Immunodeficiency 18

Summary

Immunodeficiency 18 (MONDO:0014278) is a disease caused by CD3E (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: CD3E (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 261

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 18
Mondo ID	MONDO:0014278
OMIM	615615
DOID	DOID:0060017, DOID:0111971
UMLS	C3810127
MedGen	816457
GARD	0018295
Is cancer (heuristic)	no

Also known as: CD3-Epsilon deficiency · IMD18 · immunodeficiency 18 · immunodeficiency 18, SCID variant · immunodeficiency 18, Severe combined immunodeficiency variant · immunodeficiency type 18

Data availability: 261 ClinVar variants · 2 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 › severe combined immunodeficiency › T-B+ severe combined immunodeficiency › T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta › immunodeficiency 18

Related subtypes (2): immunodeficiency 25, immunodeficiency 19

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

261 retrieved; paginated sample, class counts are floors:

143 likely benign, 70 uncertain significance, 13 pathogenic, 13 benign, 9 conflicting classifications of pathogenicity, 7 likely pathogenic, 4 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12745	NM_000733.4(CD3E):c.176G>A (p.Trp59Ter)	CD3E	Pathogenic	no assertion criteria provided
2423383	NC_000011.9:g.(?118175668)(118179176_?)del	CD3E	Pathogenic	criteria provided, single submitter
2445836	NM_000733.4(CD3E):c.288T>A (p.Tyr96Ter)	CD3E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2695048	NM_000733.4(CD3E):c.131_132del (p.Thr44fs)	CD3E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2704456	NM_000733.4(CD3E):c.190A>T (p.Lys64Ter)	CD3E	Pathogenic	criteria provided, single submitter
2735762	NM_000733.4(CD3E):c.49+1G>C	CD3E	Pathogenic	criteria provided, single submitter
2735763	NM_000733.4(CD3E):c.428del (p.Gly143fs)	CD3E	Pathogenic	criteria provided, single submitter
2786487	NM_000733.4(CD3E):c.49+1G>A	CD3E	Pathogenic	criteria provided, single submitter
2864291	NM_000733.4(CD3E):c.472A>T (p.Lys158Ter)	CD3E	Pathogenic	criteria provided, single submitter
3244672	NC_000011.9:g.(?118175668)(118178043_?)del	CD3E	Pathogenic	criteria provided, single submitter
3647560	NM_000733.4(CD3E):c.310A>T (p.Lys104Ter)	CD3E	Pathogenic	criteria provided, single submitter
4721598	NM_000733.4(CD3E):c.416dup (p.Cys139fs)	CD3E	Pathogenic	criteria provided, single submitter
847887	NM_000733.4(CD3E):c.261_262del (p.Ser88fs)	CD3E	Pathogenic	criteria provided, single submitter
847888	NM_000733.4(CD3E):c.490C>T (p.Arg164Ter)	CD3E	Pathogenic	criteria provided, single submitter
831101	NC_000011.9:g.(?117856768)(118972385_?)del	SLC37A4	Pathogenic	criteria provided, single submitter
12744	NM_000733.4(CD3E):c.520+2T>C	CD3E	Likely pathogenic	criteria provided, single submitter
1475194	NM_000733.4(CD3E):c.71-2A>G	CD3E	Likely pathogenic	criteria provided, single submitter
2700001	NM_000733.4(CD3E):c.353-1G>A	CD3E	Likely pathogenic	criteria provided, single submitter
2708832	NM_000733.4(CD3E):c.520+1G>A	CD3E	Likely pathogenic	criteria provided, single submitter
3635757	NM_000733.4(CD3E):c.86-1G>A	CD3E	Likely pathogenic	criteria provided, single submitter
570046	NM_000733.4(CD3E):c.103+1G>T	CD3E	Likely pathogenic	criteria provided, single submitter
835442	NM_000733.4(CD3E):c.103+1G>A	CD3E	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414672	NM_000733.4(CD3E):c.88G>A (p.Gly30Ser)	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302662	NM_000733.4(CD3E):c.211G>C (p.Asp71His)	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426577	NM_000733.4(CD3E):c.55G>A (p.Val19Ile)	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
496074	NM_000733.4(CD3E):c.470C>T (p.Ala157Val)	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541657	NM_000733.4(CD3E):c.353-5C>A	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541658	NM_000733.4(CD3E):c.49+3G>A	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
744708	NM_000733.4(CD3E):c.103+10T>C	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877842	NM_000733.4(CD3E):c.408G>A (p.Val136=)	CD3E	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 4 · 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
CD3E	Definitive	Autosomal recessive	immunodeficiency 18	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD3E	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
SLC37A4	Orphanet:79259	Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib
APOC3	Orphanet:181428	Familial Hyperalphalipoproteinemia
ARCN1	Orphanet:659702	Intrauterine growth retardation-micrognathia-short stature-facial dysmorphism-rhizomelic shortening syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD3E	HGNC:1674	ENSG00000198851	P07766	T-cell surface glycoprotein CD3 epsilon chain	gencc,clinvar
SLC37A4	HGNC:4061	ENSG00000137700	O43826	Glucose-6-phosphate exchanger SLC37A4	clinvar
APOC3	HGNC:610	ENSG00000110245	P02656	Apolipoprotein C-III	clinvar
ARCN1	HGNC:649	ENSG00000095139	P48444	Coatomer subunit delta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD3E	T-cell surface glycoprotein CD3 epsilon chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
SLC37A4	Glucose-6-phosphate exchanger SLC37A4	Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum.
APOC3	Apolipoprotein C-III	Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma.
ARCN1	Coatomer subunit delta	Component of the coatomer, a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to t…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Transporter	1	19.4×	0.151
Antibody/Immunoglobulin	1	7.3×	0.195
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD3E	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub2, Ig-like_fold
SLC37A4	Transporter	yes		Sugar_P_transporter, MFS, MFS_dom
APOC3	Other/Unknown	no		Apo-CIII, Apo_CIII_sf
ARCN1	Other/Unknown	no		Longin-like_dom_sf, AP_mu_sigma_su, Coatomer_dsu

