CSNK2A1

Chr 20AD

casein kinase 2 alpha 1

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

NCBI Gene: 1457 ENSG00000101266 UniProt: P68400 OMIM: 115440

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 OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOFmechanismADLOEUF 0.301 OMIM phenotype

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

133 unique Pathogenic / Likely Pathogenic· 110 VUS of 350 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 ↗

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 OE0.13 (0.06–0.30)

0≤0.351.4

Missense OE0.30 (0.24–0.37)

0≤0.61.4

Synonymous OE0.95

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

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 · 26% 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 induPMID:30655572

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