9

Benign3

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	77	0	0	77
Likely Benign	6	1	2	9
Benign	1	0	2	3
Total	84	2	4	90

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

54 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap CCN4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →