Neutropenia, severe congenital, 2, autosomal dominant

Summary

Neutropenia, severe congenital, 2, autosomal dominant (MONDO:0013139) is a disease caused by GFI1 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: GFI1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 376

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neutropenia, severe congenital, 2, autosomal dominant
Mondo ID	MONDO:0013139
MeSH	C567748
OMIM	613107
DOID	DOID:0112131
UMLS	C2751288
MedGen	413975
GARD	0015616
Is cancer (heuristic)	no

Also known as: autosomal dominant severe congenital neutropenia caused by mutation in GFI1 · GFI1 autosomal dominant severe congenital neutropenia · neutropenia, severe congenital 2, autosomal dominant · neutropenia, severe congenital, 2, autosomal dominant · SCN2

Data availability: 376 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 dominant disease › autosomal dominant severe congenital neutropenia › neutropenia, severe congenital, 2, autosomal dominant

Related subtypes (2): neutropenia, lethal congenital, with eosinophilia, neutropenia, severe congenital, 1, 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

376 retrieved; paginated sample, class counts are floors:

199 uncertain significance, 129 likely benign, 22 benign/likely benign, 15 conflicting classifications of pathogenicity, 10 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
8739	NM_005263.5(GFI1):c.1145A>G (p.Asn382Ser)	GFI1	Pathogenic	criteria provided, multiple submitters, no conflicts
1009841	NM_005263.5(GFI1):c.313A>G (p.Met105Val)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1103060	NM_005263.5(GFI1):c.572C>T (p.Ala191Val)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1127236	NM_005263.5(GFI1):c.419G>A (p.Arg140Gln)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1131120	NM_005263.5(GFI1):c.200G>A (p.Arg67Lys)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1150449	NM_005263.5(GFI1):c.538G>A (p.Gly180Arg)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337277	NM_005263.5(GFI1):c.299-12G>C	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1405692	NM_005263.5(GFI1):c.109C>G (p.Arg37Gly)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1517491	NM_005263.5(GFI1):c.233G>C (p.Ser78Thr)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1983434	NM_005263.5(GFI1):c.559G>T (p.Ala187Ser)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298181	NM_005263.5(GFI1):c.925-40CT[25]	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538139	NM_005263.5(GFI1):c.772A>G (p.Ile258Val)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538141	NM_005263.5(GFI1):c.925-40CT[26]	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801501	NM_005263.5(GFI1):c.1250C>T (p.Thr417Met)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8740	NM_005263.5(GFI1):c.1208A>G (p.Lys403Arg)	GFI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452884	NM_000459.5(TEK):c.2753G>A (p.Arg918His)	TEK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3247790	NC_000001.10:g.(?92457801)(92949044_?)dup	C1orf146	Uncertain significance	criteria provided, single submitter
642319	NM_001258392.3(CLPB):c.1570C>T (p.Arg524Trp)	CLPB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002135	NM_005263.5(GFI1):c.79C>T (p.Leu27Phe)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1006342	NM_005263.5(GFI1):c.691G>T (p.Ala231Ser)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1024307	NM_005263.5(GFI1):c.82C>T (p.Arg28Cys)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025019	NM_005263.5(GFI1):c.733T>G (p.Cys245Gly)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025209	NM_005263.5(GFI1):c.46C>G (p.His16Asp)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030898	NM_005263.5(GFI1):c.52C>T (p.Pro18Ser)	GFI1	Uncertain significance	criteria provided, single submitter
1030899	NM_005263.5(GFI1):c.577G>T (p.Ala193Ser)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1040579	NM_005263.5(GFI1):c.49C>G (p.Gln17Glu)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1042060	NC_000001.10:g.(?92941566)(92949064_?)del	GFI1	Uncertain significance	criteria provided, single submitter
1042613	NM_005263.5(GFI1):c.736A>G (p.Thr246Ala)	GFI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1042778	NM_005263.5(GFI1):c.709G>T (p.Val237Phe)	GFI1	Uncertain significance	criteria provided, single submitter
1044065	NM_005263.5(GFI1):c.376G>T (p.Gly126Cys)	GFI1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · 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
GFI1	Strong	Autosomal dominant	neutropenia, severe congenital, 2, autosomal dominant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFI1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TEK	Orphanet:1059	Blue rubber bleb nevus
TEK	Orphanet:2451	Mucocutaneous venous malformations
TEK	Orphanet:714806	Multifocal sporadic venous malformation
TEK	Orphanet:98976	Congenital glaucoma
CLPB	Orphanet:445038	3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome
CLPB	Orphanet:486	Autosomal dominant severe congenital neutropenia
HIVEP2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GFI1	HGNC:4237	ENSG00000162676	Q99684	Zinc finger protein Gfi-1	gencc,clinvar
SNORD21	HGNC:10144	ENSG00000206680		small nucleolar RNA, C/D box 21	clinvar
TEK	HGNC:11724	ENSG00000120156	Q02763	Angiopoietin-1 receptor	clinvar
C1orf146	HGNC:24032	ENSG00000203910	Q5VVC0	Protein SPO16 homolog	clinvar
CLPB	HGNC:30664	ENSG00000162129	Q9H078	Mitochondrial disaggregase	clinvar
HIVEP2	HGNC:4921	ENSG00000010818	P31629	Transcription factor HIVEP2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GFI1	Zinc finger protein Gfi-1	Transcription repressor essential for hematopoiesis.
TEK	Angiopoietin-1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskelet…
C1orf146	Protein SPO16 homolog	Plays a key role in reinforcing the integrity of the central element of the synaptonemal complex (SC) thereby stabilizing SC, ensuring progression of meiotic prophase I in male and female germ cells.
CLPB	Mitochondrial disaggregase	Functions as a regulatory ATPase and participates in secretion/protein trafficking process.
HIVEP2	Transcription factor HIVEP2	This protein specifically binds to the DNA sequence 5’-GGGACTTTCC-3’ which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 2 · Druggable fraction: 0.17

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
Kinase	1	4.6×	0.396
Transcription factor	2	2.8×	0.396
Scaffold/PPI	1	2.9×	0.401
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GFI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
SNORD21	Other/Unknown	no
TEK	Kinase	yes	2.7.10.1	Prot_kinase_dom, EGF, Ser-Thr/Tyr_kinase_cat_dom
C1orf146	Other/Unknown	no		SCRE
CLPB	Scaffold/PPI	no		ClpA/B, Ankyrin_rpt, AAA+_ATPase
HIVEP2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
granulocyte	1
adrenal tissue	1
liver	1
sural nerve	1
diaphragm	1
right lung	1
visceral pleura	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
testis	1
left testis	1
right testis	1
sperm	1
lateral nuclear group of thalamus	1
tendon of biceps brachii	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GFI1	153	broad	yes	granulocyte, bone marrow, bone marrow cell
SNORD21	59		yes	sural nerve, liver, adrenal tissue
TEK	223	broad	marker	right lung, diaphragm, visceral pleura
C1orf146	115	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis
CLPB	205	ubiquitous	marker	sperm, left testis, right testis
HIVEP2	296	ubiquitous	marker	tendon of biceps brachii, vena cava, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPB	5,095
TEK	2,762
GFI1	2,148
HIVEP2	1,489
C1orf146	955
SNORD21	0

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TEK	Q02763	17
CLPB	Q9H078	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C1orf146	Q5VVC0	86.23
GFI1	Q99684	58.33
HIVEP2	P31629	36.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 6 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
Tie2 Signaling	1	300.5×	0.027	TEK
MAPK1/MAPK3 signaling	1	65.6×	0.033	TEK
Transcriptional regulation of granulopoiesis	1	62.8×	0.033	GFI1
MAPK family signaling cascades	1	51.4×	0.033	TEK
Cell surface interactions at the vascular wall	1	47.6×	0.033	TEK
RAF/MAP kinase cascade	1	30.5×	0.043	TEK
Hemostasis	1	18.0×	0.063	TEK
Signal Transduction	1	5.1×	0.187	TEK

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
regulation of endothelial cell apoptotic process	1	1685.2×	0.011	TEK
positive regulation of interleukin-6-mediated signaling pathway	1	1123.5×	0.011	GFI1
negative regulation of vitamin D biosynthetic process	1	842.6×	0.011	GFI1
glomerulus vasculature development	1	842.6×	0.011	TEK
regulation of establishment or maintenance of cell polarity	1	674.1×	0.011	TEK
Tie signaling pathway	1	674.1×	0.011	TEK
RIG-I signaling pathway	1	481.5×	0.014	CLPB
regulation of toll-like receptor signaling pathway	1	306.4×	0.019	GFI1
granulocyte differentiation	1	240.7×	0.019	CLPB
regulation of vascular permeability	1	224.7×	0.019	TEK
heart trabecula formation	1	224.7×	0.019	TEK
definitive hemopoiesis	1	187.2×	0.020	TEK
synaptonemal complex assembly	1	129.6×	0.022	C1orf146
positive regulation of Rac protein signal transduction	1	129.6×	0.022	TEK
positive regulation of focal adhesion assembly	1	129.6×	0.022	TEK
positive regulation of intracellular signal transduction	1	129.6×	0.022	TEK
positive regulation of Rho protein signal transduction	1	116.2×	0.022	TEK
reciprocal meiotic recombination	1	112.3×	0.022	C1orf146
endothelial cell proliferation	1	108.7×	0.022	TEK
negative regulation of endothelial cell apoptotic process	1	99.1×	0.023	TEK
sprouting angiogenesis	1	96.3×	0.023	TEK
obsolete negative regulation of NF-kappaB transcription factor activity	1	71.7×	0.028	GFI1
substrate adhesion-dependent cell spreading	1	68.8×	0.028	TEK
cellular response to heat	1	68.8×	0.028	CLPB
positive regulation of endothelial cell migration	1	50.3×	0.036	TEK
negative regulation of neuron projection development	1	47.5×	0.036	GFI1
positive regulation of endothelial cell proliferation	1	46.2×	0.036	TEK
antiviral innate immune response	1	45.5×	0.036	CLPB
cellular response to mechanical stimulus	1	43.2×	0.036	TEK
cell surface receptor protein tyrosine kinase signaling pathway	1	34.8×	0.044	TEK

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
TEK	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TEK	46	4
GFI1	0	0
SNORD21	0	0
C1orf146	0	0
CLPB	0	0
HIVEP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	TEK
FEDRATINIB	4	TEK
TIVOZANIB	4	TEK
AXITINIB	4	TEK
SORAFENIB	4	TEK
NICLOSAMIDE	4	TEK
AMPICILLIN	4	TEK
NERATINIB	4	TEK
INFIGRATINIB PHOSPHATE	4	TEK
INFIGRATINIB	4	TEK
REGORAFENIB	4	TEK
CABOZANTINIB	4	TEK
VANDETANIB	4	TEK
NILOTINIB	4	TEK
BOSUTINIB	4	TEK
PAZOPANIB	4	TEK
NINTEDANIB	4	TEK
QUIZARTINIB	4	TEK
CRIZOTINIB	4	TEK
MIDOSTAURIN	4	TEK
LOPERAMIDE	4	TEK
LINIFANIB	3	TEK
BRIVANIB	3	TEK
CEDIRANIB	3	TEK
LESTAURTINIB	3	TEK
DORAMAPIMOD	2	TEK
FORETINIB	2	TEK
REBASTINIB	2	TEK
CEP-11981	2	TEK
DEFOSBARASERTIB	2	TEK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TEK	707	Binding:701, Functional:4, ADMET:2
GFI1	6	Binding:6
HIVEP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TEK	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TEK	707

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
CETIRIZINE	4	TEK
FEDRATINIB	4	TEK
TIVOZANIB	4	TEK
AXITINIB	4	TEK
SORAFENIB	4	TEK
NICLOSAMIDE	4	TEK
AMPICILLIN	4	TEK
NERATINIB	4	TEK
INFIGRATINIB PHOSPHATE	4	TEK
INFIGRATINIB	4	TEK
REGORAFENIB	4	TEK
CABOZANTINIB	4	TEK
VANDETANIB	4	TEK
NILOTINIB	4	TEK
BOSUTINIB	4	TEK
PAZOPANIB	4	TEK
NINTEDANIB	4	TEK
QUIZARTINIB	4	TEK
CRIZOTINIB	4	TEK
MIDOSTAURIN	4	TEK
LOPERAMIDE	4	TEK
LINIFANIB	3	TEK
BRIVANIB	3	TEK
CEDIRANIB	3	TEK
LESTAURTINIB	3	TEK
DORAMAPIMOD	2	TEK
FORETINIB	2	TEK
REBASTINIB	2	TEK
CEP-11981	2	TEK
DEFOSBARASERTIB	2	TEK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TEK
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	5	GFI1, SNORD21, C1orf146, CLPB, HIVEP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GFI1	6	—
SNORD21	0	—
C1orf146	0	—
CLPB	0	—
HIVEP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.