SIK3

protein-coding

SIK family kinase 3, the group of SIK family kinases

Gene summary

Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in positive regulation of TORC1 signaling; positive regulation of TORC2 signaling; and protein phosphorylation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001366686.3

Inheritance

AD, AR

ClinVar variants

P:2U:152B:33

Top phenotype

Spondyloepimetaphyseal dysplasia, Krakow type

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr11:116,843,402-117,098,437

External References & Databases

Ensembl (ENSG00000160584)

Transcript & Mutation Effects

hg38 • Region Span ~255.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005365

Submitter: Ambry Genetics

autismLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: Ambry Genetics

spondyloepimetaphyseal dysplasia, Krakow typeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032571

Submitter: Ambry Genetics

spondyloepimetaphyseal dysplasia, Krakow typeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032571

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, Krakow typeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032571

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spondyloepimetaphyseal dysplasia, Krakow typeAR

Manifestation: Allergy/Immunology/Infectious; Endocrine; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: The condition can include immunodeficiency, and awareness may allow antiinfectious prophylaxis and early and aggressive treatment of infection

Refs: 30232230

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIK3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 151

not providedTotal: 19

SIK3-related disorderTotal: 17

Spondyloepimetaphyseal dysplasia, Krakow typeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366686.3. 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	20 clinvar	1 clinvar	27
missense	1 clinvar	1 clinvar	140 clinvar	11 clinvar	1 clinvar	154
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	1	1	152	31	2	187

Highest pathogenic variant AF is 6.84149e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366686.3	RefSeq	NP_001353615.1	24	MANE Select
ENST00000445177.6	Ensembl	ENSP00000391295.2	24	MANE Select
NM_001281748.3	RefSeq	NP_001268677.1	20	Standard
NM_001281749.3	RefSeq	NP_001268678.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

LKB1 signaling events

Biological Process

microtubule cytoskeleton organization
protein phosphorylation
intracellular signal transduction

Molecular Function

magnesium ion binding
protein serine/threonine kinase activity
protein binding
ATP binding
tau-protein kinase activity

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292055
Coding exons: 23
Length: 255036
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.83	524	741	0.707	0.0000420	8338
Missense (PolyPhen)		145	289.33	0.50117		3448
Synonymous	-0.440	298	288	1.03	0.0000169	2450
Loss of Function	6.85	3	60.5	0.0496	0.00000275	688

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00098	0.00049	rare
Latino/Admixed American	0.000087	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Intolerance Scores

LoFtool: 0.312
RVIS EVS: -0.99
RVIS percentile EVS: 8.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.781