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STK4
serine/threonine kinase 4
STK4 is located on the long (q) arm of chromosome 20, at band 20q13.12. Arm ratio per GRCh38 - banding schematic.
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Overview
STK4 (serine/threonine kinase 4) encodes a protein kinase that plays an essential role in immune system function. The encoded enzyme acts as a molecular switch, controlling whether immune cells survive, divide, or undergo programmed cell death. This regulation is particularly important for T lymphocytes and B lymphocytes, which form the adaptive immune response.
When both copies of STK4 carry pathogenic variants, the resulting enzyme deficiency impairs immune cell development and function. This autosomal recessive condition manifests as primary immunodeficiency, characterised by recurrent bacterial and viral infections. The gene is located on chromosome 20 and is recognised in UK clinical genomics pathways for immunodeficiency assessment.
What the gene does
The STK4 protein functions as a serine/threonine kinase, meaning it adds phosphate groups to specific serine and threonine amino acids in target proteins. This phosphorylation activity regulates multiple cellular processes essential for immune cell biology. The kinase controls pathways that determine whether lymphocytes survive or undergo apoptosis, ensuring proper immune cell turnover and preventing autoimmunity.
STK4 regulates the localisation and activity of proteins involved in cell migration, allowing immune cells to move to sites of infection or inflammation. The enzyme also influences lymphocyte trafficking between blood, lymphoid organs, and tissues. Within immune cells, STK4 contributes to cytoskeletal reorganisation and cell polarity, processes required for effective immune surveillance.
The protein's kinase activity is regulated through interactions with other signalling molecules and through its own domain structure. When activated, STK4 phosphorylates downstream targets that control gene expression programmes determining immune cell fate and function.
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Chromosome location
STK4 is located on the long arm of chromosome 20 at band 20q13.12. This chromosomal region contains multiple genes involved in diverse biological processes. The precise genomic coordinates and exon structure of STK4 allow for targeted sequencing approaches when investigating suspected immunodeficiency conditions.
Protein structure
The STK4 protein comprises 487 amino acids organised into several functional regions. The N-terminal Protein kinase domain, spanning amino acids 30 to 281, contains the catalytic machinery responsible for phosphorylating target proteins. This domain exhibits the characteristic fold and active-site architecture of serine/threonine kinases.
A Coiled coil region between amino acids 290 and 310 likely mediates protein-protein interactions, allowing STK4 to form dimers or interact with regulatory partners. A Disordered region from amino acids 303 to 332 provides structural flexibility that may facilitate conformational changes during activation.
The C-terminal SARAH domain, occupying amino acids 433 to 480, is a conserved protein interaction module. This domain enables STK4 to engage with specific binding partners, coordinating the enzyme's localisation and activity within cellular signalling networks.
Key variants
Pathogenic variants in STK4 follow an autosomal recessive inheritance pattern, meaning individuals require variants in both gene copies to develop immunodeficiency. Loss-of-function variants that eliminate kinase activity or severely reduce protein stability are most commonly associated with clinical manifestations. Missense variants affecting critical residues within the kinase domain may also impair enzyme function sufficiently to cause disease.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in STK4 cause a form of primary immunodeficiency characterised by reduced numbers and impaired function of T lymphocytes and B lymphocytes. Affected individuals typically present in early childhood with recurrent bacterial and viral infections, particularly affecting the respiratory tract and skin. Some patients develop autoimmune manifestations, including cytopenias and inflammatory complications, reflecting the loss of normal immune regulation that STK4 provides.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic STK4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
STK4 is included on the NHS Genomic Medicine Service panel for Primary immunodeficiency or monogenic inflammatory bowel disease, reflecting its established role in inherited immune disorders. The gene holds green classification status on this panel, indicating strong evidence supporting its clinical validity. STK4 also appears on the COVID-19 research panel, where investigations continue into genetic factors influencing susceptibility to severe viral infection.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What type of inheritance pattern does STK4 follow?
STK4-related immunodeficiency follows an autosomal recessive pattern, meaning an individual must inherit pathogenic variants in both gene copies (one from each parent) to develop the condition. Carriers with one variant copy typically remain healthy.
How does STK4 differ from other immunodeficiency genes?
STK4 specifically regulates immune cell survival and migration through its kinase activity, distinguishing it from immunodeficiency genes affecting antibody production, complement activation, or other immune pathways. The clinical presentation reflects this particular cellular dysfunction.
Is STK4 testing available through the NHS?
STK4 is included on NHS Genomic Medicine Service panels for primary immunodeficiency, meaning testing may be available through appropriate clinical referral pathways when a patient's presentation suggests an inherited immune disorder.