CSN3

Chr 4

casein kappa

Also known as: CNS10, CSN10, CSNK, KCA

NCBI Gene: 1448 ENSG00000171209 UniProt: P07498 OMIM: 601695

The CSN3 protein is a component of the COP9 signalosome complex that regulates protein degradation pathways by controlling ubiquitin ligase activity and mediating phosphorylation of key cellular proteins including p53. Mutations in CSN3 cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting neurological development and brain growth. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

Involved in lactation and protein stabilization. Located in obsolete extracellular space. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.71

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.71LOEUF

pLI 0.012

Z-score 0.48

OE 0.74 (0.33–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.03Z-score

OE missense 1.01 (0.86–1.19)

105 obs / 104.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.74 (0.33–1.71)

0≤0.351.4

Missense OE?1.01 (0.86–1.19)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 3 / 4.0Missense obs/exp: 105 / 104.2Syn Z: -0.86

Background carrier burden — how many people carry a rare variant somewhere in CSN3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

275 rare PASS variants

Rare truncating (LoF)

1 in 4,100

38 rare PASS variants

Rare synonymous (reference)

1 in 1,200

95 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CSN3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 200	1 in 18,000
South Asian	~43k	1 in 240	1 in 760
Remaining (unassigned)	~30k	1 in 110	1 in 4,200
European (Finnish)	~27k	1 in 760	none seen
Admixed American	~22k	1 in 180	1 in 4,300
African / African American	~21k	1 in 170	1 in 2,100
East Asian	~20k	1 in 190	1 in 1,100
Ashkenazi Jewish	~13k	1 in 1,400	none seen
Middle Eastern	~2,884	1 in 190	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 1 of 3 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 3.? see exons ↓