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
granulocyte	1
lymph node	1
vermiform appendix	1
duodenum	1
jejunal mucosa	1
body of pancreas	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD3E	168	broad	marker	granulocyte, vermiform appendix, lymph node
SLC37A4	134	ubiquitous	marker	right lobe of liver, liver, duodenum
APOC3	156	tissue_specific	marker	jejunal mucosa, right lobe of liver, liver
ARCN1	299	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARCN1	3,064
CD3E	2,267
APOC3	1,895
SLC37A4	1,242

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD3E	P07766	44
SLC37A4	O43826	25
APOC3	P02656	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARCN1	P48444	84.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 4 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
Chylomicron assembly	1	380.7×	0.017	APOC3
Chylomicron remodeling	1	380.7×	0.017	APOC3
HDL remodeling	1	380.7×	0.017	APOC3
Plasma lipoprotein assembly	1	237.9×	0.017	APOC3
Translocation of ZAP-70 to Immunological synapse	1	211.5×	0.017	CD3E
Phosphorylation of CD3 and TCR zeta chains	1	181.3×	0.017	CD3E
Co-inhibition by PD-1	1	173.0×	0.017	CD3E
TCR signaling	1	165.5×	0.017	CD3E
Plasma lipoprotein remodeling	1	158.6×	0.017	APOC3
Regulation of T cell activation by CD28 family	1	141.0×	0.018	CD3E
Metabolism of fat-soluble vitamins	1	126.9×	0.018	APOC3
Generation of second messenger molecules	1	115.3×	0.018	CD3E
Visual phototransduction	1	86.5×	0.021	APOC3
Retinoid metabolism and transport	1	82.8×	0.021	APOC3
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.022	APOC3
Downstream TCR signaling	1	42.8×	0.036	CD3E
Metabolism of vitamins and cofactors	1	38.8×	0.036	APOC3
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.036	ARCN1
COPI-mediated anterograde transport	1	36.6×	0.036	ARCN1
Sensory Perception	1	31.7×	0.039	APOC3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	29.1×	0.041	CD3E
Adaptive Immune System	1	9.9×	0.111	CD3E
Transport of small molecules	1	8.4×	0.125	APOC3
Immune System	1	4.3×	0.223	CD3E
Metabolism	1	3.9×	0.237	APOC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of high-density lipoprotein particle clearance	1	4213.0×	0.008	APOC3
cerebellar Purkinje cell layer maturation	1	2106.5×	0.008	ARCN1
negative regulation of cholesterol import	1	1404.3×	0.008	APOC3
T cell anergy	1	1053.2×	0.008	CD3E
negative regulation of very-low-density lipoprotein particle clearance	1	1053.2×	0.008	APOC3
negative regulation of lipid metabolic process	1	842.6×	0.008	APOC3
alpha-beta T cell activation	1	842.6×	0.008	CD3E
positive regulation of T cell anergy	1	702.2×	0.008	CD3E
negative regulation of triglyceride catabolic process	1	702.2×	0.008	APOC3
negative regulation of very-low-density lipoprotein particle remodeling	1	702.2×	0.008	APOC3
glucose-6-phosphate transport	1	702.2×	0.008	SLC37A4
chylomicron remnant clearance	1	702.2×	0.008	APOC3
signal complex assembly	1	526.6×	0.008	CD3E
positive regulation of cell-cell adhesion mediated by integrin	1	526.6×	0.008	CD3E
gamma-delta T cell activation	1	526.6×	0.008	CD3E
Golgi localization	1	526.6×	0.008	ARCN1
CD4-positive, alpha-beta T cell proliferation	1	468.1×	0.008	CD3E
negative regulation of receptor-mediated endocytosis	1	468.1×	0.008	APOC3
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	421.3×	0.008	CD3E
negative regulation of low-density lipoprotein particle clearance	1	383.0×	0.008	APOC3
regulation of Cdc42 protein signal transduction	1	351.1×	0.008	APOC3
positive thymic T cell selection	1	351.1×	0.008	CD3E
negative thymic T cell selection	1	351.1×	0.008	CD3E
very-low-density lipoprotein particle assembly	1	300.9×	0.009	APOC3
phosphate ion transmembrane transport	1	300.9×	0.009	SLC37A4
phospholipid efflux	1	280.9×	0.009	APOC3
lipoprotein metabolic process	1	234.1×	0.010	APOC3
reverse cholesterol transport	1	234.1×	0.010	APOC3
negative regulation of fatty acid biosynthetic process	1	221.7×	0.010	APOC3
G protein-coupled receptor signaling pathway	2	18.1×	0.010	CD3E, APOC3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CD3E	0	0
SLC37A4	0	0
APOC3	0	0
ARCN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC37A4	5	Binding:5
APOC3	1	Binding:1
ARCN1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CD3E, SLC37A4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	APOC3, ARCN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CD3E	0	—
SLC37A4	5	—
APOC3	1	—
ARCN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.