hyper-IgE recurrent infection syndrome 5, autosomal recessive

Summary

hyper-IgE recurrent infection syndrome 5, autosomal recessive (MONDO:0030069) is a disease caused by IL6R (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: IL6R (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyper-IgE recurrent infection syndrome 5, autosomal recessive
Mondo ID	MONDO:0030069
OMIM	618944
UMLS	C5394550
MedGen	1716052
GARD	0025521
Is cancer (heuristic)	no

Also known as: HIES5 · HYPER-IgE RECURRENT INFECTION SYNDROME 5, AUTOSOMAL RECESSIVE · hyper-IgE recurrent infection syndrome 5, autosomal recessive

Data availability: 7 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgE syndrome › hyper-IgE recurrent infection syndrome 5, autosomal recessive

Related subtypes (13): hyper-IgE recurrent infection syndrome 1, autosomal dominant, combined immunodeficiency due to DOCK8 deficiency, Netherton syndrome, immunodeficiency 94 with autoinflammation and dysmorphic facies, hyper-IgE recurrent infection syndrome 3, autosomal recessive, hyper-IgE recurrent infection syndrome 4, autosomal recessive, hyper-IgE recurrent infection syndrome 4A, autosomal dominant, hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, 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

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

7 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
1036785	NM_000565.4(IL6R):c.923C>T (p.Pro308Leu)	IL6R	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356226	NM_000565.4(IL6R):c.127G>A (p.Val43Met)	IL6R	Uncertain significance	criteria provided, multiple submitters, no conflicts
2167190	NM_000565.4(IL6R):c.992T>C (p.Met331Thr)	IL6R	Uncertain significance	criteria provided, single submitter
3242202	NM_000565.4(IL6R):c.284C>G (p.Ser95Ter)	IL6R	Uncertain significance	criteria provided, single submitter
3250425	NM_000565.4(IL6R):c.368G>A (p.Arg123Gln)	IL6R	Uncertain significance	criteria provided, single submitter
973502	NM_000565.4(IL6R):c.548del (p.Gly183fs)	IL6R	no classifications from unflagged records	no classifications from unflagged records
973503	NM_000565.4(IL6R):c.836T>A (p.Ile279Asn)	IL6R	no classifications from unflagged records	no classifications from unflagged records

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
IL6R	Strong	Autosomal recessive	hyper-IgE recurrent infection syndrome 5, autosomal recessive	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL6R	Orphanet:656326	Autosomal recessive combined immunodeficiency due to IL6R deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL6R	HGNC:6019	ENSG00000160712	P08887	Interleukin-6 receptor subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL6R	Interleukin-6 receptor subunit alpha	Part of the receptor for interleukin 6.

Protein-family classification

Druggable: 1 · 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	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL6R	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_L_F3_CS, Ig_sub2, Ig_sub

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL6R	271	ubiquitous	marker	blood, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6R	2,805

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL6R	P08887	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MAPK1 (ERK2) activation	1	1142.0×	0.002	IL6R
MAPK3 (ERK1) activation	1	1038.2×	0.002	IL6R
Interleukin-6 signaling	1	951.7×	0.002	IL6R
Activation of STAT3 by cadherin engagement	1	163.1×	0.010	IL6R
Transcriptional regulation of granulopoiesis	1	125.5×	0.010	IL6R
Potential therapeutics for SARS	1	114.2×	0.010	IL6R
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.010	IL6R

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hepatic immune response	1	5617.3×	0.002	IL6R
ciliary neurotrophic factor-mediated signaling pathway	1	3370.4×	0.002	IL6R
positive regulation of glomerular mesangial cell proliferation	1	2808.7×	0.002	IL6R
vascular endothelial growth factor production	1	2407.4×	0.002	IL6R
T-helper 17 cell lineage commitment	1	1532.0×	0.002	IL6R
neutrophil mediated immunity	1	1404.3×	0.002	IL6R
positive regulation of leukocyte chemotaxis	1	1296.3×	0.002	IL6R
negative regulation of collagen biosynthetic process	1	1123.5×	0.002	IL6R
interleukin-6-mediated signaling pathway	1	1123.5×	0.002	IL6R
negative regulation of interleukin-8 production	1	991.3×	0.002	IL6R
endocrine pancreas development	1	936.2×	0.002	IL6R
monocyte chemotaxis	1	581.1×	0.003	IL6R
cell surface receptor signaling pathway via STAT	1	561.7×	0.003	IL6R
acute-phase response	1	421.3×	0.004	IL6R
positive regulation of chemokine production	1	374.5×	0.004	IL6R
response to cytokine	1	374.5×	0.004	IL6R
positive regulation of smooth muscle cell proliferation	1	330.4×	0.004	IL6R
extrinsic apoptotic signaling pathway	1	306.4×	0.005	IL6R
positive regulation of osteoblast differentiation	1	224.7×	0.006	IL6R
defense response to Gram-negative bacterium	1	168.5×	0.007	IL6R
positive regulation of interleukin-6 production	1	166.8×	0.007	IL6R
cytokine-mediated signaling pathway	1	130.6×	0.009	IL6R
defense response to Gram-positive bacterium	1	127.7×	0.009	IL6R
positive regulation of MAPK cascade	1	80.6×	0.013	IL6R
positive regulation of cell population proliferation	1	33.6×	0.030	IL6R

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL6R	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
IL6R	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	IL6R
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
IL6R	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.