TNIK

protein-coding

TRAF2 and NCK interacting kinase, the group of MicroRNA protein coding host genes

Gene summary

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]

MANE transcript

NM_015028.4

Inheritance

ClinVar variants

P:1U:161B:42

Top phenotype

Intellectual developmental disorder, autosomal recessive 54

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr3:171,058,414-171,460,408

External References & Databases

Ensembl (ENSG00000154310)

Transcript & Mutation Effects

hg38 • Region Span ~402.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 54LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014876

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 54LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014876

Submitter: Ambry Genetics

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 54MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014876

Submitter: PanelApp Australia

non-syndromic intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000509

Submitter: ClinGen

*TNIK* encodes the TRAF2 and NCK-interacting protein kinase involved in dendrite development and synaptic transmission. *TNIK* was first reported in relation to autosomal recessive non-syndromic intellectual disability in 2016 (Anazi et al., PMID: 27106596). A homozygous nonsense variant (p.Arg180*) was reported in two multiplex, consanguineous Saudi Arabian families with five affected males, and was determined to be a founder variant. Affected individuals exhibit intellectual disability, speech delay, and hyperactivity. Western blot analysis of patient cells showed absence of the TNIK protein. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including functional alterations in human cells, and a mouse model. TNIK functions as a postsynaptic density (PSD) signaling hub, and *TNIK* mutations in hiPSC-derived excitatory neurons have been shown to disrupt immature synapse function and impair MAPK-dependent phosphorylation of core PSD proteins (PMID: 38638602). *Tnik* knock-out mice show impairments in dentate gyrus neurogenesis, cognitive deficits, and hyperlocomotor behavior (PMID: 23035106). In summary, there is limited evidence supporting the relationship between *TNIK* and autosomal recessive non-syndromic intellectual disability. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. The classification was downgraded from moderate to limited because only two families with the same founder variant have been reported since 2016. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 6, 2025 (SOP Version 12).

intellectual developmental disorder, autosomal recessive 54LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014876

Submitter: Illumina

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 54AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27106596

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNIK variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 141

not providedTotal: 53

Intellectual disability, autosomal recessive 54Total: 13

TNIK-related disorderTotal: 13

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015028.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	38 clinvar	2 clinvar	46
missense			140 clinvar	2 clinvar		142
nonsense	1 clinvar		4 clinvar			5
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	1	0	161	40	2	204

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015028.4	RefSeq	NP_055843.1	33	MANE Select
ENST00000436636.7	Ensembl	ENSP00000399511.2	33	MANE Select
NM_001161560.3	RefSeq	NP_001155032.1	32	Standard
NM_001161561.3	RefSeq	NP_001155033.1	32	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tnika	Danio rerio	Structure: EVL Quality: structure abnormal

Gene / Model

Organism

Observed Phenotype

tnika

Danio rerio

Structure: EVL

Quality: structure

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxidative Stress Induced Senescence
Oxidative Stress Induced Senescence
Cellular Senescence
Cellular responses to stress
Cellular responses to external stimuli

Biological Process

MAPK cascade
positive regulation of protein phosphorylation
protein phosphorylation
cytoskeleton organization
activation of JNKK activity

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000436636
Coding exons: 33
Length: 399070
Individuals with no LoFs: 124696
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 124709
p: 0.0000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.10	436	753	0.579	0.0000427	8865
Missense (PolyPhen)		160	294.46	0.54336		3558
Synonymous	0.423	262	271	0.967	0.0000148	2555
Loss of Function	7.75	9	87.0	0.103	0.00000533	945

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000072	0.000071	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:10521462, ECO:0000269|PubMed:15342639, ECO:0000269|PubMed:19061864, ECO:0000269|PubMed:19816403, ECO:0000269|PubMed:20159449, ECO:0000269|PubMed:21690388}.;
Disease: DISEASE: Mental retardation, autosomal recessive 54 (MRT54) [MIM:617028]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT54 patients manifest intellectual disability, delayed speech and hyperactivity. {ECO:0000269|PubMed:27106596}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.188

Intolerance Scores

LoFtool: 0.467
RVIS EVS: -1.44
RVIS percentile EVS: 3.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.978

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium