immunodeficiency 27A

Summary

immunodeficiency 27A (MONDO:0008856) is a disease caused by IFNGR1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: IFNGR1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 90

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 27A
Mondo ID	MONDO:0008856
OMIM	209950
DOID	DOID:0111955
NCIT	C176806
UMLS	C4011949
MedGen	860386
GARD	0027788
Is cancer (heuristic)	no

Also known as: atypical mycobacterial infection, disseminated · atypical mycobacterial infection, familial disseminated · atypical mycobacteriosis, familial · IMD27A · immunodeficiency 27A · immunodeficiency 27A, mycobacteriosis, AR · immunodeficiency type 27A · mycobacterial disease, Mendelian susceptibility to

Data availability: 90 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › immunodeficiency 27A

Related subtypes (13): Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency, Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency, autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, X-linked Mendelian susceptibility to mycobacterial diseases, Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to a complete deficiency, Mendelian susceptibility to mycobacterial diseases due to a partial deficiency

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

90 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 14 pathogenic, 13 benign/likely benign, 10 benign, 6 conflicting classifications of pathogenicity, 5 likely benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17942	NM_000416.3(IFNGR1):c.446C>A (p.Ser149Ter)	IFNGR1	Pathogenic	no assertion criteria provided
17943	NM_000416.3(IFNGR1):c.131del (p.Pro44fs)	IFNGR1	Pathogenic	no assertion criteria provided
17944	NM_000416.3(IFNGR1):c.260T>C (p.Ile87Thr)	IFNGR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17945	NM_000416.3(IFNGR1):c.104_107dup (p.Ile37fs)	IFNGR1	Pathogenic	no assertion criteria provided
17946	NM_000416.3(IFNGR1):c.200+1G>A	IFNGR1	Pathogenic	no assertion criteria provided
17947	NM_000416.3(IFNGR1):c.819_822del (p.Asn274fs)	IFNGR1	Pathogenic	criteria provided, multiple submitters, no conflicts
17948	NM_000416.3(IFNGR1):c.295_306del (p.Trp99_Val102del)	IFNGR1	Pathogenic	no assertion criteria provided
17949	NM_000416.3(IFNGR1):c.230G>A (p.Cys77Tyr)	IFNGR1	Pathogenic	no assertion criteria provided
17950	NM_000416.3(IFNGR1):c.182T>A (p.Val61Glu)	IFNGR1	Pathogenic	no assertion criteria provided
208588	NM_000416.3(IFNGR1):c.523del (p.Tyr175fs)	IFNGR1	Pathogenic	criteria provided, multiple submitters, no conflicts
29607	NM_000416.3(IFNGR1):c.2T>A (p.Met1Lys)	IFNGR1	Pathogenic	no assertion criteria provided
4292897	NM_000416.3(IFNGR1):c.573_574dup (p.Glu192fs)	IFNGR1	Pathogenic	criteria provided, single submitter
802277	NM_000416.3(IFNGR1):c.86-1_93del	IFNGR1	Pathogenic	criteria provided, single submitter
830065	NM_000416.3(IFNGR1):c.476del (p.Val159fs)	IFNGR1	Pathogenic	criteria provided, single submitter
830657	NC_000006.11:g.(?136482728)(137540520_?)del	IL22RA2	Pathogenic	criteria provided, single submitter
2585538	NM_000416.3(IFNGR1):c.85+1G>T	IFNGR1	Likely pathogenic	criteria provided, single submitter
4071539	NM_000416.3(IFNGR1):c.55dup (p.Met19fs)	IFNGR1	Likely pathogenic	criteria provided, single submitter
802275	NM_000416.3(IFNGR1):c.547-42A>T	IFNGR1	Likely pathogenic	criteria provided, single submitter
830064	NM_000416.3(IFNGR1):c.295T>C (p.Trp99Arg)	IFNGR1	Likely pathogenic	criteria provided, single submitter
355556	NM_000416.3(IFNGR1):c.711C>T (p.Thr237=)	IFNGR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355558	NM_000416.3(IFNGR1):c.588C>T (p.Asp196=)	IFNGR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
531671	NM_000416.3(IFNGR1):c.1341C>T (p.Thr447=)	IFNGR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
531672	NM_000416.3(IFNGR1):c.609G>A (p.Ala203=)	IFNGR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
642105	NM_000416.3(IFNGR1):c.589G>A (p.Glu197Lys)	IFNGR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
723758	NM_000416.3(IFNGR1):c.40G>A (p.Val14Met)	IFNGR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
111205	NM_000416.3(IFNGR1):c.*450C>T	IFNGR1	Uncertain significance	criteria provided, single submitter
111208	NM_000416.3(IFNGR1):c.1034A>G (p.His345Arg)	IFNGR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
17951	NM_000416.3(IFNGR1):c.653_655del (p.Glu218del)	IFNGR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
355546	NM_000416.3(IFNGR1):c.*466A>G	IFNGR1	Uncertain significance	criteria provided, single submitter
355547	NM_000416.3(IFNGR1):c.*297G>A	IFNGR1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 9 · 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
IFNGR1	Definitive	Autosomal recessive	immunodeficiency 27A	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFNGR1	Orphanet:117	Behçet disease
IFNGR1	Orphanet:319569	Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency
IFNGR1	Orphanet:319581	Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency
IFNGR1	Orphanet:99898	Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency
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
IL12RB1	Orphanet:186	Primary biliary cholangitis
IL12RB1	Orphanet:319552	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 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
IFNGR1	HGNC:5439	ENSG00000027697	P15260	Interferon gamma receptor 1	gencc,clinvar
IL22RA2	HGNC:14901	ENSG00000164485	Q969J5	Interleukin-22 receptor subunit alpha-2	clinvar
IFNGR2	HGNC:5440	ENSG00000159128	P38484	Interferon gamma receptor 2	clinvar
IL12RB1	HGNC:5971	ENSG00000096996	P42701	Interleukin-12 receptor subunit beta-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFNGR1	Interferon gamma receptor 1	Receptor subunit for interferon gamma/INFG that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation.
IL22RA2	Interleukin-22 receptor subunit alpha-2	Isoform 2 is a receptor for IL22.
IFNGR2	Interferon gamma receptor 2	Associates with IFNGR1 to form a receptor for the cytokine interferon gamma (IFNG).
IL12RB1	Interleukin-12 receptor subunit beta-1	Functions as an interleukin receptor which binds interleukin-12 with low affinity and is involved in IL12 transduction.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	4	29.2×	1e-06

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFNGR1	Antibody/Immunoglobulin	yes		FN3_dom, Interferon_gamma_rcpt_asu, Ig-like_fold
IL22RA2	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Interferon/interleukin_rcp_dom
IFNGR2	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Interferon/interleukin_rcp_dom
IL12RB1	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

3 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
epithelium of nasopharynx	2
blood	2
leukocyte	2
lower lobe of lung	1
right lung	1
buccal mucosa cell	1
vermiform appendix	1
monocyte	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFNGR1	295	ubiquitous	marker	lower lobe of lung, epithelium of nasopharynx, right lung
IL22RA2	39	tissue_specific	marker	vermiform appendix, epithelium of nasopharynx, buccal mucosa cell
IFNGR2	144	ubiquitous	marker	monocyte, leukocyte, blood
IL12RB1	177	broad	yes	granulocyte, leukocyte, blood

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFNGR1	2,353
IL12RB1	2,259
IFNGR2	1,794
IL22RA2	784

Intra-cohort edges

A	B	Sources
IFNGR1	IFNGR2	string_interaction
IFNGR1	IL12RB1	string_interaction
IFNGR1	IL22RA2	string_interaction
IFNGR2	IL12RB1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL12RB1	P42701	7
IFNGR1	P15260	5
IFNGR2	P38484	3
IL22RA2	Q969J5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 4 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
IFNG signaling activates MAPKs	2	713.8×	4e-05	IFNGR1, IFNGR2
Regulation of IFNG signaling	2	407.9×	6e-05	IFNGR1, IFNGR2
Interferon gamma signaling	2	62.8×	0.001	IFNGR1, IFNGR2
Interferon Signaling	2	60.1×	0.001	IFNGR1, IFNGR2
Potential therapeutics for SARS	2	57.1×	0.001	IFNGR1, IFNGR2
SARS-CoV Infections	2	27.7×	0.004	IFNGR1, IFNGR2
Interleukin-23 signaling	1	317.2×	0.006	IL12RB1
Cytokine Signaling in Immune system	2	20.4×	0.006	IFNGR1, IFNGR2
Viral Infection Pathways	2	15.4×	0.009	IFNGR1, IFNGR2
Interleukin-20 family signaling	1	105.7×	0.011	IL22RA2
Interleukin-12 signaling	1	102.0×	0.011	IL12RB1
Infectious disease	2	12.4×	0.011	IFNGR1, IFNGR2
Disease	2	6.5×	0.032	IFNGR1, IFNGR2
Immune System	2	6.5×	0.032	IFNGR1, IFNGR2

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
cytokine-mediated signaling pathway	4	130.6×	9e-08	IFNGR1, IL22RA2, IFNGR2, IL12RB1
type III interferon-mediated signaling pathway	2	766.0×	3e-05	IFNGR1, IFNGR2
type II interferon-mediated signaling pathway	2	601.9×	4e-05	IFNGR1, IFNGR2
microglial cell activation	2	312.1×	1e-04	IFNGR1, IFNGR2
cellular response to virus	2	100.3×	8e-04	IFNGR1, IFNGR2
response to virus	2	72.0×	0.001	IFNGR1, IFNGR2
defense response to virus	2	34.7×	0.005	IFNGR1, IFNGR2
interleukin-23-mediated signaling pathway	1	702.2×	0.005	IL12RB1
positive regulation of T-helper 17 cell lineage commitment	1	526.6×	0.005	IL12RB1
interleukin-12-mediated signaling pathway	1	468.1×	0.005	IL12RB1
positive regulation of memory T cell differentiation	1	468.1×	0.005	IL12RB1
positive regulation of T-helper 1 type immune response	1	421.3×	0.005	IL12RB1
negative regulation of amyloid-beta clearance	1	421.3×	0.005	IFNGR1
positive regulation of glutamate receptor signaling pathway	1	383.0×	0.005	IFNGR2
positive regulation of T-helper 17 type immune response	1	351.1×	0.005	IL12RB1
astrocyte activation	1	247.8×	0.007	IFNGR1
positive regulation of amyloid-beta formation	1	221.7×	0.007	IFNGR1
positive regulation of activated T cell proliferation	1	168.5×	0.009	IL12RB1
positive regulation of defense response to virus by host	1	131.7×	0.011	IL12RB1
positive regulation of T cell mediated cytotoxicity	1	127.7×	0.011	IL12RB1
positive regulation of type II interferon production	1	56.2×	0.024	IL12RB1
cellular response to type II interferon	1	52.0×	0.024	IL12RB1
signal transduction	2	8.0×	0.026	IFNGR1, IL12RB1
positive regulation of tumor necrosis factor production	1	38.3×	0.030	IFNGR1
negative regulation of inflammatory response	1	34.2×	0.032	IL22RA2
cell surface receptor signaling pathway	1	16.0×	0.066	IFNGR2
positive regulation of gene expression	1	9.7×	0.103	IFNGR1
positive regulation of cell population proliferation	1	8.4×	0.114	IL12RB1

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
IFNGR1	0	0
IL22RA2	0	0
IFNGR2	0	0
IL12RB1	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
IL12RB1	2	Binding:2

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	4	IFNGR1, IL22RA2, IFNGR2, IL12RB1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
IFNGR1	0	—
IL22RA2	0	—
IFNGR2	0	—
IL12RB1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.