TNIK

Chr 3AR

TRAF2 and NCK interacting kinase

Also known as: MRT54

NCBI Gene: 23043ENSG00000154310UniProt: Q9UKE5

Wnt signaling plays important roles in carcinogenesis and embryonic development. The protein encoded by this gene is a serine/threonine kinase that functions as an activator of the Wnt signaling pathway. Mutations in this gene are associated with an autosomal recessive form of cognitive disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 54MIM #617028
AR
203
ClinVar variants
23
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— TNIK
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Gene-Disease Validity (ClinGen)
non-syndromic intellectual disability · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
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
23 Pathogenic / Likely Pathogenic· 126 VUS of 203 total submissions

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.
0.18LOEUF
pLI 1.000
Z-score 7.75
OE 0.10 (0.06–0.18)
Highly constrained

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

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.
4.10Z-score
OE missense 0.58 (0.53–0.63)
436 obs / 753.0 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.0.10 (0.06–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.53–0.63)
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.0.97
0≤1.21.6
LoF obs/exp: 9 / 87.0Missense obs/exp: 436 / 753.0Syn Z: 0.42

ClinVar Variant Classifications

203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic2
VUS126
Likely Benign38
Benign16
21
Pathogenic
2
Likely Pathogenic
126
VUS
38
Likely Benign
16
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
21
0
21
Likely Pathogenic
0
0
2
0
2
VUS
0
121
4
1
126
Likely Benign
0
2
9
27
38
Benign
0
1
6
9
16
Total01244237203

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

View in ClinVar →

Protein Context — Lollipop Plot

TNIK · 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

Intellectual developmental disorder, autosomal recessive 54

MIM #617028

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.
Ren F et al.·Nat Biotechnol
2025Clinical trial
A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.
Xu Z et al.·Nat Med
2025Clinical trial
TNIK's emerging role in cancer, metabolism, and age-related diseases.
Ewald CY et al.·Trends Pharmacol Sci
2024Review
Emergence of TNIK inhibitors in cancer therapeutics.
Yamada T et al.·Cancer Sci
2017Review
Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis.
Aladinskiy V et al.·J Med Chem
2024
Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression.
Zhang R et al.·Med Oncol
2024
STRIPAK complexes: structure, biological function, and involvement in human diseases.
Hwang J et al.·Int J Biochem Cell Biol
2014Review
TNIK Regulates Cytoskeletal Organization to Promote Focal Adhesion Turnover and Mitosis in Lung Adenocarcinoma.
Li Y et al.·Front Biosci (Landmark Ed)
2025
Traf2- and Nck-interacting kinase inhibitors: a patent review (2008-2024).
Qin L et al.·Expert Opin Ther Pat
2025Review
Weight-loss associated DNA methylation patterns: targetable biomarkers and pathway insights.
Zeng L et al.·BMC Res Notes
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools