combined immunodeficiency due to CD3gamma deficiency

Summary

combined immunodeficiency due to CD3gamma deficiency (MONDO:0014276) is a disease caused by CD3G (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: CD3G (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 167

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to CD3gamma deficiency
Mondo ID	MONDO:0014276
OMIM	615607
Orphanet	169082
DOID	DOID:0060018, DOID:0111973
SNOMED CT	725135004
UMLS	C3810107
MedGen	816437
GARD	0017046
Is cancer (heuristic)	no

Also known as: CD3 deficiency · CD3-gamma deficiency · CD3gamma deficiency · combined immunodeficiency due to CD3gamma deficiency · IMD17 · immunodeficiency 17 · immunodeficiency type 17 · SCID-like immunodeficiency, T cell-partial, B cell-positive, NK cell-positive

Data availability: 167 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 › combined immunodeficiency due to CD3gamma 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 STK4 deficiency, combined immunodeficiency due to MALT1 deficiency, combined immunodeficiency due to OX40 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

167 retrieved; paginated sample, class counts are floors:

64 likely benign, 61 uncertain significance, 12 conflicting classifications of pathogenicity, 11 pathogenic, 8 likely pathogenic, 6 benign, 3 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070478	NM_000073.3(CD3G):c.178A>T (p.Lys60Ter)	CD3G	Pathogenic	criteria provided, single submitter
12753	NM_000073.3(CD3G):c.1A>G (p.Met1Val)	CD3G	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12754	NC_000011.10:g.118349744_118349760del	CD3G	Pathogenic	no assertion criteria provided
1452317	NM_000073.3(CD3G):c.71C>G (p.Ser24Ter)	CD3G	Pathogenic	criteria provided, single submitter
1457956	NM_000073.3(CD3G):c.496C>T (p.Arg166Ter)	CD3G	Pathogenic	criteria provided, single submitter
2053595	NM_000073.3(CD3G):c.513C>G (p.Tyr171Ter)	CD3G	Pathogenic	criteria provided, single submitter
2833798	NM_000073.3(CD3G):c.109C>T (p.Gln37Ter)	CD3G	Pathogenic	criteria provided, single submitter
4709890	NM_000073.3(CD3G):c.80-1G>C	CD3G	Pathogenic	criteria provided, single submitter
541654	NM_000073.3(CD3G):c.213del (p.Lys71fs)	CD3G	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
580586	NM_000073.3(CD3G):c.213dup (p.Trp72fs)	CD3G	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
965164	NM_000073.3(CD3G):c.13A>T (p.Lys5Ter)	CD3G	Pathogenic	criteria provided, single submitter
100626	NM_000073.3(CD3G):c.205A>T (p.Lys69Ter)	LOC126861358	Pathogenic	criteria provided, multiple submitters, no conflicts
1993104	NM_000073.3(CD3G):c.357_358del (p.Phe120fs)	LOC126861358	Pathogenic	criteria provided, single submitter
831101	NC_000011.9:g.(?117856768)(118972385_?)del	SLC37A4	Pathogenic	criteria provided, single submitter
1964376	NM_000073.3(CD3G):c.70_79+5del	CD3G	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431635	NM_000073.3:c.70_80del	CD3G	Likely pathogenic	criteria provided, single submitter
3599122	NM_000073.3(CD3G):c.55+1G>T	CD3G	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599123	NM_000073.3(CD3G):c.56-1G>A	CD3G	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3652400	NM_000073.3(CD3G):c.2T>A (p.Met1Lys)	CD3G	Likely pathogenic	criteria provided, single submitter
4712950	NM_000073.3(CD3G):c.2T>C (p.Met1Thr)	CD3G	Likely pathogenic	criteria provided, single submitter
4738867	NM_000073.3(CD3G):c.79+1G>A	CD3G	Likely pathogenic	criteria provided, single submitter
4845742	NM_000073.3(CD3G):c.56-2del	CD3G	Likely pathogenic	criteria provided, single submitter
302679	NM_000073.3(CD3G):c.-17G>T	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302681	NM_000073.3(CD3G):c.158T>C (p.Ile53Thr)	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302686	NM_000073.3(CD3G):c.511T>C (p.Tyr171His)	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445361	NM_000073.3(CD3G):c.439+12C>T	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
474801	NM_000073.3(CD3G):c.79+10A>G	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541655	NM_000073.3(CD3G):c.496C>A (p.Arg166=)	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541656	NM_000073.3(CD3G):c.56G>A (p.Gly19Asp)	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
572829	NM_000073.3(CD3G):c.187G>A (p.Gly63Ser)	CD3G	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 5 · 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
CD3G	Strong	Autosomal recessive	combined immunodeficiency due to CD3gamma deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD3G	Orphanet:169082	Combined immunodeficiency due to CD3gamma deficiency
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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD3G	HGNC:1675	ENSG00000160654	P09693	T-cell surface glycoprotein CD3 gamma chain	gencc,clinvar
CD3D	HGNC:1673	ENSG00000167286	P04234	T-cell surface glycoprotein CD3 delta chain	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)
CD3G	T-cell surface glycoprotein CD3 gamma chain	Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
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: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Antibody/Immunoglobulin	2	11.7×	0.033
Transporter	1	15.6×	0.094
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD3G	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub2, Ig-like_fold
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.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	2
thymus	2
liver	2
right lobe of liver	2
buccal mucosa cell	1
granulocyte	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
CD3G	166	broad	marker	buccal mucosa cell, lymph node, thymus
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: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD3D	4,789
ARCN1	3,064
APOC3	1,895
CD3G	1,616
SLC37A4	1,242

Intra-cohort edges

A	B	Sources
CD3D	CD3G	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD3G	P09693	38
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: 44. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	2	317.2×	3e-04	CD3G, CD3D
Phosphorylation of CD3 and TCR zeta chains	2	271.9×	3e-04	CD3G, CD3D
Co-inhibition by PD-1	2	259.6×	3e-04	CD3G, CD3D
TCR signaling	2	248.3×	3e-04	CD3G, CD3D
Regulation of T cell activation by CD28 family	2	211.5×	3e-04	CD3G, CD3D
Generation of second messenger molecules	2	173.0×	4e-04	CD3G, CD3D
Downstream TCR signaling	2	64.2×	0.002	CD3G, CD3D
Cargo recognition for clathrin-mediated endocytosis	2	52.4×	0.003	CD3G, CD3D
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	43.6×	0.004	CD3G, CD3D
Clathrin-mediated endocytosis	2	42.6×	0.004	CD3G, CD3D
Chylomicron assembly	1	285.5×	0.012	APOC3
Chylomicron remodeling	1	285.5×	0.012	APOC3
HDL remodeling	1	285.5×	0.012	APOC3
FCGR activation	1	219.6×	0.013	CD3G
Membrane Trafficking	2	18.5×	0.013	CD3G, CD3D
Vesicle-mediated transport	2	17.4×	0.013	CD3G, CD3D
Plasma lipoprotein assembly	1	178.4×	0.014	APOC3
Adaptive Immune System	2	14.9×	0.016	CD3G, CD3D
Plasma lipoprotein remodeling	1	119.0×	0.019	APOC3
Role of phospholipids in phagocytosis	1	114.2×	0.019	CD3G
Anti-inflammatory response favouring Leishmania parasite infection	1	98.5×	0.020	CD3G
Leishmania parasite growth and survival	1	98.5×	0.020	CD3G
Metabolism of fat-soluble vitamins	1	95.2×	0.020	APOC3
Parasite infection	1	86.5×	0.020	CD3G
Leishmania phagocytosis	1	86.5×	0.020	CD3G
FCGR3A-mediated IL10 synthesis	1	73.2×	0.023	CD3G
Fcgamma receptor (FCGR) dependent phagocytosis	1	69.6×	0.023	CD3G
Visual phototransduction	1	64.9×	0.024	APOC3
Retinoid metabolism and transport	1	62.1×	0.024	APOC3
Plasma lipoprotein assembly, remodeling, and clearance	1	57.1×	0.026	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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
alpha-beta T cell activation	2	1348.2×	3e-05	CD3G, CD3D
positive thymic T cell selection	2	561.7×	1e-04	CD3G, CD3D
negative regulation of high-density lipoprotein particle clearance	1	3370.4×	0.003	APOC3
regulation of lymphocyte apoptotic process	1	3370.4×	0.003	CD3G
T cell receptor signaling pathway	2	60.7×	0.004	CD3G, CD3D
cerebellar Purkinje cell layer maturation	1	1685.2×	0.005	ARCN1
negative regulation of cholesterol import	1	1123.5×	0.006	APOC3
negative regulation of very-low-density lipoprotein particle clearance	1	842.6×	0.006	APOC3
negative regulation of lipid metabolic process	1	674.1×	0.006	APOC3
negative regulation of triglyceride catabolic process	1	561.7×	0.006	APOC3
negative regulation of very-low-density lipoprotein particle remodeling	1	561.7×	0.006	APOC3
glucose-6-phosphate transport	1	561.7×	0.006	SLC37A4
chylomicron remnant clearance	1	561.7×	0.006	APOC3
adaptive immune response	2	33.7×	0.006	CD3G, CD3D
gamma-delta T cell activation	1	421.3×	0.006	CD3G
Golgi localization	1	421.3×	0.006	ARCN1
cell surface receptor signaling pathway	2	25.6×	0.006	CD3G, CD3D
negative regulation of receptor-mediated endocytosis	1	374.5×	0.007	APOC3
negative regulation of low-density lipoprotein particle clearance	1	306.4×	0.008	APOC3
regulation of Cdc42 protein signal transduction	1	280.9×	0.008	APOC3
very-low-density lipoprotein particle assembly	1	240.7×	0.009	APOC3
phosphate ion transmembrane transport	1	240.7×	0.009	SLC37A4
phospholipid efflux	1	224.7×	0.009	APOC3
lipoprotein metabolic process	1	187.2×	0.010	APOC3
reverse cholesterol transport	1	187.2×	0.010	APOC3
negative regulation of fatty acid biosynthetic process	1	177.4×	0.010	APOC3
negative regulation of lipid catabolic process	1	168.5×	0.010	APOC3
triglyceride catabolic process	1	160.5×	0.010	APOC3
high-density lipoprotein particle remodeling	1	160.5×	0.010	APOC3
pigmentation	1	140.4×	0.011	ARCN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CD3G	0	0
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: 5; 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	3	CD3G, CD3D, SLC37A4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	APOC3, ARCN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CD3G	0	—
CD3D	0	—
SLC37A4	5	—
APOC3	1	—
ARCN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.