COPS3

Chr 17

COP9 signalosome subunit 3

Also known as: CSN3, SGN3

NCBI Gene: 8533 ENSG00000141030 UniProt: Q9UNS2

The COPS3 protein is a component of the COP9 signalosome complex that regulates protein degradation pathways by controlling ubiquitin ligase activity and phosphorylating key signaling proteins including p53 and c-Jun. Mutations in COPS3 cause autosomal dominant syndromic intellectual disability with developmental delay and dysmorphic features. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical consequences.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene possesses kinase activity that phosphorylates regulators involved in signal transduction. It phosphorylates I kappa-Balpha, p105, and c-Jun. It acts as a docking site for complex-mediated phosphorylation. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.18

Clinical Summary— COPS3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

23 VUS of 43 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

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 0.999

Z-score 4.57

OE 0.04 (0.01–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.37Z-score

OE missense 0.56 (0.48–0.65)

129 obs / 229.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.18)

0≤0.351.4

Missense OE?0.56 (0.48–0.65)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 26.2Missense obs/exp: 129 / 229.9Syn Z: 0.17

This gene — mechanism propensity

0.3395th %ile

GOF

0.3392th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.18

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

43 submitted variants in ClinVar

ClinVar

Classification Summary

VUS23

Likely Benign2

Benign1

VUS

Likely Benign

Benign

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	1	22	0	0	23
Likely Benign	0	0	1	1	2
Benign	0	0	0	1	1
Total	1	22	1	2	26

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

View in ClinVar →

114 pathogenic / likely-pathogenic (of 121) ClinVar copy-number / structural variants overlap COPS3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →