TNIK

Chr 3

TRAF2 and NCK interacting kinase

Also known as: MAP4K7, MRT54

NCBI Gene: 23043 ENSG00000154310 UniProt: Q9UKE5

This serine/threonine kinase functions as an essential activator of the Wnt signaling pathway and plays roles in neuronal dendrite development and the Hippo signaling pathway. Mutations cause autosomal recessive intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI ~1.0), indicating intolerance to haploinsufficiency in the general population.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.18

Clinical Summary— TNIK

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Gene-Disease Validity (ClinGen)

non-syndromic intellectual disability · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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

1 unique Pathogenic / Likely Pathogenic· 126 VUS of 229 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

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.10 (0.06–0.18)

0≤0.351.4

Missense OE?0.58 (0.53–0.63)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 9 / 87.0Missense obs/exp: 436 / 753.0Syn Z: 0.42

This gene — mechanism propensity

0.4982th %ile

GOF

0.6051th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.18

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

229 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS126

Likely Benign44

Benign14

Pathogenic

126

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	122	2	1	126
Likely Benign	0	2	10	32	44
Benign	0	1	6	7	14
Total	2	125	18	40	185

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap TNIK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →