combined immunodeficiency due to STK4 deficiency

Summary

combined immunodeficiency due to STK4 deficiency (MONDO:0013934) is a disease caused by STK4 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STK4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 263

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to STK4 deficiency
Mondo ID	MONDO:0013934
OMIM	614868
Orphanet	314689
UMLS	C3553943
MedGen	766857
GARD	0017430
Is cancer (heuristic)	no

Also known as: CID due to STK4 deficiency · MST1 deficiency · STK4 deficiency · T-cell immunodeficiency, recurrent infections, and autoimmunity with or without CARDIAC malformations · T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations · TIIAC

Data availability: 263 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › combined immunodeficiency due to STK4 deficiency

Related subtypes (32): ataxia telangiectasia, combined immunodeficiency due to ZAP70 deficiency, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia, combined immunodeficiency due to moesin deficiency, Wiskott-Aldrich syndrome, MHC class I deficiency, combined immunodeficiency due to MALT1 deficiency, combined immunodeficiency due to OX40 deficiency, combined immunodeficiency due to CD3gamma deficiency, combined immunodeficiency due to CTPS1 deficiency, combined immunodeficiency due to CRAC channel dysfunction, severe combined immunodeficiency, non-SCID combined immunodeficiency, combined immunodeficiency due to RELA haploinsufficiency, combined immunodeficiency due to GINS1 deficiency, combined immunodeficiency syndrome, combined immunodeficiency due to POLE2 deficiency, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency, combined immunodeficiency due to TBX1 deficiency, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, combined immunodeficiency due to dimerization defective IKAROS mutation, late-onset combined immunodeficiency due to ICOSL deficiency, combined immunodeficiency-hypogammaglobulinemia-skeletal anomalies syndrome due to IKBKA deficiency, early-onset combined immunodeficiency with low ig due to dominant negative IKAROS mutation, combined immunodeficiency with low Ig due to BCL10 deficiency, IRF4-related combined immunodeficiency, NFATC1-related combined immunodeficiency, POLD3-related combined immunodeficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

263 retrieved; paginated sample, class counts are floors:

127 likely benign, 101 uncertain significance, 16 pathogenic, 7 benign, 6 benign/likely benign, 3 conflicting classifications of pathogenicity, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425559	NC_000020.10:g.(?42223339)(44638757_?)del	ACOT8	Pathogenic	criteria provided, single submitter
1068530	NM_006282.5(STK4):c.922C>T (p.Gln308Ter)	STK4	Pathogenic	criteria provided, single submitter
1075656	NM_006282.5(STK4):c.442C>T (p.Arg148Ter)	STK4	Pathogenic	criteria provided, multiple submitters, no conflicts
1455329	NM_006282.5(STK4):c.373G>T (p.Glu125Ter)	STK4	Pathogenic	criteria provided, single submitter
2727529	NM_006282.5(STK4):c.871C>T (p.Arg291Ter)	STK4	Pathogenic	criteria provided, single submitter
2993502	NM_006282.5(STK4):c.994C>T (p.Arg332Ter)	STK4	Pathogenic	criteria provided, single submitter
3587269	NM_006282.5(STK4):c.343C>T (p.Arg115Ter)	STK4	Pathogenic	criteria provided, multiple submitters, no conflicts
3642667	NM_006282.5(STK4):c.964G>T (p.Glu322Ter)	STK4	Pathogenic	criteria provided, single submitter
3727861	NM_006282.5(STK4):c.92dup (p.Asp31fs)	STK4	Pathogenic	criteria provided, single submitter
37323	NM_006282.5(STK4):c.349C>T (p.Arg117Ter)	STK4	Pathogenic	criteria provided, multiple submitters, no conflicts
37324	NM_006282.5(STK4):c.1103del (p.Met368fs)	STK4	Pathogenic	criteria provided, single submitter
37325	NM_006282.5(STK4):c.749G>A (p.Trp250Ter)	STK4	Pathogenic	criteria provided, single submitter
4695606	NM_006282.5(STK4):c.297G>A (p.Trp99Ter)	STK4	Pathogenic	criteria provided, single submitter
4717418	NM_006282.5(STK4):c.1135_1138del (p.Gly379fs)	STK4	Pathogenic	criteria provided, single submitter
4849144	NC_000020.10:g.(?43595152)(43708663_?)del	STK4	Pathogenic	criteria provided, single submitter
835262	NM_006282.5(STK4):c.733C>T (p.Arg245Ter)	STK4	Pathogenic	criteria provided, multiple submitters, no conflicts
2020904	NM_006282.5(STK4):c.36-1G>A	STK4	Likely pathogenic	criteria provided, single submitter
2050900	NM_006282.5(STK4):c.961-2A>G	STK4	Likely pathogenic	criteria provided, single submitter
3587270	NM_006282.5(STK4):c.775A>T (p.Lys259Ter)	STK4	Likely pathogenic	criteria provided, single submitter
1911839	NM_006282.5(STK4):c.246C>T (p.Ser82=)	STK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2629147	NM_006282.5(STK4):c.484C>A (p.His162Asn)	STK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721197	NM_006282.5(STK4):c.1057A>G (p.Thr353Ala)	STK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4763905	NM_006282.5(STK4):c.1A>T (p.Met1Leu)	LOC130065950	Uncertain significance	criteria provided, single submitter
1001952	NM_006282.5(STK4):c.155C>T (p.Thr52Ile)	STK4	Uncertain significance	criteria provided, single submitter
1008149	NM_006282.5(STK4):c.370G>T (p.Asp124Tyr)	STK4	Uncertain significance	criteria provided, single submitter
1018275	NM_006282.5(STK4):c.370G>A (p.Asp124Asn)	STK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022878	NM_006282.5(STK4):c.1388G>A (p.Arg463Gln)	STK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025335	NM_006282.5(STK4):c.804G>C (p.Gln268His)	STK4	Uncertain significance	criteria provided, single submitter
1035045	NM_006282.5(STK4):c.796C>A (p.Pro266Thr)	STK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1037245	NM_006282.5(STK4):c.1409G>A (p.Arg470Gln)	STK4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
STK4	Definitive	Autosomal recessive	combined immunodeficiency due to STK4 deficiency	5
MST1	Moderate	Autosomal recessive	combined immunodeficiency due to STK4 deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STK4	Orphanet:314689	Combined immunodeficiency due to STK4 deficiency
MST1	Orphanet:171	Primary sclerosing cholangitis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STK4	HGNC:11408	ENSG00000101109	Q13043	Serine/threonine-protein kinase 4	gencc,clinvar
MST1	HGNC:7380	ENSG00000173531	P26927	Hepatocyte growth factor-like protein	gencc
ACOT8	HGNC:15919	ENSG00000101473	O14734	Acyl-coenzyme A thioesterase 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STK4	Serine/threonine-protein kinase 4	Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation.
ACOT8	Acyl-coenzyme A thioesterase 8	Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	12.2×	0.157
Kinase	1	9.2×	0.157
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STK4	Kinase	yes	2.7.11.1	Prot_kinase_dom, Kinase-like_dom_sf, SARAH_dom
MST1	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A
ACOT8	Enzyme (other)	yes	3.1.2.2	Acyl_CoA_thio, HotDog_dom_sf, Acyl-CoA_hotdog

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
buccal mucosa cell	1
colonic epithelium	1
duodenum	1
liver	1
right lobe of liver	1
mucosa of transverse colon	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STK4	267	ubiquitous	marker	colonic epithelium, buccal mucosa cell, blood
MST1	134	broad	marker	right lobe of liver, liver, duodenum
ACOT8	250	ubiquitous	marker	mucosa of transverse colon, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STK4	3,467
ACOT8	1,826
MST1	1,172

