Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

Summary

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (MONDO:0013507) is a disease caused by NCF4 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: NCF4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 359

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3
Mondo ID	MONDO:0013507
OMIM	613960
DOID	DOID:0070194
UMLS	C3151409
MedGen	462759
GARD	0015736
Is cancer (heuristic)	no

Also known as: CDG3 · chronic granulomatous disease 3, autosomal recessive · granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

Data availability: 359 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › chronic granulomatous disease › granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

Related subtypes (6): granulomatous disease with defect in neutrophil chemotaxis, granulomatous disease, chronic, autosomal recessive, cytochrome b-negative, granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1, granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2, granulomatous disease, chronic, X-linked, granulomatous disease, chronic, autosomal recessive, 5

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

359 retrieved; paginated sample, class counts are floors:

161 likely benign, 147 uncertain significance, 15 pathogenic, 13 benign, 8 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324783	NM_000631.5(NCF4):c.529-2A>T	NCF4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1933256	NM_000631.5(NCF4):c.256del (p.Leu86fs)	NCF4	Pathogenic	criteria provided, single submitter
1991035	NM_000631.5(NCF4):c.759-19C>T	NCF4	Pathogenic	criteria provided, single submitter
2085367	NM_000631.5(NCF4):c.758+28_758+29insA	NCF4	Pathogenic	criteria provided, single submitter
222998	NM_000631.5(NCF4):c.143_152dup (p.Lys52fs)	NCF4	Pathogenic	criteria provided, single submitter
2429239	NM_000631.5(NCF4):c.759-40C>T	NCF4	Pathogenic	criteria provided, multiple submitters, no conflicts
2585469	NM_000631.5(NCF4):c.614_615del (p.Lys205fs)	NCF4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2696736	NM_000631.5(NCF4):c.758+36_758+81del	NCF4	Pathogenic	criteria provided, single submitter
2762518	NM_000631.5(NCF4):c.367del (p.Val123fs)	NCF4	Pathogenic	criteria provided, single submitter
2828193	NM_000631.5(NCF4):c.456del (p.Arg153fs)	NCF4	Pathogenic	criteria provided, single submitter
2834848	NM_000631.5(NCF4):c.759-24T>G	NCF4	Pathogenic	criteria provided, single submitter
30193	NM_000631.5(NCF4):c.143_152del (p.Lys48fs)	NCF4	Pathogenic	no assertion criteria provided
30194	NM_000631.5(NCF4):c.314G>A (p.Arg105Gln)	NCF4	Pathogenic	criteria provided, multiple submitters, no conflicts
3605021	NM_000631.5(NCF4):c.13C>T (p.Gln5Ter)	NCF4	Pathogenic	criteria provided, single submitter
4695244	NM_000631.5(NCF4):c.771G>A (p.Val257=)	NCF4	Pathogenic	criteria provided, single submitter
652770	NM_000631.5(NCF4):c.758+50C>T	NCF4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932309	NM_000631.5(NCF4):c.716G>A (p.Trp239Ter)	NCF4	Pathogenic	no assertion criteria provided
932310	NM_000631.5(NCF4):c.32+2T>G	NCF4	Pathogenic	no assertion criteria provided
425281	NM_000631.5(NCF4):c.118-1G>A	NCF4-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3588030	NM_000631.5(NCF4):c.3G>A (p.Met1Ile)	NCF4	Likely pathogenic	criteria provided, single submitter
3588031	NM_000631.5(NCF4):c.32+2T>C	NCF4	Likely pathogenic	criteria provided, single submitter
3654709	NM_000631.5(NCF4):c.470+2T>G	NCF4	Likely pathogenic	criteria provided, single submitter
803685	NC_000022.11:g.36864921_36864935del	NCF4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
842976	NM_000631.5(NCF4):c.270_271+16del	NCF4	Likely pathogenic	criteria provided, single submitter
1384830	NM_000631.5(NCF4):c.409C>T (p.Pro137Ser)	NCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1391298	NM_000631.5(NCF4):c.768G>A (p.Ala256=)	NCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432872	NM_000631.5(NCF4):c.344G>A (p.Ser115Asn)	NCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2198294	NM_000631.5(NCF4):c.283G>A (p.Val95Met)	NCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341547	NM_000631.5(NCF4):c.33-6G>A	NCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341555	NM_000631.5(NCF4):c.647C>T (p.Thr216Met)	NCF4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
NCF4	Strong	Autosomal recessive	granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NCF4	Orphanet:379	Chronic granulomatous disease

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NCF4	HGNC:7662	ENSG00000100365	Q15080	Neutrophil cytosol factor 4	gencc,clinvar
CIMIP4	HGNC:28568	ENSG00000185264	O43247	Ciliary microtubule inner protein 4	clinvar
NCF4-AS1	HGNC:40393	ENSG00000183822		NCF4 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NCF4	Neutrophil cytosol factor 4	Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)).
CIMIP4	Ciliary microtubule inner protein 4	Seems to be associated with spermiogenesis but is not essential for sperm development and male fertility.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NCF4	Scaffold/PPI	no		PB1_dom, p40phox, SH3_domain
CIMIP4	Other/Unknown	no		CIMIP4
NCF4-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	2
male germ line stem cell (sensu Vertebrata) in testis	2
granulocyte	1
spleen	1
left testis	1
right testis	1
bone marrow cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NCF4	139	broad	marker	blood, spleen, granulocyte
CIMIP4	50	tissue_specific	yes	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis
NCF4-AS1	100	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, blood, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NCF4	2,758
CIMIP4	368
NCF4-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NCF4	Q15080	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CIMIP4	O43247	60.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 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
Cross-presentation of particulate exogenous antigens (phagosomes)	1	1427.5×	0.015	NCF4
RHO GTPases Activate NADPH Oxidases	1	456.8×	0.015	NCF4
ROS and RNS production in phagocytes	1	335.9×	0.015	NCF4
Antigen processing-Cross presentation	1	317.2×	0.015	NCF4
Detoxification of Reactive Oxygen Species	1	300.5×	0.015	NCF4
Signaling by VEGF	1	219.6×	0.017	NCF4
Cellular response to chemical stress	1	142.8×	0.019	NCF4
VEGFA-VEGFR2 Pathway	1	139.3×	0.019	NCF4
RAC2 GTPase cycle	1	126.9×	0.019	NCF4
RAC3 GTPase cycle	1	119.0×	0.019	NCF4
Class I MHC mediated antigen processing & presentation	1	70.1×	0.027	NCF4
RHO GTPase Effectors	1	68.0×	0.027	NCF4
RAC1 GTPase cycle	1	61.1×	0.027	NCF4
RHO GTPase cycle	1	60.1×	0.027	NCF4
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.030	NCF4
Cellular responses to stress	1	36.8×	0.038	NCF4
Signaling by Rho GTPases	1	34.2×	0.038	NCF4
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.038	NCF4
Cellular responses to stimuli	1	31.5×	0.038	NCF4
Adaptive Immune System	1	29.8×	0.039	NCF4
Innate Immune System	1	25.5×	0.043	NCF4
Immune System	1	13.0×	0.081	NCF4
Signal Transduction	1	10.2×	0.098	NCF4

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
respiratory burst	1	1296.3×	0.002	NCF4
superoxide anion generation	1	674.1×	0.002	NCF4
phagocytosis	1	240.7×	0.004	NCF4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NCF4	0	0
CIMIP4	0	0
NCF4-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	NCF4, CIMIP4, NCF4-AS1

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)
NCF4	0	—
CIMIP4	0	—
NCF4-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.