TLK2

Chr 17AD

tousled like kinase 2

Also known as: HsHPK, MRD57, PKU-ALPHA

NCBI Gene: 11011ENSG00000146872UniProt: Q86UE8

This gene encodes a nuclear serine/threonine kinase that was first identified in Arabidopsis. The encoded protein is thought to function in the regulation of chromatin assembly in the S phase of the cell cycle by regulating the levels of a histone H3/H4 chaperone. This protein is associated with double-strand break repair of DNA damage caused by radiation. Pseudogenes of this gene are present on chromosomes 10 and 17. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 57MIM #618050
AD
298
ClinVar variants
99
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— TLK2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
99 Pathogenic / Likely Pathogenic· 159 VUS of 298 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.37 (0.32–0.42)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 2 / 55.0Missense obs/exp: 148 / 401.1Syn Z: 0.03

ClinVar Variant Classifications

298 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic44
VUS159
Likely Benign30
Benign1
Conflicting9
55
Pathogenic
44
Likely Pathogenic
159
VUS
30
Likely Benign
1
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
27
0
28
0
55
Likely Pathogenic
9
19
16
0
44
VUS
7
133
17
2
159
Likely Benign
0
10
5
15
30
Benign
0
0
0
1
1
Conflicting
—9
Total431626618298

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

View in 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.

Gene2Phenotype Curations

TLK2-related intellectual developmental disorder

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 57

MIM #618050

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.
Reijnders MRF et al.·Am J Hum Genet
2018
Report of one case with de novo mutation in TLK2 and literature review.
Li HY et al.·BMC Pediatr
2024Review
Report of two children with global developmental delay in association with de novo TLK2 variant and literature review.
Woods E et al.·Am J Med Genet A
2022Review
Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis.
Pavinato L et al.·J Med Genet
2022Functional
The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1β-mediated AML progression.
Lin HY et al.·Blood
2024
Severe neurodevelopmental disease caused by a homozygous TLK2 variant.
Töpf A et al.·Eur J Hum Genet
2020Case report
The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.
Toni L et al.·Horm Res Paediatr
2024
Differential requirements for Tousled-like kinases 1 and 2 in mammalian development.
Segura-Bayona S et al.·Cell Death Differ
2017
Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers.
Kim JA et al.·Nat Commun
2016Functional
Exploring the role of TLK2 mutation in tropical calcific pancreatitis: an in silico and molecular dynamics simulation study.
Shrivastava A et al.·J Biomol Struct Dyn
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools