CSNK2A1

Chr 20

casein kinase 2 alpha 1

Also known as: CK2A1, CKII, Cka1, Cka2, OCNDS

NCBI Gene: 1457 ENSG00000101266 UniProt: P68400

The protein is the catalytic alpha subunit of casein kinase II, a serine/threonine protein kinase that phosphorylates acidic proteins and regulates cell cycle control, apoptosis, and circadian rhythm. Loss-of-function mutations cause Okur-Chung neurodevelopmental syndrome through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. It is involved in various cellular processes, including cell cycle control, apoptosis, and circadian rhythm. The kinase exists as a tetramer and is composed of an alpha, an alpha-prime, and two beta subunits. The alpha subunits contain the catalytic activity while the beta subunits undergo autophosphorylation. The protein encoded by this gene represents the alpha subunit. Multiple transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Apr 2018]

GeneReviews ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.30

Clinical Summary— CSNK2A1

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

81 unique Pathogenic / Likely Pathogenic· 83 VUS of 272 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CSNK2A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.30LOEUF

pLI 0.987

Z-score 4.47

OE 0.13 (0.06–0.30)

Highly constrained

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

Missense Constraint?

3.71Z-score

OE missense 0.30 (0.24–0.37)

66 obs / 221.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.30)

0≤0.351.4

Missense OE?0.30 (0.24–0.37)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 4 / 30.8Missense obs/exp: 66 / 221.5Syn Z: 0.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCSNK2A1-related neurodevelopmental disorder (Okur-Chung syndrome)GOFAD

This gene — mechanism propensity

0.4388th %ile

GOF

0.5072th %ile

LOF

0.68top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 43% of P/LP variants are LoF · LOEUF 0.30

DN1 literature citation

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.

Literature Evidence

DNThe amino acid alterations in this region may cause destabilization of this critical conformation and result in impaired kinase activity. Additionally, the alteration in Asp156 residue, referred to as an active site that plays a key role in catalytic activity, had a dominant-negative effect and indu1

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

References

1.PMID 30655572 ↗

ClinVar Variant Classifications

272 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic46

VUS83

Likely Benign57

Benign24

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	17	0	0	35
Likely Pathogenic	17	28	1	0	46
VUS	7	65	11	0	83
Likely Benign	0	11	36	10	57
Benign	0	0	23	1	24
Conflicting	—				5
Total	42	121	71	11	250

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 82) ClinVar copy-number / structural variants overlap CSNK2A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →