autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Summary

autosomal recessive severe congenital neutropenia due to CSF3R deficiency (MONDO:0014865) is a disease caused by CSF3R (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CSF3R (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 696

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive severe congenital neutropenia due to CSF3R deficiency
Mondo ID	MONDO:0014865
OMIM	617014
Orphanet	420702
DOID	DOID:0112129
UMLS	C4310764
MedGen	934731
GARD	0017698
Is cancer (heuristic)	no

Also known as: neutropenia, Severe congenital, 7, autosomal recessive · SCN7

Data availability: 696 ClinVar variants · 3 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 CSF3R 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 JAGN1 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

600 retrieved; paginated sample, class counts are floors:

303 uncertain significance, 221 likely benign, 24 pathogenic, 20 conflicting classifications of pathogenicity, 13 benign/likely benign, 9 likely pathogenic, 6 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033125	NM_000760.4(CSF3R):c.843+2T>C	CSF3R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070139	NM_000760.4(CSF3R):c.32G>A (p.Trp11Ter)	CSF3R	Pathogenic	criteria provided, single submitter
1073345	NM_000760.4(CSF3R):c.1388G>A (p.Trp463Ter)	CSF3R	Pathogenic	criteria provided, single submitter
1322165	NM_000760.4(CSF3R):c.189G>A (p.Trp63Ter)	CSF3R	Pathogenic	criteria provided, multiple submitters, no conflicts
1372222	NM_000760.4(CSF3R):c.642_650delinsTTGATCCCATGGATGTTGGTGTCTTGATCCCATGGATGTTG (p.Pro215_Leu217delinsTer)	CSF3R	Pathogenic	criteria provided, single submitter
1410136	NM_000760.4(CSF3R):c.218dup (p.Arg74fs)	CSF3R	Pathogenic	criteria provided, single submitter
1416044	NM_000760.4(CSF3R):c.78C>A (p.Cys26Ter)	CSF3R	Pathogenic	criteria provided, single submitter
1431609	NM_000760.4(CSF3R):c.1525C>T (p.Gln509Ter)	CSF3R	Pathogenic	criteria provided, single submitter
1453348	NM_000760.4(CSF3R):c.1072-1G>C	CSF3R	Pathogenic	criteria provided, single submitter
161982	NM_000760.4(CSF3R):c.922C>T (p.Arg308Cys)	CSF3R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1981802	NM_000760.4(CSF3R):c.690dup (p.Met231fs)	CSF3R	Pathogenic	criteria provided, single submitter
1990606	NM_000760.4(CSF3R):c.769C>T (p.Gln257Ter)	CSF3R	Pathogenic	criteria provided, single submitter
2041994	NM_000760.4(CSF3R):c.1003del (p.Thr335fs)	CSF3R	Pathogenic	criteria provided, single submitter
208339	NM_000760.4(CSF3R):c.1853C>T (p.Thr618Ile)	CSF3R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242629	NM_000760.4(CSF3R):c.948_963del (p.His317fs)	CSF3R	Pathogenic	no assertion criteria provided
242630	NM_000760.4(CSF3R):c.1245del (p.Thr416fs)	CSF3R	Pathogenic	no assertion criteria provided
2439604	NM_000760.4(CSF3R):c.1072-1G>A	CSF3R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2747049	NM_000760.4(CSF3R):c.1233_1234dup (p.Asn412fs)	CSF3R	Pathogenic	criteria provided, single submitter
2771578	NM_000760.4(CSF3R):c.1105C>T (p.Gln369Ter)	CSF3R	Pathogenic	criteria provided, single submitter
2900974	NM_000760.4(CSF3R):c.836G>A (p.Trp279Ter)	CSF3R	Pathogenic	criteria provided, single submitter
2904711	NM_000760.4(CSF3R):c.1488del (p.Gln498fs)	CSF3R	Pathogenic	criteria provided, single submitter
3004498	NM_000760.4(CSF3R):c.296_299del (p.Leu99fs)	CSF3R	Pathogenic	criteria provided, single submitter
3603443	NM_000760.4(CSF3R):c.832_835dup (p.Trp279Ter)	CSF3R	Pathogenic	criteria provided, single submitter
3663206	NM_000760.4(CSF3R):c.712dup (p.Ser238fs)	CSF3R	Pathogenic	criteria provided, single submitter
4722821	NM_000760.4(CSF3R):c.1633del (p.Leu545fs)	CSF3R	Pathogenic	criteria provided, single submitter
4741276	NM_000760.4(CSF3R):c.1318C>T (p.Arg440Ter)	CSF3R	Pathogenic	criteria provided, single submitter
542855	NM_000760.4(CSF3R):c.1216dup (p.Val406fs)	CSF3R	Pathogenic	criteria provided, single submitter
542856	NM_000760.4(CSF3R):c.799del (p.Glu267fs)	CSF3R	Pathogenic	criteria provided, single submitter
1509271	NM_000760.4(CSF3R):c.998-1G>A	CSF3R	Likely pathogenic	criteria provided, single submitter
2020016	NM_000760.4(CSF3R):c.1577-1G>A	CSF3R	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
CSF3R	Strong	Autosomal recessive	autosomal recessive severe congenital neutropenia due to CSF3R deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSF3R	Orphanet:279943	Hereditary neutrophilia
CSF3R	Orphanet:420702	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency
CSF3R	Orphanet:86829	Chronic neutrophilic leukemia
CSF3R	Orphanet:98824	Atypical chronic myeloid leukemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CSF3R	HGNC:2439	ENSG00000119535	Q99062	Granulocyte colony-stimulating factor receptor	gencc,clinvar
PIP4K2B	HGNC:8998	ENSG00000276293	P78356	Phosphatidylinositol 5-phosphate 4-kinase type-2 beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSF3R	Granulocyte colony-stimulating factor receptor	Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation.
PIP4K2B	Phosphatidylinositol 5-phosphate 4-kinase type-2 beta	Participates in the biosynthesis of phosphatidylinositol 4,5-bisphosphate.

Protein-family classification

Druggable: 2 · 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	14.6×	0.071
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSF3R	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, FN3_dom, IgC2-like_lig-bd
PIP4K2B	Kinase	yes	2.7.1.149	PInositol-4-P-4/5-kinase_core, PInositol-4/5-P-5/4-kinase, PInositol-4-P-4/5-kinase_C_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
monocyte	1
Brodmann (1909) area 9	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSF3R	192	broad	marker	granulocyte, monocyte, blood
PIP4K2B	162	ubiquitous	marker	cortical plate, ganglionic eminence, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSF3R	3,315
PIP4K2B	1,645

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIP4K2B	P78356	26
CSF3R	Q99062	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
Synthesis of PIPs in the nucleus	1	1427.5×	0.006	PIP4K2B
PI5P Regulates TP53 Acetylation	1	634.4×	0.006	PIP4K2B
Signaling by CSF3 (G-CSF)	1	285.5×	0.007	CSF3R
Other interleukin signaling	1	237.9×	0.007	CSF3R
Inactivation of CSF3 (G-CSF) signaling	1	219.6×	0.007	CSF3R
Synthesis of PIPs at the plasma membrane	1	105.7×	0.013	PIP4K2B
Transcriptional regulation of granulopoiesis	1	62.8×	0.018	CSF3R
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.021	PIP4K2B

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate biosynthetic process	1	2808.7×	0.004	PIP4K2B
regulation of myeloid cell differentiation	1	1685.2×	0.004	CSF3R
amelogenesis	1	702.2×	0.006	CSF3R
autophagosome-lysosome fusion	1	601.9×	0.006	PIP4K2B
positive regulation of autophagosome assembly	1	401.2×	0.007	PIP4K2B
phosphatidylinositol phosphate biosynthetic process	1	240.7×	0.010	PIP4K2B
negative regulation of insulin receptor signaling pathway	1	187.2×	0.011	PIP4K2B
neutrophil chemotaxis	1	142.8×	0.013	CSF3R
regulation of autophagy	1	120.4×	0.014	PIP4K2B
defense response	1	108.0×	0.014	CSF3R
cytokine-mediated signaling pathway	1	65.3×	0.021	CSF3R
cell surface receptor signaling pathway	1	32.0×	0.039	PIP4K2B
cell adhesion	1	18.7×	0.061	CSF3R
positive regulation of cell population proliferation	1	16.8×	0.063	CSF3R
signal transduction	1	8.0×	0.121	CSF3R

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
PIP4K2B	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIP4K2B	15	4
CSF3R	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	PIP4K2B
NINTEDANIB	4	PIP4K2B
SUNITINIB	4	PIP4K2B
MIDOSTAURIN	4	PIP4K2B
DOVITINIB	3	PIP4K2B
LESTAURTINIB	3	PIP4K2B
RUBOXISTAURIN	3	PIP4K2B
SU-014813	2	PIP4K2B
IMANIXIL	2	PIP4K2B
TG100-115	2	PIP4K2B
R-406	2	PIP4K2B
TOZASERTIB	2	PIP4K2B
PELITINIB	2	PIP4K2B
GSK-461364	1	PIP4K2B
KW-2449	1	PIP4K2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIP4K2B	124	Binding:124
CSF3R	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIP4K2B	2.7.1.149	1-phosphatidylinositol-5-phosphate 4-kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIP4K2B	124

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

15 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)
FEDRATINIB	4	PIP4K2B
NINTEDANIB	4	PIP4K2B
SUNITINIB	4	PIP4K2B
MIDOSTAURIN	4	PIP4K2B
DOVITINIB	3	PIP4K2B
LESTAURTINIB	3	PIP4K2B
RUBOXISTAURIN	3	PIP4K2B
SU-014813	2	PIP4K2B
IMANIXIL	2	PIP4K2B
TG100-115	2	PIP4K2B
R-406	2	PIP4K2B
TOZASERTIB	2	PIP4K2B
PELITINIB	2	PIP4K2B
GSK-461364	1	PIP4K2B
KW-2449	1	PIP4K2B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIP4K2B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CSF3R
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)
CSF3R	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.