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STK4	Q13043	16
MST1	P26927	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOT8	O14734	88.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MST1	1	761.3×	0.012	MST1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	634.4×	0.012	ACOT8
Beta-oxidation of pristanoyl-CoA	1	380.7×	0.012	ACOT8
Beta-oxidation of very long chain fatty acids	1	292.8×	0.012	ACOT8
alpha-linolenic acid (ALA) metabolism	1	237.9×	0.012	ACOT8
Peroxisomal lipid metabolism	1	223.9×	0.012	ACOT8
Signaling by Hippo	1	181.3×	0.012	STK4
Bile acid and bile salt metabolism	1	165.5×	0.012	ACOT8
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	152.3×	0.012	ACOT8
Synthesis of bile acids and bile salts	1	135.9×	0.012	ACOT8
Protein localization	1	63.4×	0.024	ACOT8
Peroxisomal protein import	1	57.7×	0.024	ACOT8
Metabolism of steroids	1	45.9×	0.028	ACOT8
Fatty acid metabolism	1	43.8×	0.028	ACOT8
Metabolism of lipids	1	10.5×	0.104	ACOT8
Metabolism	1	3.9×	0.251	ACOT8
Signal Transduction	1	3.4×	0.267	STK4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cAMP-dependent protein kinase activity	1	5617.3×	0.006	MST1
dicarboxylic acid catabolic process	1	2808.7×	0.006	ACOT8
positive regulation of hepatocyte apoptotic process	1	2808.7×	0.006	STK4
negative regulation of glycoprotein biosynthetic process	1	1404.3×	0.006	ACOT8
regulation of cell differentiation involved in embryonic placenta development	1	1404.3×	0.006	STK4
positive regulation of substrate-dependent cell migration, cell attachment to substrate	1	1404.3×	0.006	STK4
endocardium development	1	1123.5×	0.006	STK4
primitive hemopoiesis	1	1123.5×	0.006	STK4
cell differentiation involved in embryonic placenta development	1	802.5×	0.007	STK4
neural tube formation	1	702.2×	0.007	STK4
peroxisome fission	1	510.7×	0.007	ACOT8
fatty acid derivative biosynthetic process	1	510.7×	0.007	ACOT8
regulation of receptor signaling pathway via JAK-STAT	1	468.1×	0.007	MST1
negative regulation of organ growth	1	468.1×	0.007	STK4
positive regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	468.1×	0.007	STK4
fatty acid catabolic process	1	432.1×	0.007	ACOT8
fatty acid beta-oxidation using acyl-CoA oxidase	1	374.5×	0.008	ACOT8
positive regulation of hippo signaling	1	351.1×	0.008	STK4
hepatocyte apoptotic process	1	351.1×	0.008	STK4
alpha-linolenic acid metabolic process	1	295.6×	0.009	ACOT8
negative regulation of gluconeogenesis	1	267.5×	0.009	MST1
positive regulation of peptidyl-serine phosphorylation	1	255.3×	0.009	STK4
organ growth	1	244.2×	0.009	STK4
hippo signaling	1	244.2×	0.009	STK4
acyl-CoA metabolic process	1	234.1×	0.009	ACOT8
unsaturated fatty acid biosynthetic process	1	216.1×	0.009	ACOT8
bile acid biosynthetic process	1	208.1×	0.009	ACOT8
protein tetramerization	1	208.1×	0.009	STK4
branching involved in blood vessel morphogenesis	1	175.5×	0.010	STK4
peptidyl-serine phosphorylation	1	165.2×	0.010	STK4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STK4	AXITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STK4	38	4
MST1	0	0
ACOT8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AXITINIB	4	STK4
NERATINIB	4	STK4
BOSUTINIB	4	STK4
NINTEDANIB	4	STK4
SUNITINIB	4	STK4
DASATINIB	4	STK4
CRIZOTINIB	4	STK4
MIDOSTAURIN	4	STK4
CRENOLANIB	3	STK4
LINIFANIB	3	STK4
ORANTINIB	3	STK4
DEFACTINIB	3	STK4
CEDIRANIB	3	STK4
DOVITINIB	3	STK4
LESTAURTINIB	3	STK4
RUBOXISTAURIN	3	STK4
FORETINIB	2	STK4
AZD-1480	2	STK4
MOLIBRESIB	2	STK4
SU-014813	2	STK4
REBASTINIB	2	STK4
ZOTIRACICLIB	2	STK4
DANUSERTIB	2	STK4
CERDULATINIB	2	STK4
TOZASERTIB	2	STK4
UCN-01	2	STK4
PELITINIB	2	STK4
PF-00562271	1	STK4
KW-2449	1	STK4
AZD-7762	1	STK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
STK4	362	Binding:362
MST1	91	Binding:91

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK4	2.7.11.1	non-specific serine/threonine protein kinase
ACOT8	3.1.2.2, 3.1.2.20	palmitoyl-CoA hydrolase, acyl-CoA hydrolase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STK4	362

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
AXITINIB	4	STK4
NERATINIB	4	STK4
BOSUTINIB	4	STK4
NINTEDANIB	4	STK4
SUNITINIB	4	STK4
DASATINIB	4	STK4
CRIZOTINIB	4	STK4
MIDOSTAURIN	4	STK4
CRENOLANIB	3	STK4
LINIFANIB	3	STK4
ORANTINIB	3	STK4
DEFACTINIB	3	STK4
CEDIRANIB	3	STK4
DOVITINIB	3	STK4
LESTAURTINIB	3	STK4
RUBOXISTAURIN	3	STK4
FORETINIB	2	STK4
AZD-1480	2	STK4
MOLIBRESIB	2	STK4
SU-014813	2	STK4
REBASTINIB	2	STK4
ZOTIRACICLIB	2	STK4
DANUSERTIB	2	STK4
CERDULATINIB	2	STK4
TOZASERTIB	2	STK4
UCN-01	2	STK4
PELITINIB	2	STK4
PF-00562271	1	STK4
KW-2449	1	STK4
AZD-7762	1	STK4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STK4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MST1
D	Druggable family + AlphaFold only, no drug	1	ACOT8
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MST1	91	—
ACOT8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.