Immunodeficiency 28

Summary

Immunodeficiency 28 (MONDO:0013953) is a disease caused by IFNGR2 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: IFNGR2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 226

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 28
Mondo ID	MONDO:0013953
OMIM	614889
DOID	DOID:0111995
UMLS	C4013947
MedGen	862384
GARD	0024963
Is cancer (heuristic)	no

Also known as: IFNGR2 primary immunodeficiency disease · IMD28 · immunodeficiency 28 · immunodeficiency type 28 · primary immunodeficiency disease caused by mutation in IFNGR2

Data availability: 226 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › immunodeficiency 28

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

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

226 retrieved; paginated sample, class counts are floors:

98 likely benign, 88 uncertain significance, 18 benign, 9 conflicting classifications of pathogenicity, 7 pathogenic, 3 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075480	NM_005534.4(IFNGR2):c.709dup (p.Thr237fs)	IFNGR2	Pathogenic	criteria provided, single submitter
14726	NM_005534.4(IFNGR2):c.278_279del (p.Glu93fs)	IFNGR2	Pathogenic	no assertion criteria provided
14727	NM_005534.4(IFNGR2):c.503C>A (p.Thr168Asn)	IFNGR2	Pathogenic	no assertion criteria provided
14728	NM_005534.4(IFNGR2):c.663_689del (p.Phe224_Ile232del)	IFNGR2	Pathogenic	no assertion criteria provided
37286	NM_005534.4(IFNGR2):c.382_387dup (p.Thr128_Met129dup)	IFNGR2	Pathogenic	no assertion criteria provided
949584	NM_005534.4(IFNGR2):c.503_504del (p.Thr168fs)	IFNGR2	Pathogenic	criteria provided, single submitter
987750	NM_005534.4(IFNGR2):c.4del (p.Arg2fs)	IFNGR2	Pathogenic	no assertion criteria provided
1066015	NM_005534.4(IFNGR2):c.1A>C (p.Met1Leu)	IFNGR2	Likely pathogenic	criteria provided, single submitter
1299495	NM_005534.4(IFNGR2):c.800del (p.Phe267fs)	IFNGR2	Likely pathogenic	criteria provided, single submitter
987732	NM_005534.4(IFNGR2):c.1A>G (p.Met1Val)	IFNGR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
111247	NM_005534.4(IFNGR2):c.510G>A (p.Thr170=)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
111250	NM_005534.4(IFNGR2):c.708A>T (p.Glu236Asp)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1507225	NM_005534.4(IFNGR2):c.94G>A (p.Ala32Thr)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2197074	NM_005534.4(IFNGR2):c.509C>T (p.Thr170Met)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36377	NM_005534.4(IFNGR2):c.879+19del	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
474968	NM_005534.4(IFNGR2):c.37C>T (p.Leu13Phe)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569520	NM_005534.4(IFNGR2):c.780G>A (p.Ser260=)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
654567	NM_005534.4(IFNGR2):c.532C>T (p.His178Tyr)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
665306	NM_005534.4(IFNGR2):c.115C>T (p.Arg39Cys)	IFNGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1409651	NC_000021.8:g.(?32439271)(39212984_?)dup	ATP5PO	Uncertain significance	criteria provided, single submitter
541805	NC_000021.8:g.(?34638751)(34809289_?)dup	IFNAR1	Uncertain significance	criteria provided, single submitter
1000970	NM_005534.4(IFNGR2):c.48CGC[3] (p.Ala21_Ala22del)	IFNGR2	Uncertain significance	criteria provided, single submitter
1002548	NM_005534.4(IFNGR2):c.406C>T (p.Arg136Trp)	IFNGR2	Uncertain significance	criteria provided, single submitter
1008942	NM_005534.4(IFNGR2):c.451G>A (p.Gly151Arg)	IFNGR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022655	NM_005534.4(IFNGR2):c.116G>A (p.Arg39His)	IFNGR2	Uncertain significance	criteria provided, single submitter
1035663	NM_005534.4(IFNGR2):c.610C>T (p.Pro204Ser)	IFNGR2	Uncertain significance	criteria provided, single submitter
1036762	NM_005534.4(IFNGR2):c.232G>A (p.Asp78Asn)	IFNGR2	Uncertain significance	criteria provided, single submitter
1037224	NM_005534.4(IFNGR2):c.407G>A (p.Arg136Gln)	IFNGR2	Uncertain significance	criteria provided, single submitter
1046008	NM_005534.4(IFNGR2):c.990AGA[1] (p.Glu331del)	IFNGR2	Uncertain significance	criteria provided, single submitter
1052150	NM_005534.4(IFNGR2):c.718G>C (p.Asp240His)	IFNGR2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
IFNGR2	Strong	Autosomal recessive	immunodeficiency 28	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFNGR2	Orphanet:319547	Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency
IFNGR2	Orphanet:319574	Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency
IFNGR2	Orphanet:319589	Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

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
IFNGR2	HGNC:5440	ENSG00000159128	P38484	Interferon gamma receptor 2	gencc,clinvar
TMEM50B	HGNC:1280	ENSG00000142188	P56557	Transmembrane protein 50B	clinvar
IFNAR1	HGNC:5432	ENSG00000142166	P17181	Interferon alpha/beta receptor 1	clinvar
ATP5PO	HGNC:850	ENSG00000241837	P48047	ATP synthase peripheral stalk subunit OSCP, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFNGR2	Interferon gamma receptor 2	Associates with IFNGR1 to form a receptor for the cytokine interferon gamma (IFNG).
IFNAR1	Interferon alpha/beta receptor 1	Together with IFNAR2, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa).
ATP5PO	ATP synthase peripheral stalk subunit OSCP, mitochondrial	Subunit OSCP, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of…

