TNK2

Chr 3

tyrosine kinase non receptor 2

Also known as: ACK, ACK-1, ACK1, p21cdc42Hs

NCBI Gene: 10188ENSG00000061938UniProt: Q07912

This gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

586
ClinVar variants
40
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TNK2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
40 Pathogenic / Likely Pathogenic· 303 VUS of 586 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.80LOEUF
pLI 0.000
Z-score 2.61
OE 0.57 (0.42–0.80)
Tolerant

Typical tolerance to LoF variation

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.
-0.20Z-score
OE missense 1.02 (0.96–1.09)
710 obs / 695.0 exp
Tolerant

Tolerant to missense variation

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.0.57 (0.42–0.80)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.02 (0.96–1.09)
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.1.36
0≤1.21.6
LoF obs/exp: 25 / 43.6Missense obs/exp: 710 / 695.0Syn Z: -4.89

ClinVar Variant Classifications

586 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
VUS303
Likely Benign86
Benign20
Conflicting6
40
Pathogenic
303
VUS
86
Likely Benign
20
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
39
0
40
Likely Pathogenic
0
0
0
0
0
VUS
4
271
28
0
303
Likely Benign
0
9
23
54
86
Benign
0
5
4
11
20
Conflicting
—6
Total42869465455

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

View in ClinVar →

Protein Context — Lollipop Plot

TNK2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ACK1/TNK2 kinase: molecular mechanisms and emerging cancer therapeutics.
Sridaran D et al.·Trends Pharmacol Sci
2025Review
ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers.
Mahajan K et al.·Oncogene
2015Review
ZNF692 promotes osteosarcoma cell proliferation, migration, and invasion through TNK2-mediated activation of the MEK/ERK pathway.
Zheng D et al.·Biol Direct
2024
Small Molecules Targeting Activated Cdc42-Associated Kinase 1 (ACK1/TNK2) for the Treatment of Cancers.
Wang A et al.·J Med Chem
2021Review
TNK2 promoted esophageal cancer progression via activating egfr-akt signaling.
Zhang A et al.·J Clin Lab Anal
2021
Current strategies in the diagnosis and management of chronic neutrophilic leukemia.
Otgonbat A et al.·Chin Med J (Engl)
2014Review
Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation.
Huwaimel BI et al.·Bioorg Med Chem
2022
Development of novel ACK1/TNK2 inhibitors using a fragment-based approach.
Lawrence HR et al.·J Med Chem
2015
Exome-Wide Sequencing Study Identified Genetic Variants Associated With Sarcopenic Obesity.
Xu Q et al.·J Gerontol A Biol Sci Med Sci
2024
ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
Mahajan K et al.·Cancer Cell
2017
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools