CCN3

Chr 8

cellular communication network factor 3

Also known as: IBP-9, IGFBP-9, IGFBP9, NOV, NOVh

NCBI Gene: 4856 ENSG00000136999 UniProt: P48745

CCN3 encodes a secreted cysteine-rich protein that regulates cellular processes including proliferation, differentiation, and survival by binding to integrins and membrane receptors, and plays essential roles in hematopoietic stem cell function, angiogenesis, and bone development. Mutations in CCN3 cause autosomal dominant elbow-knee synostosis, a skeletal malformation syndrome affecting joint development. The gene shows low constraint to loss-of-function variants, suggesting tolerance to such mutations.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a small secreted cysteine-rich protein and a member of the CCN family of regulatory proteins. CNN family proteins associate with the extracellular matrix and play an important role in cardiovascular and skeletal development, fibrosis and cancer development. [provided by RefSeq, Feb 2009]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.81

Clinical Summary— CCN3

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

40 VUS of 51 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.007

Z-score 2.10

OE 0.41 (0.22–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.23Z-score

OE missense 0.95 (0.85–1.07)

192 obs / 201.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.22–0.81)

0≤0.351.4

Missense OE?0.95 (0.85–1.07)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 6 / 14.7Missense obs/exp: 192 / 201.3Syn Z: -0.38

This gene — mechanism propensity

0.6356th %ile

GOF

0.5170th %ile

LOF

0.3356th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

51 submitted variants in ClinVar

ClinVar

Classification Summary

VUS40

Likely Benign3

Benign1

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	40	0	0	40
Likely Benign	1	2	0	0	3
Benign	0	1	0	0	1
Conflicting	—				1
Total	1	43	0	0	45

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap CCN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →