Immunodeficiency 19

Summary

Immunodeficiency 19 (MONDO:0014280) is a disease caused by CD3D (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: CD3D (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 201

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 19
Mondo ID	MONDO:0014280
OMIM	615617
DOID	DOID:0060016, DOID:0111972
UMLS	C3810147
MedGen	816477
GARD	0018296
Is cancer (heuristic)	no

Also known as: CD3D severe combined immunodeficiency (disease) · CD3delta deficiency · IMD19 · immunodeficiency 19 · immunodeficiency type 19 · severe combined immunodeficiency (disease) caused by mutation in CD3D

Data availability: 201 ClinVar variants · 1 GenCC gene-disease record.

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 19

Related subtypes (2): immunodeficiency 25, immunodeficiency 18

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

201 retrieved; paginated sample, class counts are floors:

101 likely benign, 74 uncertain significance, 10 pathogenic, 5 benign, 5 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075708	NM_000732.6(CD3D):c.51_52del (p.Gln18fs)	CD3D	Pathogenic	criteria provided, single submitter
12747	NM_000732.6(CD3D):c.202C>T (p.Arg68Ter)	CD3D	Pathogenic	criteria provided, multiple submitters, no conflicts
12748	NM_000732.6(CD3D):c.279C>A (p.Cys93Ter)	CD3D	Pathogenic	criteria provided, multiple submitters, no conflicts
180674	NM_000732.6(CD3D):c.274+5G>A	CD3D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2697867	NM_000732.6(CD3D):c.9_10del (p.His3fs)	CD3D	Pathogenic	criteria provided, single submitter
2739601	NM_000732.6(CD3D):c.18dup (p.Leu7fs)	CD3D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2754021	NM_000732.6(CD3D):c.237C>G (p.Tyr79Ter)	CD3D	Pathogenic	criteria provided, single submitter
2766936	NM_000732.6(CD3D):c.15del (p.Leu7fs)	CD3D	Pathogenic	criteria provided, single submitter
2772341	NM_000732.6(CD3D):c.40_41dup (p.Leu15fs)	CD3D	Pathogenic	criteria provided, single submitter
2869561	NM_000732.6(CD3D):c.271C>T (p.Arg91Ter)	CD3D	Pathogenic	criteria provided, single submitter
643120	NM_000732.6(CD3D):c.128G>A (p.Trp43Ter)	CD3D	Pathogenic	criteria provided, single submitter
831101	NC_000011.9:g.(?117856768)(118972385_?)del	SLC37A4	Pathogenic	criteria provided, single submitter
1468778	NM_000732.6(CD3D):c.407-2A>G	CD3D	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1508408	NM_000732.6(CD3D):c.407-1G>A	CD3D	Likely pathogenic	criteria provided, single submitter
2759883	NM_000732.6(CD3D):c.274+2T>C	CD3D	Likely pathogenic	criteria provided, single submitter
2810710	NM_000732.6(CD3D):c.406+1G>T	CD3D	Likely pathogenic	criteria provided, single submitter
3599120	NM_000732.6(CD3D):c.450+1G>A	CD3D	Likely pathogenic	criteria provided, single submitter
302670	NM_000732.6(CD3D):c.510C>T (p.Asn170=)	CD3D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879824	NM_000732.6(CD3D):c.450+7G>T	CD3D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
940758	NM_000732.6(CD3D):c.457C>T (p.Arg153Ter)	CD3D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2422303	NC_000011.9:g.(?116691583)(121500272_?)dup	APOC3	Uncertain significance	criteria provided, single submitter
1007237	NC_000011.9:g.(?117856768)(118972385_?)dup	ARCN1	Uncertain significance	criteria provided, single submitter
1016811	NM_000732.6(CD3D):c.506G>A (p.Arg169Gln)	CD3D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1017550	NM_000732.6(CD3D):c.152T>C (p.Leu51Pro)	CD3D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1020817	NM_000732.6(CD3D):c.187C>T (p.Arg63Cys)	CD3D	Uncertain significance	criteria provided, single submitter
1022082	NM_000732.6(CD3D):c.412G>A (p.Asp138Asn)	CD3D	Uncertain significance	criteria provided, single submitter
1042647	NM_000732.6(CD3D):c.285C>A (p.Ser95Arg)	CD3D	Uncertain significance	criteria provided, single submitter
1043193	NM_000732.6(CD3D):c.77T>C (p.Ile26Thr)	CD3D	Uncertain significance	criteria provided, single submitter
1043227	NM_000732.6(CD3D):c.19C>T (p.Leu7Phe)	CD3D	Uncertain significance	criteria provided, single submitter
1056415	NM_000732.6(CD3D):c.28C>G (p.Leu10Val)	CD3D	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
CD3D	Strong	Autosomal recessive	immunodeficiency 19	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD3D	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
CD3D	HGNC:1673	ENSG00000167286	P04234	T-cell surface glycoprotein CD3 delta 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)
CD3D	T-cell surface glycoprotein CD3 delta 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)
CD3D	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig-like_fold, CD3_esu/gsu/dsu
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
thymus	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
CD3D	221	broad	marker	thymus, granulocyte, 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
CD3D	4,789
ARCN1	3,064
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
CD3D	P04234	31
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: 29. 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×	0.020	APOC3
Chylomicron remodeling	1	380.7×	0.020	APOC3
HDL remodeling	1	380.7×	0.020	APOC3
Plasma lipoprotein assembly	1	237.9×	0.020	APOC3
Translocation of ZAP-70 to Immunological synapse	1	211.5×	0.020	CD3D
Phosphorylation of CD3 and TCR zeta chains	1	181.3×	0.020	CD3D
Co-inhibition by PD-1	1	173.0×	0.020	CD3D
TCR signaling	1	165.5×	0.020	CD3D
Plasma lipoprotein remodeling	1	158.6×	0.020	APOC3
Regulation of T cell activation by CD28 family	1	141.0×	0.021	CD3D
Metabolism of fat-soluble vitamins	1	126.9×	0.021	APOC3
Generation of second messenger molecules	1	115.3×	0.021	CD3D
Visual phototransduction	1	86.5×	0.025	APOC3
Retinoid metabolism and transport	1	82.8×	0.025	APOC3
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.025	APOC3
Downstream TCR signaling	1	42.8×	0.041	CD3D
Metabolism of vitamins and cofactors	1	38.8×	0.041	APOC3
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.041	ARCN1
COPI-mediated anterograde transport	1	36.6×	0.041	ARCN1
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.041	CD3D
Sensory Perception	1	31.7×	0.043	APOC3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	29.1×	0.044	CD3D
Clathrin-mediated endocytosis	1	28.4×	0.044	CD3D
Membrane Trafficking	1	12.4×	0.095	CD3D
Vesicle-mediated transport	1	11.6×	0.097	CD3D
Adaptive Immune System	1	9.9×	0.109	CD3D
Transport of small molecules	1	8.4×	0.123	APOC3
Immune System	1	4.3×	0.222	CD3D
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×	0.006	APOC3
cerebellar Purkinje cell layer maturation	1	2106.5×	0.006	ARCN1
negative regulation of cholesterol import	1	1404.3×	0.006	APOC3
negative regulation of very-low-density lipoprotein particle clearance	1	1053.2×	0.006	APOC3
negative regulation of lipid metabolic process	1	842.6×	0.006	APOC3
alpha-beta T cell activation	1	842.6×	0.006	CD3D
negative regulation of triglyceride catabolic process	1	702.2×	0.006	APOC3
negative regulation of very-low-density lipoprotein particle remodeling	1	702.2×	0.006	APOC3
glucose-6-phosphate transport	1	702.2×	0.006	SLC37A4
chylomicron remnant clearance	1	702.2×	0.006	APOC3
Golgi localization	1	526.6×	0.007	ARCN1
negative regulation of receptor-mediated endocytosis	1	468.1×	0.007	APOC3
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	CD3D
very-low-density lipoprotein particle assembly	1	300.9×	0.008	APOC3
phosphate ion transmembrane transport	1	300.9×	0.008	SLC37A4
phospholipid efflux	1	280.9×	0.008	APOC3
lipoprotein metabolic process	1	234.1×	0.008	APOC3
reverse cholesterol transport	1	234.1×	0.008	APOC3
negative regulation of fatty acid biosynthetic process	1	221.7×	0.008	APOC3
negative regulation of lipid catabolic process	1	210.7×	0.008	APOC3
triglyceride catabolic process	1	200.6×	0.008	APOC3
high-density lipoprotein particle remodeling	1	200.6×	0.008	APOC3
pigmentation	1	175.5×	0.009	ARCN1
cholesterol efflux	1	131.7×	0.012	APOC3
triglyceride homeostasis	1	120.4×	0.012	APOC3
triglyceride metabolic process	1	110.9×	0.013	APOC3
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	84.3×	0.016	ARCN1
gluconeogenesis	1	81.0×	0.016	SLC37A4

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
CD3D	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	CD3D, 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)
CD3D	0	—
SLC37A4	5	—
APOC3	1	—
ARCN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.