TLK1

Chr 2

tousled like kinase 1

Also known as: PKU-beta

NCBI Gene: 9874 ENSG00000198586 UniProt: Q9UKI8 OMIM: 608438

The protein encoded by this gene is a serine/threonine kinase that may be involved in the regulation of chromatin assembly. The encoded protein is only active when it is phosphorylated, and this phosphorylation is cell cycle-dependent, with the maximal activity of this protein coming during S phase. The catalytic activity of this protein is diminished by DNA damage and by blockage of DNA replication. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.17

Clinical Summary— TLK1

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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

47 VUS of 83 total submissions

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?

0.17LOEUF

pLI 1.000

Z-score 5.95

OE 0.06 (0.03–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.56Z-score

OE missense 0.50 (0.44–0.56)

200 obs / 400.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.17)

0≤0.351.4

Missense OE?0.50 (0.44–0.56)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 3 / 47.0Missense obs/exp: 200 / 400.8Syn Z: 0.44

This gene — mechanism propensity

0.3693th %ile

GOF

0.3689th %ile

LOF

0.81top 5%

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

LOFprediction above median · LOEUF 0.17

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

83 submitted variants in ClinVar

ClinVar

Classification Summary

VUS47

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	46	0	47
Likely Benign	0	0	1	1
Benign	0	0	0	0
Total	1	46	1	48

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap TLK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →