autosomal recessive severe congenital neutropenia due to JAGN1 deficiency

Summary

autosomal recessive severe congenital neutropenia due to JAGN1 deficiency (MONDO:0014456) is a disease caused by JAGN1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: JAGN1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 138

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive severe congenital neutropenia due to JAGN1 deficiency
Mondo ID	MONDO:0014456
OMIM	616022
Orphanet	423384
DOID	DOID:0112134
UMLS	C4014954
MedGen	863391
GARD	0017702
Is cancer (heuristic)	no

Also known as: neutropenia, severe congenital, 6, autosomal recessive · SCN6

Data availability: 138 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive severe congenital neutropenia › autosomal recessive severe congenital neutropenia due to JAGN1 deficiency

Related subtypes (5): Kostmann syndrome, autosomal recessive severe congenital neutropenia due to G6PC3 deficiency, congenital neutropenia-myelofibrosis-nephromegaly syndrome, autosomal recessive severe congenital neutropenia due to CSF3R deficiency, autosomal recessive severe congenital neutropenia due to CXCR2 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

138 retrieved; paginated sample, class counts are floors:

70 uncertain significance, 47 likely benign, 8 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
156116	NM_032492.4(JAGN1):c.485A>G (p.Gln162Arg)	JAGN1	Pathogenic	criteria provided, single submitter
4076146	NM_032492.4(JAGN1):c.361G>T (p.Glu121Ter)	JAGN1	Likely pathogenic	no assertion criteria provided
1128794	NM_032492.4(JAGN1):c.52C>A (p.Gln18Lys)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156113	NM_032492.4(JAGN1):c.3G>A (p.Met1Ile)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156114	NM_032492.4(JAGN1):c.130C>T (p.His44Tyr)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156115	NM_032492.4(JAGN1):c.63G>T (p.Glu21Asp)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156117	NM_032492.4(JAGN1):c.35_43del (p.Thr12_Gly14del)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190479	NM_032492.4(JAGN1):c.59G>A (p.Arg20Gln)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190480	NM_032492.4(JAGN1):c.40G>A (p.Gly14Ser)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
943976	NM_032492.4(JAGN1):c.56A>G (p.His19Arg)	JAGN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2427040	NC_000003.11:g.(?9908818)(9932515_?)dup	CIDEC	Uncertain significance	criteria provided, single submitter
1412574	NC_000003.11:g.(?9908818)(10191649_?)dup	IL17RE	Uncertain significance	criteria provided, single submitter
1002786	NM_032492.4(JAGN1):c.503A>G (p.Lys168Arg)	JAGN1	Uncertain significance	criteria provided, single submitter
1006422	NM_032492.4(JAGN1):c.346A>G (p.Ile116Val)	JAGN1	Uncertain significance	criteria provided, single submitter
1009400	NM_032492.4(JAGN1):c.211C>T (p.Pro71Ser)	JAGN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1011467	NM_032492.4(JAGN1):c.317G>A (p.Ser106Asn)	JAGN1	Uncertain significance	criteria provided, single submitter
1017842	NM_032492.4(JAGN1):c.517T>A (p.Trp173Arg)	JAGN1	Uncertain significance	criteria provided, single submitter
1020952	NM_032492.4(JAGN1):c.127G>A (p.Val43Ile)	JAGN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047313	NM_032492.4(JAGN1):c.205G>A (p.Ala69Thr)	JAGN1	Uncertain significance	criteria provided, single submitter
1055949	NM_032492.4(JAGN1):c.43A>G (p.Ser15Gly)	JAGN1	Uncertain significance	criteria provided, single submitter
1057517	NM_032492.4(JAGN1):c.89+4T>C	JAGN1	Uncertain significance	criteria provided, single submitter
1060531	NM_032492.4(JAGN1):c.77A>T (p.His26Leu)	JAGN1	Uncertain significance	criteria provided, single submitter
1205600	NM_032492.4(JAGN1):c.258_259del (p.Leu87fs)	JAGN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1361485	NM_032492.4(JAGN1):c.542A>G (p.Lys181Arg)	JAGN1	Uncertain significance	criteria provided, single submitter
1366171	NM_032492.4(JAGN1):c.389A>G (p.Tyr130Cys)	JAGN1	Uncertain significance	criteria provided, single submitter
1370140	NM_032492.4(JAGN1):c.519G>T (p.Trp173Cys)	JAGN1	Uncertain significance	criteria provided, single submitter
1371122	NM_032492.4(JAGN1):c.111C>G (p.Ile37Met)	JAGN1	Uncertain significance	criteria provided, single submitter
1388265	NM_032492.4(JAGN1):c.421G>C (p.Gly141Arg)	JAGN1	Uncertain significance	criteria provided, single submitter
1400765	NM_032492.4(JAGN1):c.522C>G (p.Phe174Leu)	JAGN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1402910	NM_032492.4(JAGN1):c.184C>T (p.Leu62Phe)	JAGN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
JAGN1	Definitive	Autosomal recessive	autosomal recessive severe congenital neutropenia due to JAGN1 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
JAGN1	Orphanet:423384	Severe congenital neutropenia due to JAGN1 deficiency
CIDEC	Orphanet:435651	CIDEC-related familial partial lipodystrophy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
JAGN1	HGNC:26926	ENSG00000171135	Q8N5M9	Protein jagunal homolog 1	gencc,clinvar
IL17RE	HGNC:18439	ENSG00000163701	Q8NFR9	Interleukin-17 receptor E	clinvar
CIDEC	HGNC:24229	ENSG00000187288	Q96AQ7	Lipid transferase CIDEC	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JAGN1	Protein jagunal homolog 1	Endoplasmic reticulum transmembrane protein involved in vesicle-mediated transport, which is required for neutrophil function.
IL17RE	Interleukin-17 receptor E	Specific functional receptor for IL17C.
CIDEC	Lipid transferase CIDEC	Lipid transferase specifically expressed in white adipose tissue, which promotes unilocular lipid droplet formation by mediating lipid droplet fusion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
JAGN1	Other/Unknown	no		Jagunal
IL17RE	Other/Unknown	no		SEFIR_dom, IL-17_rcpt_C/E_N, IL-17_rcpt-like
CIDEC	Other/Unknown	no		CIDE-N_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
right adrenal gland	1
tibialis anterior	1
mucosa of transverse colon	1
skin of abdomen	1
skin of leg	1
adipose tissue	1
adipose tissue of abdominal region	1
subcutaneous adipose tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JAGN1	253	ubiquitous	marker	ileal mucosa, tibialis anterior, right adrenal gland
IL17RE	156	ubiquitous	marker	skin of leg, skin of abdomen, mucosa of transverse colon
CIDEC	185	tissue_specific	marker	subcutaneous adipose tissue, adipose tissue, adipose tissue of abdominal region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAGN1	1,200
CIDEC	947
IL17RE	559

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAGN1	Q8N5M9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CIDEC	Q96AQ7	74.19
IL17RE	Q8NFR9	68.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
Lipid particle organization	1	951.7×	0.004	CIDEC
Assembly of active LPL and LIPC lipase complexes	1	300.5×	0.007	CIDEC
Interleukin-17 signaling	1	126.9×	0.010	IL17RE
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.024	CIDEC

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of triglyceride metabolic process	1	1404.3×	0.006	CIDEC
granulocyte colony-stimulating factor signaling pathway	1	1123.5×	0.006	JAGN1
lipid droplet fusion	1	1123.5×	0.006	CIDEC
insulin metabolic process	1	802.5×	0.006	JAGN1
neutrophil differentiation	1	624.1×	0.006	JAGN1
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	561.7×	0.006	JAGN1
neutrophil mediated immunity	1	468.1×	0.006	JAGN1
neutrophil migration	1	468.1×	0.006	JAGN1
lipid droplet organization	1	312.1×	0.007	CIDEC
negative regulation of lipid catabolic process	1	280.9×	0.007	CIDEC
execution phase of apoptosis	1	255.3×	0.007	CIDEC
lipid storage	1	181.2×	0.010	CIDEC
defense response to fungus	1	147.8×	0.010	JAGN1
insulin secretion	1	144.0×	0.010	JAGN1
endoplasmic reticulum organization	1	140.4×	0.010	JAGN1
response to glucose	1	85.1×	0.015	JAGN1
response to endoplasmic reticulum stress	1	55.6×	0.022	JAGN1
exocytosis	1	50.6×	0.023	JAGN1
vesicle-mediated transport	1	32.1×	0.034	JAGN1
inflammatory response	1	12.6×	0.081	IL17RE
apoptotic process	1	9.6×	0.101	CIDEC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAGN1	0	0
IL17RE	0	0
CIDEC	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
IL17RE	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	JAGN1, IL17RE, CIDEC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
JAGN1	0	—
IL17RE	2	—
CIDEC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.