TLK2

Chr 17AD

tousled like kinase 2

Also known as: HsHPK, MRD57, PKU-ALPHA

NCBI Gene: 11011 ENSG00000146872 UniProt: Q86UE8 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

95 unique Pathogenic / Likely Pathogenic· 160 VUS of 313 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 →

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 OE?0.04 (0.01–0.11)

0≤0.351.4

Missense OE?0.37 (0.32–0.42)

0≤0.61.4

Synonymous OE?1.00

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

This gene — mechanism propensity

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 · 75% of P/LP variants are LoF · 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 truncated1

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 29861108 ↗

ClinVar Variant Classifications

313 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46

Likely Pathogenic49

VUS160

Likely Benign32

Benign2

Conflicting9

Pathogenic

Likely Pathogenic

160

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	0	0	0	46
Likely Pathogenic	25	21	3	0	49
VUS	7	140	11	2	160
Likely Benign	0	12	4	16	32
Benign	0	0	1	1	2
Conflicting	—				9
Total	78	173	19	19	298

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap TLK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →