TAOK1

protein-coding

TAO kinase 1, the group of Mitogen-activated protein kinase kinase kinases

Gene summary

Enables alpha-tubulin binding activity; beta-tubulin binding activity; and kinase activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; negative regulation of microtubule depolymerization; and positive regulation of MAPK cascade. Located in cytosol; microtubule cytoskeleton; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_020791.4

Inheritance

ClinVar variants

P:86U:229B:33

Top phenotype

Developmental delay with or without intellectual impairment or behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr17:29,390,363-29,551,903

External References & Databases

Ensembl (ENSG00000160551)

Transcript & Mutation Effects

hg38 • Region Span ~161.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

developmental delay with or without intellectual impairment or behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859199

Submitter: PanelApp Australia

developmental delay with or without intellectual impairment or behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859199

Submitter: G2P

developmental delay with or without intellectual impairment or behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859199

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Although intragenic deletions in TAOK1 had been observed in large cohort studies of individuals with neurodevelopmental disorders in 2011 and 2018 (PMIDs: 21841781, 29674594), the first report focusing on variants in TAOK1 as a cause of autosomal dominant syndromic intellectual disability was published in 2019 (PMID: 31230721). TAOK1 (thousand and one amino acid kinase 1) encodes the serine/threonine-protein kinase TAO1. Individuals with pathogenic variants in this gene present with variable degrees of developmental delay and/or intellectual disability, behavior problems (including autism in some), hypotonia, macrocephaly, dysmorphic facial features, and joint hypermobility (PMID: 33565190). Truncating variants in this gene have been reported in 18 individuals in 2 publications that included detailed phenotype information and were the basis of this curation (PMIDs: 31230721, 33565190), although only 6 probands were scored in this curation because the maximum score for genetic evidence has been reached. Most variants occurred de novo; in two instances, they were inherited from affected parents. Additional de novo truncating variants have been identified by exome sequencing in affected individuals from large cohort studies of autism spectrum disorder and developmental disorders, but detailed phenotype information is not available in those studies (PMIDs: 31981491, 33057194). Furthermore, nine de novo TAOK1 missense variants were reported in the 2 publications focused on TAOK1 (PMIDs: 31230721, 33565190). Although the clinical interpretation of these variants is difficult in the context of nonspecific phenotypes, functional analysis showed that some missense variants resulted in loss of protein function, while others led to dominant-negative effects (PMID: 33565190). Thus, while the mechanism for disease is predicted to be haploinsufficiency based on protein truncating variants reported in affected individuals and functional studies in patient-derived fibroblasts (PMID: 31230721), further studies are needed to confirm the mechanisms of missense variants. This gene-disease relationship is also supported by experimental evidence, including non-human model organisms (PMIDs: 26996505, 31230721, 33565190) and functional in vitro studies (PMID: 14517247, 33565190). In summary, there is sufficient genetic evidence to support a definitive gene-disease relationship between TAOK1 and syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 08/04/21 (SOP Version 8).

Clinical Genomic Database (CGD)

Developmental delay with or without intellectual impairment or behavioral abnormalitiesAD

Manifestation: Craniofacial; 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: 31230721; 33565190

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TAOK1 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 175

Inborn genetic diseasesTotal: 94

Developmental delay with or without intellectual impairment or behavioral abnormalitiesTotal: 80

TAOK1-related disorderTotal: 28

not specifiedTotal: 16

Neurodevelopmental disorderTotal: 10

TAOK1-related neurodevelopmental disorderTotal: 3

See casesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020791.4. 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			4 clinvar	19 clinvar	2 clinvar	25
missense	1 clinvar	17 clinvar	208 clinvar	12 clinvar		238
nonsense	17 clinvar	14 clinvar	6 clinvar			37
start loss						0
frameshift	13 clinvar	8 clinvar	1 clinvar			22
splice donor/acceptor (+/-2bp)	4 clinvar	12 clinvar	10 clinvar			26
Total	35	51	229	31	2	348

Highest pathogenic variant AF is 0.0000065703885

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020791.4	RefSeq	NP_065842.1	19	MANE Select
ENST00000261716.8	Ensembl	ENSP00000261716.3	19	MANE Select
NM_025142.1	RefSeq	NP_079418.1	17	Standard
ENST00000536202.1	Ensembl	ENSP00000438819.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MAPK signaling pathway - Homo sapiens (human)
EGF-Core
Regulation of Microtubule Cytoskeleton
MAPK Signaling Pathway
Signal Transduction

Biological Process

activation of MAPKK activity
activation of MAPK activity
microtubule cytoskeleton organization
DNA repair
protein phosphorylation

Molecular Function

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

Cellular Component

nucleus
cytoplasm
cytosol
microtubule cytoskeleton
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261716
Coding exons: 19
Length: 161441
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.82	234	553	0.423	0.0000300	6629
Missense (PolyPhen)		23	132.82	0.17317		1671
Synonymous	0.920	162	178	0.912	0.00000843	1801
Loss of Function	6.31	11	66.5	0.165	0.00000431	678

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.00013	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability. Phosphorylates MAP2K3, MAP2K6 and MARK2. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade by mediating phosphorylation and subsequent activation of the upstream MAP2K3 and MAP2K6 kinases. Involved in G-protein coupled receptor signaling to p38/MAPK14. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of MAP2K3 and MAP2K6. Acts as a regulator of cytoskeleton stability by phosphorylating 'Thr-208' of MARK2, leading to activate MARK2 kinase activity and subsequent phosphorylation and detachment of MAPT/TAU from microtubules. Also acts as a regulator of apoptosis: regulates apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation via activation of the MAPK8/JNK cascade. {ECO:0000269|PubMed:12665513, ECO:0000269|PubMed:13679851, ECO:0000269|PubMed:16407310, ECO:0000269|PubMed:17396146, ECO:0000269|PubMed:17900936}.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.102
RVIS EVS: -0.62
RVIS percentile EVS: 17.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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