TNK1

Chr 17

tyrosine kinase non receptor 1

Also known as: KOS1

NCBI Gene: 8711 ENSG00000174292 UniProt: Q13470

TNK1 encodes a tyrosine protein kinase that negatively regulates the Ras-MAPK pathway and has tumor suppressor properties, with high expression during fetal development and selective expression in adult lymphohematopoietic tissues. Mutations cause autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain abnormalities, typically presenting in early childhood. The gene shows very low constraint against loss-of-function variants (pLI near zero), which is consistent with the recessive inheritance pattern observed clinically.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the tyrosine protein kinase family. Tyrosine protein kinases are important regulators of intracellular signal transduction pathways, mediating cellular proliferation, survival, and development. This gene is highly expressed in fetal tissues and at lower levels in few adult tissues, thus may function in signaling pathways utilized broadly during fetal development, and more selectively in adult tissues. It plays a negative regulatory role in the Ras-Raf1-MAPK pathway, and knockout mice have been shown to develop spontaneous tumors, suggesting a role as a tumor suppressor gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.95

Clinical Summary— TNK1

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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

91 VUS of 137 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?

0.95LOEUF

pLI 0.000

Z-score 1.77

OE 0.62 (0.42–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.00Z-score

OE missense 0.86 (0.78–0.94)

328 obs / 383.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.42–0.95)

0≤0.351.4

Missense OE?0.86 (0.78–0.94)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 16 / 25.7Missense obs/exp: 328 / 383.1Syn Z: 1.73

This gene — mechanism propensity

0.7132th %ile

GOF

0.80top 10%

LOF

0.3163th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

137 submitted variants in ClinVar

ClinVar

Classification Summary

VUS91

Likely Benign13

Benign13

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	91	0	0	91
Likely Benign	0	8	1	4	13
Benign	1	5	0	7	13
Total	1	104	1	11	117

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap TNK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →