Neutropenia, severe congenital, 1, autosomal dominant

Summary

Neutropenia, severe congenital, 1, autosomal dominant (MONDO:0042490) is a disease with 5 cohort genes. The dominant Reactome pathway is Neutrophil degranulation (3 cohort genes).

At a glance

• Cohort genes: 5
• ClinVar variants: 545

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neutropenia, severe congenital, 1, autosomal dominant
Mondo ID	MONDO:0042490
MeSH	C565969
OMIM	202700
DOID	DOID:0080625
UMLS	C1859966
MedGen	348506
GARD	0025849
Is cancer (heuristic)	no

Also known as: neutropenia, severe congenital 1, autosomal dominant · neutropenia, severe congenital, 1, autosomal dominant · SCN1

Data availability: 545 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant severe congenital neutropenia › neutropenia, severe congenital, 1, autosomal dominant

Related subtypes (2): neutropenia, lethal congenital, with eosinophilia, neutropenia, severe congenital, 2, autosomal dominant

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

545 retrieved; paginated sample, class counts are floors:

244 uncertain significance, 140 likely benign, 56 conflicting classifications of pathogenicity, 41 pathogenic, 29 likely pathogenic, 22 benign/likely benign, 8 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16747	NM_001972.2(ELANE):c.[292G>T;301G>T]		Pathogenic	no assertion criteria provided
16745	NM_001972.4(ELANE):c.377C>T (p.Ser126Leu)	CFD	Pathogenic	criteria provided, multiple submitters, no conflicts
939547	NM_001972.4(ELANE):c.607G>C (p.Gly203Arg)	CFD	Pathogenic	criteria provided, multiple submitters, no conflicts
1052483	NM_001972.4(ELANE):c.723G>A (p.Trp241Ter)	ELANE	Pathogenic	criteria provided, single submitter
1069597	NM_001972.4(ELANE):c.597+5G>T	ELANE	Pathogenic	criteria provided, single submitter
1069598	NM_001972.4(ELANE):c.687del (p.Asp230fs)	ELANE	Pathogenic	criteria provided, single submitter
1339552	NM_001972.4(ELANE):c.452G>C (p.Cys151Ser)	ELANE	Pathogenic	criteria provided, single submitter
1339651	NM_001972.4(ELANE):c.574_583del (p.Gly192fs)	ELANE	Pathogenic	criteria provided, single submitter
1343367	NM_001972.4(ELANE):c.1A>G (p.Met1Val)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
1343817	NM_001972.4(ELANE):c.242G>C (p.Arg81Pro)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1372707	NM_001972.4(ELANE):c.461T>G (p.Met154Arg)	ELANE	Pathogenic	criteria provided, single submitter
1402531	NM_001972.4(ELANE):c.367-8C>A	ELANE	Pathogenic	criteria provided, single submitter
1495615	NM_001972.4(ELANE):c.169G>A (p.Ala57Thr)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
16738	NM_001972.4(ELANE):c.659G>A (p.Arg220Gln)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16740	NM_001972.4(ELANE):c.182C>T (p.Ala61Val)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16743	NM_001972.4(ELANE):c.416C>T (p.Pro139Leu)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16746	NM_001972.4(ELANE):c.211T>C (p.Cys71Arg)	ELANE	Pathogenic	no assertion criteria provided
16748	NM_001972.4(ELANE):c.640G>A (p.Gly214Arg)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
1693275	NM_001972.4(ELANE):c.289_300dup (p.Ala100_Val101insGlnValPheAla)	ELANE	Pathogenic	criteria provided, single submitter
1918199	NM_001972.4(ELANE):c.538del (p.Leu180fs)	ELANE	Pathogenic	criteria provided, single submitter
208494	NM_001972.4(ELANE):c.561C>A (p.Cys187Ter)	ELANE	Pathogenic	criteria provided, single submitter
2138169	NM_001972.4(ELANE):c.197T>G (p.Met66Arg)	ELANE	Pathogenic	criteria provided, single submitter
2138170	NM_001972.4(ELANE):c.416C>G (p.Pro139Arg)	ELANE	Pathogenic	criteria provided, single submitter
242278	NM_001972.4(ELANE):c.212G>T (p.Cys71Phe)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242287	NM_001972.4(ELANE):c.597+1G>A	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
242289	NM_001972.4(ELANE):c.140T>C (p.Leu47Pro)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
245598	NM_001972.4(ELANE):c.597+5G>A	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
245599	NM_001972.4(ELANE):c.597+1G>C	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
2925630	NM_001972.4(ELANE):c.164G>A (p.Cys55Tyr)	ELANE	Pathogenic	criteria provided, single submitter
2942789	NM_001972.4(ELANE):c.639del (p.His213fs)	ELANE	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
VPS13B	Orphanet:193	Cohen syndrome
CFD	Orphanet:169467	Recurrent Neisseria infections due to factor D deficiency
ELANE	Orphanet:2686	Cyclic neutropenia
ELANE	Orphanet:486	Autosomal dominant severe congenital neutropenia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	clinvar
VPS13B	HGNC:2183	ENSG00000132549	Q7Z7G8	Intermembrane lipid transfer protein VPS13B	clinvar
CFD	HGNC:2771	ENSG00000197766	P00746	Complement factor D	clinvar
ELANE	HGNC:3309	ENSG00000197561	P08246	Neutrophil elastase	clinvar
ABCA7	HGNC:37	ENSG00000064687	Q8IZY2	Phospholipid-transporting ATPase ABCA7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
VPS13B	Intermembrane lipid transfer protein VPS13B	Mediates the transfer of lipids between membranes at organelle contact sites.
CFD	Complement factor D	Serine protease that initiates the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.
ELANE	Neutrophil elastase	Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes.
ABCA7	Phospholipid-transporting ATPase ABCA7	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Protease	2	14.7×	0.021
Transporter	1	15.6×	0.094
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
VPS13B	Other/Unknown	no		VPS13_VAB, VPS13_N, VPS13B
CFD	Protease	yes	3.4.21.46	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
ELANE	Protease	yes	3.4.21.37	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
ABCA7	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
blood	1
spleen	1
bronchial epithelial cell	1
nipple	1
sural nerve	1
adipose tissue	1
mucosa of stomach	1
subcutaneous adipose tissue	1
bone marrow	1
bone marrow cell	1
monocyte	1
adenohypophysis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
VPS13B	291	ubiquitous	marker	sural nerve, nipple, bronchial epithelial cell
CFD	133	broad	marker	subcutaneous adipose tissue, adipose tissue, mucosa of stomach
ELANE	124	tissue_specific	marker	bone marrow, bone marrow cell, monocyte
ABCA7	231	ubiquitous	marker	granulocyte, adenohypophysis, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELANE	2,758
VPS13B	1,950
TCIRG1	1,931
CFD	1,604
ABCA7	1,520

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFD	P00746	40
ELANE	P08246	38
ABCA7	Q8IZY2	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52
VPS13B	Q7Z7G8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 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
Neutrophil degranulation	3	17.3×	0.006	TCIRG1, CFD, ELANE
Alternative complement activation	1	571.0×	0.011	CFD
Expression of NOTCH2NL genes	1	571.0×	0.011	ELANE
ABC transporters in lipid homeostasis	1	150.3×	0.026	ABCA7
Pyroptosis	1	105.7×	0.026	ELANE
Insulin receptor recycling	1	95.2×	0.026	TCIRG1
Transferrin endocytosis and recycling	1	92.1×	0.026	TCIRG1
ROS and RNS production in phagocytes	1	84.0×	0.026	TCIRG1
Activation of Matrix Metalloproteinases	1	77.2×	0.026	ELANE
Regulation of Complement cascade	1	58.3×	0.029	ELANE
Antimicrobial peptides	1	56.0×	0.029	ELANE
Amino acids regulate mTORC1	1	50.1×	0.030	TCIRG1
Collagen degradation	1	43.9×	0.031	ELANE
ABC-family protein mediated transport	1	30.4×	0.040	ABCA7
Degradation of the extracellular matrix	1	29.4×	0.040	ELANE
Ion channel transport	1	24.0×	0.046	TCIRG1
Platelet degranulation	1	22.0×	0.047	CFD
Transport of small molecules	1	6.3×	0.150	ABCA7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
biosynthetic process of antibacterial peptides active against Gram-negative bacteria	1	3370.4×	0.006	ELANE
response to silver ion	1	3370.4×	0.006	TCIRG1
dentin mineralization	1	3370.4×	0.006	TCIRG1
protein catabolic process in the vacuole	1	1685.2×	0.006	TCIRG1
slow endocytic recycling	1	1685.2×	0.006	VPS13B
memory T cell activation	1	1685.2×	0.006	TCIRG1
neutrophil-mediated killing of fungus	1	1685.2×	0.006	ELANE
positive regulation of engulfment of apoptotic cell	1	1685.2×	0.006	ABCA7
phagocytosis	2	96.3×	0.006	ELANE, ABCA7
memory	2	73.3×	0.006	VPS13B, ABCA7
intracellular calcium ion homeostasis	2	58.1×	0.006	TCIRG1, ELANE
regulation of proton transport	1	1123.5×	0.007	TCIRG1
T-helper 1 cell activation	1	1123.5×	0.007	TCIRG1
negative regulation of chemotaxis	1	1123.5×	0.007	ELANE
apolipoprotein A-I-mediated signaling pathway	1	842.6×	0.008	ABCA7
positive regulation of phospholipid efflux	1	842.6×	0.008	ABCA7
osteoclast proliferation	1	674.1×	0.008	TCIRG1
tooth eruption	1	674.1×	0.008	TCIRG1
neutrophil-mediated killing of gram-negative bacterium	1	674.1×	0.008	ELANE
Golgi reassembly	1	674.1×	0.008	VPS13B
regulation of amyloid precursor protein catabolic process	1	674.1×	0.008	ABCA7
acute inflammatory response to antigenic stimulus	1	561.7×	0.008	ELANE
plasma membrane raft organization	1	561.7×	0.008	ABCA7
pH reduction	1	481.5×	0.008	TCIRG1
establishment of vesicle localization	1	481.5×	0.008	TCIRG1
phagosome acidification	1	481.5×	0.008	TCIRG1
response to yeast	1	421.3×	0.008	ELANE
negative regulation of chemokine production	1	421.3×	0.008	ELANE
maintenance of lens transparency	1	421.3×	0.008	VPS13B
negative regulation of amyloid precursor protein biosynthetic process	1	421.3×	0.008	ABCA7

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
CFD	DANICOPAN
ELANE	BOCEPREVIR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ELANE	11	4
CFD	1	4
TCIRG1	0	0
VPS13B	0	0
ABCA7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DANICOPAN	4	CFD
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
EPIGALOCATECHIN GALLATE	3	ELANE
QUERCETIN	3	ELANE
SIVELESTAT	3	ELANE
LUTEOLIN	2	ELANE
MIDESTEINE	2	ELANE
FRESELESTAT	2	ELANE
DELANZOMIB	2	ELANE
ALVELESTAT	2	ELANE

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ELANE	801	Binding:758, Functional:35, ADMET:6, Toxicity:2
CFD	82	Binding:81, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFD	3.4.21.46	complement factor D
ELANE	3.4.21.37	leukocyte elastase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ELANE	801

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
DANICOPAN	4	CFD
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
EPIGALOCATECHIN GALLATE	3	ELANE
QUERCETIN	3	ELANE
SIVELESTAT	3	ELANE
LUTEOLIN	2	ELANE
MIDESTEINE	2	ELANE
FRESELESTAT	2	ELANE
DELANZOMIB	2	ELANE
ALVELESTAT	2	ELANE

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CFD, ELANE
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCA7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TCIRG1, VPS13B

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)
TCIRG1	0	—
VPS13B	0	—
ABCA7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.