CLK1

Chr 2

CDC like kinase 1

Also known as: CLK, CLK/STY, STY

NCBI Gene: 1195 ENSG00000013441 UniProt: P49759

The protein is a dual specificity kinase that phosphorylates serine/arginine-rich proteins in the spliceosomal complex to regulate RNA splicing. Mutations cause autosomal recessive intellectual disability with seizures and spasticity, typically presenting in early childhood. The gene is not highly constrained against loss-of-function variants, which is consistent with the recessive inheritance pattern observed in affected individuals.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the CDC2-like (or LAMMER) family of dual specificity protein kinases. In the nucleus, the encoded protein phosphorylates serine/arginine-rich proteins involved in pre-mRNA processing, releasing them into the nucleoplasm. The choice of splice sites during pre-mRNA processing may be regulated by the concentration of transacting factors, including serine/arginine rich proteins. Therefore, the encoded protein may play an indirect role in governing splice site selection. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.77

Clinical Summary— CLK1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

67 VUS of 99 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?

0.77LOEUF

pLI 0.000

Z-score 2.54

OE 0.50 (0.33–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.92 (0.84–1.02)

276 obs / 298.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.33–0.77)

0≤0.351.4

Missense OE?0.92 (0.84–1.02)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 15 / 30.0Missense obs/exp: 276 / 298.8Syn Z: -0.82

This gene — mechanism propensity

0.77top 25%

GOF

0.5367th %ile

LOF

0.2872th %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

99 submitted variants in ClinVar

ClinVar

Classification Summary

VUS67

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	67	67
Likely Benign	3	3
Benign	0	0
Total	70	70

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CLK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →