STK4

serine/threonine kinase 4

Basic information

Region (hg38): 20:44966493-45080021

Links

ENSG00000101109 ∙ NCBI:6789 ∙ OMIM:604965 ∙ HGNC:11408 ∙ Uniprot:Q13043 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined immunodeficiency due to STK4 deficiency (Supportive), mode of inheritance: AR
• combined immunodeficiency due to STK4 deficiency (Definitive), mode of inheritance: AR
• combined immunodeficiency due to STK4 deficiency (Strong), mode of inheritance: AR
• combined immunodeficiency due to STK4 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 110 with lymphoproliferation	AR	Allergy/Immunology/Infectious; Cardiovascular	Individuals are susceptible to recurrent and severe viral, bacterial, and fungal infections (as well as sequelae such as EBV-related lymphoma), and and prophylaxis, as well as prompt and aggressive treatment of infections may be beneficial; Individuals may have cardiovascular anomalies, and surveillance (including with echocardiogram) may allow early detection and management; HSCT has been described	Allergy/Immunology/Infectious; Cardiovascular	22294732; 22174160

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the STK4 gene.

• Combined immunodeficiency due to STK4 deficiency (179 variants)
• Inborn genetic diseases (14 variants)
• not specified (8 variants)
• not provided (8 variants)
• STK4-related condition (3 variants)
• Severe combined immunodeficiency disease (2 variants)
• Inherited Immunodeficiency Diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the STK4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				42	1	43
missense			84	4	3	91
nonsense	7	1	1			9
start loss						0
frameshift	1					1
inframe indel			1			1
splice donor/acceptor (+/-2bp)		3	1	1		5
splice region			4	9	1	14
non coding				17	11	28
Total	8	4	87	64	15

Highest pathogenic variant AF is 0.0000198

Variants in STK4

This is a list of pathogenic ClinVar variants found in the STK4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-44966567-C-G			Likely benign (Oct 01, 2023)
20-44966597-C-T		Combined immunodeficiency due to STK4 deficiency	Uncertain significance (Jan 16, 2022)
20-44966611-G-A		Combined immunodeficiency due to STK4 deficiency	Likely benign (Mar 27, 2023)
20-44966611-G-T		Combined immunodeficiency due to STK4 deficiency	Likely benign (May 11, 2023)
20-44966611-GC-TT		Combined immunodeficiency due to STK4 deficiency	Likely benign (Jul 08, 2023)
20-44967227-T-A		not specified	Benign (Jan 24, 2024)
20-44972032-C-G		Combined immunodeficiency due to STK4 deficiency • not specified	Benign (Nov 12, 2023)
20-44972060-A-G		Combined immunodeficiency due to STK4 deficiency	Likely benign (Oct 20, 2023)
20-44972066-C-G		Combined immunodeficiency due to STK4 deficiency	Benign (Jan 25, 2024)
20-44972074-A-G		Combined immunodeficiency due to STK4 deficiency	Likely benign (Mar 09, 2022)
20-44972075-C-T		Combined immunodeficiency due to STK4 deficiency	Uncertain significance (May 24, 2022)
20-44972077-G-A		Combined immunodeficiency due to STK4 deficiency	Likely pathogenic (Nov 28, 2023)
20-44972080-A-C		Combined immunodeficiency due to STK4 deficiency	Uncertain significance (Jun 03, 2021)
20-44972087-A-G		Combined immunodeficiency due to STK4 deficiency	Likely benign (Jul 14, 2023)
20-44972089-A-G		Combined immunodeficiency due to STK4 deficiency	Uncertain significance (Sep 13, 2022)
20-44972096-T-C		Combined immunodeficiency due to STK4 deficiency	Likely benign (Apr 15, 2023)
20-44972120-A-G		Combined immunodeficiency due to STK4 deficiency	Likely benign (Jan 29, 2024)
20-44972149-T-C		Combined immunodeficiency due to STK4 deficiency	Uncertain significance (Jan 09, 2019)
20-44972168-A-G		Combined immunodeficiency due to STK4 deficiency	Likely benign (Apr 22, 2022)
20-44972178-A-G		Combined immunodeficiency due to STK4 deficiency	Benign (Dec 07, 2023)
20-44973280-G-T		not specified	Benign (Jan 24, 2024)
20-44975362-C-T		not specified	Benign (Jan 24, 2024)
20-44978436-T-C		Combined immunodeficiency due to STK4 deficiency	Likely benign (Sep 25, 2023)
20-44978446-C-G		Combined immunodeficiency due to STK4 deficiency	Likely benign (Oct 04, 2022)
20-44978455-C-T		Combined immunodeficiency due to STK4 deficiency • STK4-related disorder	Likely benign (Nov 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
STK4	protein_coding	protein_coding	ENST00000372806	11	113486

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0146	0.985	125726	0	22	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.47	197	264	0.746	0.0000137	3225
Missense in Polyphen		37	82.455	0.44873		984
Synonymous	0.383	85	89.6	0.949	0.00000463	879
Loss of Function	3.55	9	30.0	0.300	0.00000185	323

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.000102	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000142	0.000141
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes. {ECO:0000250|UniProtKB:Q9JI11, ECO:0000269|PubMed:11278283, ECO:0000269|PubMed:11517310, ECO:0000269|PubMed:12757711, ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:16510573, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18986304, ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:21212262, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:21512132, ECO:0000269|PubMed:8702870, ECO:0000269|PubMed:8816758}.
• Disease: DISEASE: T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations (TIIAC) [MIM:614868]: A primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T-cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect. {ECO:0000269|PubMed:22294732}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Non-small cell lung cancer - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);EGF-Core;MAPK Signaling Pathway;Ras Signaling;Signal Transduction;TCR;Signaling by Hippo (Consensus)

Recessive Scores

• pRec: 0.120

Intolerance Scores

• loftool: 0.526
• rvis_EVS: -0.42
• rvis_percentile_EVS: 25.56

Haploinsufficiency Scores

• pHI: 0.854
• hipred: Y
• hipred_score: 0.756
• ghis: 0.620

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Stk4
• Phenotype: skeleton phenotype; immune system phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: cell morphogenesis;branching involved in blood vessel morphogenesis;neural tube formation;positive regulation of protein phosphorylation;endocardium development;protein phosphorylation;apoptotic process;signal transduction;central nervous system development;negative regulation of cell population proliferation;peptidyl-serine phosphorylation;signal transduction by protein phosphorylation;keratinocyte differentiation;stress-activated protein kinase signaling cascade;positive regulation of protein binding;activation of protein kinase activity;positive regulation of peptidyl-serine phosphorylation;hippo signaling;intracellular signal transduction;positive regulation of apoptotic process;positive regulation of fat cell differentiation;negative regulation of organ growth;protein autophosphorylation;protein stabilization;primitive hemopoiesis;cell differentiation involved in embryonic placenta development;regulation of cell differentiation involved in embryonic placenta development;positive regulation of protein serine/threonine kinase activity;negative regulation of canonical Wnt signaling pathway;hepatocyte apoptotic process;positive regulation of extrinsic apoptotic signaling pathway via death domain receptors;positive regulation of vascular associated smooth muscle cell apoptotic process
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;nuclear body;protein-containing complex
• Molecular function: magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;protein binding;ATP binding;transcription factor binding;identical protein binding;protein homodimerization activity;protein serine/threonine kinase activator activity;protein dimerization activity