Immunodeficiency 127

Summary

Immunodeficiency 127 (MONDO:0975832) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 127
Mondo ID	MONDO:0975832
OMIM	620977
DOID	DOID:0061092
UMLS	C5975454
MedGen	1874984
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 127

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3362900	THOC2, 4-BP DEL, 2482GTCA	THOC2	Pathogenic	no assertion criteria provided
3362893	TNF, 20-BP INS, NT190	TNF	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THOC2	Orphanet:457240	X-linked intellectual disability-short stature-overweight syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNF	HGNC:11892	ENSG00000232810	P01375	Tumor necrosis factor	clinvar
THOC2	HGNC:19073	ENSG00000125676	Q8NI27	THO complex subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNF	Tumor necrosis factor	Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR.
THOC2	THO complex subunit 2	Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNF	Other/Unknown	no		TNF_alpha, TNF_dom, TNF
THOC2	Other/Unknown	no		THO_THOC2_C, THO_THOC2_N, THOC2_N

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
calcaneal tendon	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNF	119	broad	marker	granulocyte, male germ line stem cell (sensu Vertebrata) in testis, bone marrow
THOC2	297	ubiquitous	marker	secondary oocyte, calcaneal tendon, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNF	11,116
THOC2	3,251

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNF	P01375	52
THOC2	Q8NI27	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR1-mediated ceramide production	1	951.7×	0.018	TNF
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	439.2×	0.018	TNF
TNFR1-induced proapoptotic signaling	1	219.6×	0.018	TNF
TNF signaling	1	211.5×	0.018	TNF
Transport of Mature Transcript to Cytoplasm	1	190.3×	0.018	THOC2
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.018	TNF
Interleukin-10 signaling	1	116.5×	0.018	TNF
Regulation of TNFR1 signaling	1	112.0×	0.018	TNF
RNA Polymerase II Transcription Termination	1	109.8×	0.018	THOC2
mRNA 3’-end processing	1	98.5×	0.018	THOC2
TNFR2 non-canonical NF-kB pathway	1	90.6×	0.018	TNF
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	76.1×	0.020	THOC2
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.021	TNF
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.025	TNF
Processing of Capped Intron-Containing Pre-mRNA	1	41.1×	0.029	THOC2
Metabolism of RNA	1	20.8×	0.053	THOC2
RNA Polymerase II Transcription	1	11.3×	0.092	THOC2
Gene expression (Transcription)	1	8.9×	0.109	THOC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of translational initiation by iron	1	8426.0×	0.003	TNF
negative regulation of branching involved in lung morphogenesis	1	8426.0×	0.003	TNF
negative regulation of bile acid secretion	1	8426.0×	0.003	TNF
response to Gram-negative bacterium	1	8426.0×	0.003	TNF
positive regulation of interleukin-33 production	1	8426.0×	0.003	TNF
response to 3,3’,5-triiodo-L-thyronine	1	8426.0×	0.003	TNF
negative regulation of L-glutamate import across plasma membrane	1	4213.0×	0.003	TNF
chronic inflammatory response to antigenic stimulus	1	4213.0×	0.003	TNF
positive regulation of chronic inflammatory response to antigenic stimulus	1	4213.0×	0.003	TNF
positive regulation of fractalkine production	1	4213.0×	0.003	TNF
positive regulation of protein transport	1	4213.0×	0.003	TNF
positive regulation of vitamin D biosynthetic process	1	4213.0×	0.003	TNF
response to hydrogen sulfide	1	4213.0×	0.003	TNF
response to quercetin	1	4213.0×	0.003	TNF
response to gold nanoparticle	1	4213.0×	0.003	TNF
positive regulation of blood microparticle formation	1	4213.0×	0.003	TNF
regulation of endothelial cell apoptotic process	1	4213.0×	0.003	TNF
regulation of branching involved in salivary gland morphogenesis	1	2808.7×	0.003	TNF
positive regulation of synoviocyte proliferation	1	2808.7×	0.003	TNF
positive regulation of neutrophil activation	1	2808.7×	0.003	TNF
obsolete regulation of membrane lipid metabolic process	1	2808.7×	0.003	TNF
positive regulation of fever generation	1	2106.5×	0.003	TNF
response to isolation stress	1	2106.5×	0.003	TNF
response to macrophage colony-stimulating factor	1	2106.5×	0.003	TNF
negative regulation of protein-containing complex disassembly	1	2106.5×	0.003	TNF
positive regulation of protein-containing complex disassembly	1	2106.5×	0.003	TNF
positive regulation of leukocyte adhesion to arterial endothelial cell	1	2106.5×	0.003	TNF
positive regulation of humoral immune response mediated by circulating immunoglobulin	1	1685.2×	0.003	TNF
epithelial cell proliferation involved in salivary gland morphogenesis	1	1685.2×	0.003	TNF
negative regulation of vascular wound healing	1	1685.2×	0.003	TNF

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
TNF	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNF	12	4
THOC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	TNF
POMALIDOMIDE	4	TNF
PENTOXIFYLLINE	4	TNF
MESALAMINE	4	TNF
LENALIDOMIDE	4	TNF
MARIMASTAT	3	TNF
IBERDOMIDE	3	TNF
DORAMAPIMOD	2	TNF
AVADOMIDE	2	TNF
MIZACORAT	2	TNF
LINPERLISIB	2	TNF
ROLIPRAM	2	TNF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TNF	193	Binding:162, Functional:31
THOC2	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TNF	193

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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)
PREDNISOLONE	4	TNF
POMALIDOMIDE	4	TNF
PENTOXIFYLLINE	4	TNF
MESALAMINE	4	TNF
LENALIDOMIDE	4	TNF
MARIMASTAT	3	TNF
IBERDOMIDE	3	TNF
DORAMAPIMOD	2	TNF
AVADOMIDE	2	TNF
MIZACORAT	2	TNF
LINPERLISIB	2	TNF
ROLIPRAM	2	TNF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TNF
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	THOC2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
THOC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.