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
Antibody/Immunoglobulin	2	14.6×	0.013
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFNGR2	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Interferon/interleukin_rcp_dom
TMEM50B	Other/Unknown	no		UPF0220
IFNAR1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Interferon/interleukin_rcp_dom
ATP5PO	Other/Unknown	no		ATPase_OSCP/dsu, ATPase_OSCP/d_CS, ATP_synth_OSCP/delta_N_sf

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
leukocyte	2
monocyte	2
blood	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
mononuclear cell	1
apex of heart	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFNGR2	144	ubiquitous	marker	monocyte, leukocyte, blood
TMEM50B	134	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
IFNAR1	258	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
ATP5PO	149	ubiquitous	marker	heart left ventricle, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP5PO	3,811
IFNAR1	2,300
IFNGR2	1,794
TMEM50B	509

Intra-cohort edges

A	B	Sources
IFNAR1	IFNGR2	string_interaction
IFNGR2	TMEM50B	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP5PO	P48047	9
IFNAR1	P17181	5
IFNGR2	P38484	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM50B	P56557	83.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. 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
Interferon Signaling	2	80.1×	0.003	IFNGR2, IFNAR1
Potential therapeutics for SARS	2	76.1×	0.003	IFNGR2, IFNAR1
SARS-CoV Infections	2	37.0×	0.009	IFNGR2, IFNAR1
IFNG signaling activates MAPKs	1	475.8×	0.011	IFNGR2
Cytokine Signaling in Immune system	2	27.2×	0.011	IFNGR2, IFNAR1
Viral Infection Pathways	2	20.5×	0.014	IFNGR2, IFNAR1
Regulation of IFNG signaling	1	271.9×	0.014	IFNGR2
Formation of ATP by chemiosmotic coupling	1	190.3×	0.016	ATP5PO
Infectious disease	2	16.6×	0.016	IFNGR2, IFNAR1
Regulation of IFNA/IFNB signaling	1	146.4×	0.018	IFNAR1
Cristae formation	1	115.3×	0.021	ATP5PO
Evasion by RSV of host interferon responses	1	108.8×	0.021	IFNAR1
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.029	IFNAR1
Mitochondrial biogenesis	1	56.0×	0.029	ATP5PO
RSV-host interactions	1	52.1×	0.029	IFNAR1
Interferon alpha/beta signaling	1	50.8×	0.029	IFNAR1
Disease	2	8.7×	0.029	IFNGR2, IFNAR1
Immune System	2	8.6×	0.029	IFNGR2, IFNAR1
Interferon gamma signaling	1	41.8×	0.033	IFNGR2
SARS-CoV-2-host interactions	1	39.6×	0.033	IFNAR1
Mitochondrial protein degradation	1	38.1×	0.033	ATP5PO
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	29.7×	0.039	IFNAR1
Aerobic respiration and respiratory electron transport	1	29.5×	0.039	ATP5PO
SARS-CoV-2 Infection	1	26.8×	0.041	IFNAR1
Organelle biogenesis and maintenance	1	22.0×	0.048	ATP5PO
Metabolism of proteins	1	4.1×	0.232	ATP5PO
Metabolism	1	3.9×	0.237	ATP5PO

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
cellular response to virus	2	100.3×	0.003	IFNGR2, IFNAR1
response to virus	2	72.0×	0.003	IFNGR2, IFNAR1
positive regulation of cellular respiration	1	468.1×	0.008	IFNAR1
late endosome to vacuole transport via multivesicular body sorting pathway	1	383.0×	0.008	TMEM50B
cellular response to interferon-alpha	1	383.0×	0.008	IFNAR1
type III interferon-mediated signaling pathway	1	383.0×	0.008	IFNGR2
positive regulation of glutamate receptor signaling pathway	1	383.0×	0.008	IFNGR2
type II interferon-mediated signaling pathway	1	300.9×	0.009	IFNGR2
ATP biosynthetic process	1	247.8×	0.010	ATP5PO
proton motive force-driven ATP synthesis	1	200.6×	0.011	ATP5PO
microglial cell activation	1	156.0×	0.013	IFNGR2
cellular response to cytokine stimulus	1	135.9×	0.013	ATP5PO
cellular response to interferon-beta	1	131.7×	0.013	IFNAR1
type I interferon-mediated signaling pathway	1	86.0×	0.018	IFNAR1
proton transmembrane transport	1	78.0×	0.018	ATP5PO
cell surface receptor signaling pathway via JAK-STAT	1	72.6×	0.018	IFNAR1
cellular response to cAMP	1	72.6×	0.018	ATP5PO
proton motive force-driven mitochondrial ATP synthesis	1	65.8×	0.018	ATP5PO
cytokine-mediated signaling pathway	1	32.7×	0.035	IFNGR2
response to lipopolysaccharide	1	31.2×	0.035	IFNAR1
defense response to virus	1	17.3×	0.059	IFNGR2
cell surface receptor signaling pathway	1	16.0×	0.061	IFNGR2

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
IFNGR2	0	0
TMEM50B	0	0
IFNAR1	0	0
ATP5PO	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
IFNAR1	8	Binding:5, Functional:3
ATP5PO	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	IFNGR2, IFNAR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TMEM50B, ATP5PO

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)
IFNGR2	0	—
TMEM50B	0	—
IFNAR1	8	—
ATP5PO	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.