TLK2

Chr 17AD

tousled like kinase 2

Also known as: HsHPK, MRD57, PKU-ALPHA

NCBI Gene: 11011ENSG00000146872UniProt: Q86UE8OMIM: 608439

This gene encodes a nuclear serine/threonine kinase that phosphorylates chromatin assembly factors and regulates chromatin assembly during S phase of the cell cycle, DNA repair, and autophagy. Mutations cause autosomal dominant intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.11), indicating intolerance to disruption.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.111 OMIM phenotype
Clinical Summary— TLK2
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · 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 1.00). One damaged copy is likely sufficient to cause disease.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.11LOEUF
pLI 1.000
Z-score 6.62
OE 0.04 (0.01–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
4.49Z-score
OE missense 0.37 (0.32–0.42)
148 obs / 401.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.04 (0.01–0.11)
0≤0.351.4
Missense OE0.37 (0.32–0.42)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 2 / 55.0Missense obs/exp: 148 / 401.1Syn Z: 0.03
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTLK2-related intellectual developmental disorderLOFAD
DN
0.3097th %ile
GOF
0.3986th %ile
LOF
0.83top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.11

Literature Evidence

LOFThe authors performed RNA analysis of cells derived from 3 patients, which demonstrated that 2 of the mutations were subject to nonsense-mediated mRNA decay (NMD), resulting in haploinsufficiency; the third mutation was a nonsense mutation that escaped NMD, but was predicted to result in a truncatedPMID:29861108

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

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TLK2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Neuronal differentiation and activity drive nucleocytoplasmic shuttling of the intellectual disability kinase TLK2.
Nuhu-Soso L et al.·Front Cell Neurosci
2026Open Access
Expanding the Phenotype of TLK2-Related Neurodevelopmental Disorder: Longitudinal Presentation in Two Young Adult Females.
Ivaniuk A et al.·Am J Med Genet B Neuropsychiatr Genet
2026Natural history
Targeting TLK2 with antisense oligonucleotides as a new strategy in acute myeloid leukemia.
Lin HY et al.·Front Oncol
2026Open Access
Chromatin looping-based CRISPR screen identifies TLK2 as chromatin loop formation regulator in cancer stemness plasticity.
Wang Z et al.·Nat Commun
2025Open Access
A TLK2-mediated calcium-driven cell death pathway links neuronal degeneration to nuclear envelope disruption.
Li Y et al.·Nat Commun
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients