Immunodeficiency 104

Summary

Immunodeficiency 104 (MONDO:0012163) is a disease caused by variants in IL7R and PTPRC, with 5 cohort genes. The dominant Reactome pathway is Interleukin-7 signaling (3 cohort genes).

At a glance

• Causal genes: IL7R (GenCC Definitive), PTPRC (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 1,652

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 104
Mondo ID	MONDO:0012163
MeSH	C563822
OMIM	608971
DOID	DOID:0090014
UMLS	C5676890
MedGen	1801019
GARD	0018293
Is cancer (heuristic)	no

Also known as: autosomal recessive T cell-negative, B-cell negative, NK cell-positive SCID · IMD104 · severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive · severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive · severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type

Data availability: 1,652 ClinVar variants · 41 ClinGen variant curations · 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 › severe combined immunodeficiency › familial severe combined immunodeficiency › immunodeficiency 104

Related subtypes (13): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, MHC class II deficiency, reticular dysgenesis, T-B+ severe combined immunodeficiency due to gamma chain deficiency, T-B+ severe combined immunodeficiency due to JAK3 deficiency, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, Cernunnos-XLF deficiency, immunodeficiency 18, immunodeficiency 19, immunodeficiency 49, immunodeficiency 105

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

600 retrieved; paginated sample, class counts are floors:

265 uncertain significance, 263 likely benign, 32 benign, 18 pathogenic, 10 conflicting classifications of pathogenicity, 7 benign/likely benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073963	NC_000005.9:g.(?35857060)(35857181_?)del	IL7R	Pathogenic	criteria provided, single submitter
1298987	NM_002185.5(IL7R):c.616C>T (p.Arg206Ter)	IL7R	Pathogenic	reviewed by expert panel
1339483	NM_002185.5(IL7R):c.379G>A (p.Val127Ile)	IL7R	Pathogenic	reviewed by expert panel
134528	NM_002185.5(IL7R):c.662G>T (p.Ser221Ile)	IL7R	Pathogenic	reviewed by expert panel
1437489	NM_002185.5(IL7R):c.514del (p.Glu172fs)	IL7R	Pathogenic	criteria provided, single submitter
1453790	NM_002185.5(IL7R):c.37del (p.Ser13fs)	IL7R	Pathogenic	criteria provided, single submitter
1465004	NM_002185.5(IL7R):c.126C>G (p.Cys42Trp)	IL7R	Pathogenic	criteria provided, single submitter
14841	NM_002185.5(IL7R):c.538-1G>A	IL7R	Pathogenic	reviewed by expert panel
14842	NM_002185.5(IL7R):c.651G>A (p.Trp217Ter)	IL7R	Pathogenic	criteria provided, single submitter
208851	NM_002185.5(IL7R):c.333T>A (p.Val111=)	IL7R	Pathogenic	no assertion criteria provided
2203628	NM_002185.5(IL7R):c.562del (p.Lys187_Leu188insTer)	IL7R	Pathogenic	criteria provided, single submitter
224841	NM_002185.5(IL7R):c.361dup (p.Ile121fs)	IL7R	Pathogenic	reviewed by expert panel
224842	Single allele	IL7R	Pathogenic	criteria provided, single submitter
2445731	NM_002185.5(IL7R):c.788T>A (p.Leu263Ter)	IL7R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265195	NM_002185.5(IL7R):c.221+2T>G	IL7R	Pathogenic	criteria provided, multiple submitters, no conflicts
2697973	NM_002185.5(IL7R):c.639_640insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCCCCTGATCACTATTTT (p.Lys214delinsPhePhePhePhePhePheXaaXaaXaaXaaTer)	IL7R	Pathogenic	criteria provided, single submitter
1420165	NM_002838.5(PTPRC):c.1625_1626dup (p.Asp543fs)	PTPRC	Pathogenic	criteria provided, single submitter
1460093	NM_002838.5(PTPRC):c.308C>G (p.Ser103Ter)	PTPRC	Pathogenic	criteria provided, single submitter
2696181	NM_002838.5(PTPRC):c.3236dup (p.Gln1081fs)	PTPRC	Pathogenic	criteria provided, single submitter
1323115	NM_002185.5(IL7R):c.235G>T (p.Glu79Ter)	IL7R	Likely pathogenic	reviewed by expert panel
14843	NM_002185.5(IL7R):c.394C>T (p.Pro132Ser)	IL7R	Likely pathogenic	reviewed by expert panel
1068274	NM_002838.5(PTPRC):c.1864+2T>A	PTPRC	Likely pathogenic	criteria provided, single submitter
1468346	NM_002838.5(PTPRC):c.905-2A>G	PTPRC	Likely pathogenic	criteria provided, single submitter
134531	NM_002185.5(IL7R):c.760G>A (p.Ala254Thr)	IL7R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134539	NM_002185.5(IL7R):c.1096T>C (p.Ser366Pro)	IL7R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1448910	NM_002185.5(IL7R):c.1274T>C (p.Ile425Thr)	IL7R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1896138	NM_002185.5(IL7R):c.735C>T (p.Ile245=)	IL7R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2151997	NM_002185.5(IL7R):c.536C>T (p.Thr179Met)	IL7R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2151998	NM_002185.5(IL7R):c.898_902del (p.Pro300fs)	IL7R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016502	NM_002838.5(PTPRC):c.1612G>A (p.Asp538Asn)	PTPRC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 11 · 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
IL7R	Definitive	Autosomal recessive	immunodeficiency 104	6
PTPRC	Strong	Autosomal recessive	immunodeficiency 104	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL7R	Orphanet:169154	T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
IL7R	Orphanet:39041	Omenn syndrome
PTPRC	Orphanet:169157	T-B+ severe combined immunodeficiency due to CD45 deficiency
CD3D	Orphanet:169160	T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	Orphanet:39041	Omenn syndrome
RAG2	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG2	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG2	Orphanet:39041	Omenn 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
IL7R	HGNC:6024	ENSG00000168685	P16871	Interleukin-7 receptor subunit alpha	gencc,clinvar
PTPRC	HGNC:9666	ENSG00000081237	P08575	Receptor-type tyrosine-protein phosphatase C	gencc,clinvar
CD3D	HGNC:1673	ENSG00000167286	P04234	T-cell surface glycoprotein CD3 delta chain	clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	clinvar
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL7R	Interleukin-7 receptor subunit alpha	Receptor for interleukin-7.
PTPRC	Receptor-type tyrosine-protein phosphatase C	Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor.
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.
RAG1	V(D)J recombination-activating protein 1	Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.
RAG2	V(D)J recombination-activating protein 2	Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 0 · 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
Phosphatase	1	16.8×	0.087
Transcription factor	2	3.3×	0.114

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL7R	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
PTPRC	Phosphatase	yes		PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
CD3D	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig-like_fold, CD3_esu/gsu/dsu
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RAG2	Transcription factor	no		RAG2, Znf_FYVE_PHD, Gal_Oxase/kelch_b-propeller

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
thymus	3
granulocyte	2
lymph node	2
right lung	1
leukocyte	1
monocyte	1
mononuclear cell	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
bone marrow	1
left lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL7R	220	ubiquitous	marker	right lung, granulocyte, lymph node
PTPRC	277	broad	marker	monocyte, mononuclear cell, leukocyte
CD3D	221	broad	marker	thymus, granulocyte, lymph node
RAG1	164	broad	marker	thymus, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis
RAG2	119	tissue_specific	marker	thymus, bone marrow, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPRC	6,849
CD3D	4,789
RAG1	3,549
IL7R	3,412
RAG2	2,319

Intra-cohort edges

A	B	Sources
CD3D	PTPRC	string_interaction
IL7R	RAG1	string_interaction
PTPRC	RAG1	string_interaction
PTPRC	RAG2	string_interaction
RAG1	RAG2	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD3D	P04234	31
IL7R	P16871	8
PTPRC	P08575	6
RAG2	P55895	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-7 signaling	3	190.3×	5e-06	IL7R, RAG1, RAG2
Phosphorylation of CD3 and TCR zeta chains	2	217.5×	3e-04	PTPRC, CD3D
MAPK6/MAPK4 signaling	2	54.4×	0.003	RAG1, RAG2
Cargo recognition for clathrin-mediated endocytosis	2	41.9×	0.004	IL7R, CD3D
Clathrin-mediated endocytosis	2	34.1×	0.005	IL7R, CD3D
Translocation of ZAP-70 to Immunological synapse	1	126.9×	0.020	CD3D
Other semaphorin interactions	1	120.2×	0.020	PTPRC
Co-inhibition by PD-1	1	103.8×	0.020	CD3D
TCR signaling	1	99.3×	0.020	CD3D
Regulation of T cell activation by CD28 family	1	84.6×	0.021	CD3D
Generation of second messenger molecules	1	69.2×	0.024	CD3D
Downstream TCR signaling	1	25.7×	0.058	CD3D
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	17.4×	0.078	CD3D
Membrane Trafficking	1	7.4×	0.163	CD3D
Vesicle-mediated transport	1	7.0×	0.163	CD3D
Adaptive Immune System	1	6.0×	0.176	CD3D
Neutrophil degranulation	1	4.6×	0.210	PTPRC
Immune System	1	2.6×	0.331	CD3D

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
pre-B cell allelic exclusion	2	2246.9×	1e-05	RAG1, RAG2
T cell differentiation in thymus	3	246.6×	1e-05	IL7R, RAG1, RAG2
DN2 thymocyte differentiation	2	1685.2×	1e-05	PTPRC, RAG2
B cell differentiation	3	131.3×	2e-05	PTPRC, RAG1, RAG2
negative regulation of T cell mediated cytotoxicity	2	842.6×	3e-05	IL7R, PTPRC
V(D)J recombination	2	842.6×	3e-05	RAG1, RAG2
positive thymic T cell selection	2	561.7×	7e-05	PTPRC, CD3D
cell surface receptor signaling pathway	3	38.5×	5e-04	IL7R, PTPRC, CD3D
B cell proliferation	2	192.6×	5e-04	IL7R, PTPRC
T cell homeostasis	2	182.2×	5e-04	IL7R, RAG1
plasma membrane raft distribution	1	3370.4×	0.003	PTPRC
positive regulation of antigen receptor-mediated signaling pathway	1	3370.4×	0.003	PTPRC
T cell receptor signaling pathway	2	60.7×	0.003	PTPRC, CD3D
B cell homeostatic proliferation	1	1685.2×	0.004	RAG2
negative regulation of interleukin-4-mediated signaling pathway	1	1685.2×	0.004	PTPRC
positive regulation of hematopoietic stem cell migration	1	1685.2×	0.004	PTPRC
alpha-beta T cell proliferation	1	1123.5×	0.005	PTPRC
regulation of DNA recombination	1	842.6×	0.005	IL7R
mature B cell differentiation involved in immune response	1	842.6×	0.005	RAG2
negative regulation of cell adhesion involved in substrate-bound cell migration	1	842.6×	0.005	PTPRC
regulation of interleukin-8 production	1	842.6×	0.005	PTPRC
regulation of T cell receptor signaling pathway	1	842.6×	0.005	PTPRC
regulation of behavioral fear response	1	842.6×	0.005	RAG1
B cell lineage commitment	1	674.1×	0.005	RAG2
T cell lineage commitment	1	674.1×	0.005	RAG2
positive regulation of humoral immune response mediated by circulating immunoglobulin	1	674.1×	0.005	PTPRC
alpha-beta T cell activation	1	674.1×	0.005	CD3D
positive regulation of Fc receptor mediated stimulatory signaling pathway	1	674.1×	0.005	PTPRC
adaptive immune response	2	33.7×	0.005	CD3D, RAG1
negative regulation of T cell differentiation in thymus	1	561.7×	0.006	RAG2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL7R	0	0
PTPRC	0	0
CD3D	0	0
RAG1	0	0
RAG2	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
PTPRC	111	Binding:110, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PTPRC	111

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	IL7R, PTPRC, CD3D
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RAG1, RAG2

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)
PTPRC	111	—
IL7R	0	—
CD3D	0	—
RAG1	0	—
RAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.