Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Summary

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative (MONDO:0009308) is a disease caused by CYBA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CYBA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 457

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	granulomatous disease, chronic, autosomal recessive, cytochrome b-negative
Mondo ID	MONDO:0009308
MeSH	C565533
OMIM	233690
DOID	DOID:0070193
UMLS	C1856255
MedGen	383872
GARD	0015175
Is cancer (heuristic)	no

Also known as: chronic granulomatous disease 4, autosomal recessive · granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Data availability: 457 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-negative

Related subtypes (6): granulomatous disease with defect in neutrophil chemotaxis, 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, cytochrome b-positive, type 3, 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

457 retrieved; paginated sample, class counts are floors:

237 likely benign, 116 uncertain significance, 39 pathogenic, 20 pathogenic/likely pathogenic, 17 likely pathogenic, 14 benign, 12 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074796	NC_000016.9:g.(?88709737)(89220635_?)del	ACSF3	Pathogenic	criteria provided, single submitter
1032885	NM_000101.4(CYBA):c.393G>A (p.Trp131Ter)	CYBA	Pathogenic	criteria provided, single submitter
1071345	NM_000101.4(CYBA):c.111C>G (p.Tyr37Ter)	CYBA	Pathogenic	criteria provided, single submitter
1072119	NM_000101.4(CYBA):c.166dup (p.Arg56fs)	CYBA	Pathogenic	criteria provided, multiple submitters, no conflicts
1074797	NC_000016.9:g.(?88713499)(88714532_?)del	CYBA	Pathogenic	criteria provided, single submitter
1371434	NM_000101.4(CYBA):c.399del (p.Ile134fs)	CYBA	Pathogenic	criteria provided, single submitter
1429693	NC_000016.9:g.(?88713499)(88718353_?)del	CYBA	Pathogenic	criteria provided, single submitter
1458360	NC_000016.9:g.(?88717354)(88718353_?)del	CYBA	Pathogenic	criteria provided, single submitter
1458496	NM_000101.4(CYBA):c.17G>A (p.Trp6Ter)	CYBA	Pathogenic	criteria provided, single submitter
1458628	NC_000016.9:g.(?88712514)(88718096_?)del	CYBA	Pathogenic	criteria provided, single submitter
1459158	NM_000101.4(CYBA):c.77del (p.Ile26fs)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1489230	NM_000101.4(CYBA):c.59-2A>T	CYBA	Pathogenic	criteria provided, single submitter
1494695	NM_000101.4(CYBA):c.472_484del (p.Pro160fs)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1967713	NM_000101.4(CYBA):c.68_76del (p.Thr23_Gly25del)	CYBA	Pathogenic	criteria provided, single submitter
1977314	NM_000101.4(CYBA):c.467dup (p.Pro157fs)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2028965	NM_000101.4(CYBA):c.108G>A (p.Trp36Ter)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2070087	NM_000101.4(CYBA):c.267del (p.Arg90fs)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2098988	NM_000101.4(CYBA):c.288-1G>T	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137853	NM_000101.4(CYBA):c.295_301del (p.Val99fs)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137856	NM_000101.4(CYBA):c.287+1G>T	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2256	NC_000016.10:g.(?_88638115)(88648115_88650955)del	CYBA	Pathogenic	no assertion criteria provided
2258	NM_000101.4(CYBA):c.269G>A (p.Arg90Gln)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2259	NM_000101.4(CYBA):c.354C>A (p.Ser118Arg)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2262	NM_000101.4(CYBA):c.287+1G>A	CYBA	Pathogenic	no assertion criteria provided
2264	NM_000101.4(CYBA):c.7C>T (p.Gln3Ter)	CYBA	Pathogenic	criteria provided, multiple submitters, no conflicts
2265	NM_000101.4(CYBA):c.70G>A (p.Gly24Arg)	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2266	NM_000101.4(CYBA):c.288-13_310del	CYBA	Pathogenic	no assertion criteria provided
2267	NM_000101.4(CYBA):c.373G>A (p.Ala125Thr)	CYBA	Pathogenic	no assertion criteria provided
2698449	NM_000101.4(CYBA):c.58+2T>C	CYBA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736377	NM_000101.4(CYBA):c.107G>A (p.Trp36Ter)	CYBA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CYBA	Definitive	Autosomal recessive	granulomatous disease, chronic, autosomal recessive, cytochrome b-negative	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYBA	Orphanet:379	Chronic granulomatous disease
ACSF3	Orphanet:289504	Combined malonic and methylmalonic acidemia

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
CYBA	HGNC:2577	ENSG00000051523	P13498	Cytochrome b-245 light chain	gencc,clinvar
ACSF3	HGNC:27288	ENSG00000176715	Q4G176	Malonate–CoA ligase ACSF3, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYBA	Cytochrome b-245 light chain	Subunit of NADPH oxidase complexes that is required for the NADPH oxidase activity that generates, in various cell types, superoxide from molecular oxygen utilizing NADPH as an electron donor.
ACSF3	Malonate–CoA ligase ACSF3, mitochondrial	Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYBA	Other/Unknown	no		Cyt_b558_asu
ACSF3	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C

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
granulocyte	2
leukocyte	1
monocyte	1
mucosa of transverse colon	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYBA	267	ubiquitous	marker	granulocyte, monocyte, leukocyte
ACSF3	173	ubiquitous	marker	mucosa of transverse colon, granulocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACSF3	2,854
CYBA	1,699

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYBA	P13498	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSF3	Q4G176	86.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Cross-presentation of particulate exogenous antigens (phagosomes)	1	713.8×	0.014	CYBA
WNT5:FZD7-mediated leishmania damping	1	475.8×	0.014	CYBA
RHO GTPases Activate NADPH Oxidases	1	228.4×	0.014	CYBA
Synthesis of very long-chain fatty acyl-CoAs	1	228.4×	0.014	ACSF3
Fatty acyl-CoA biosynthesis	1	219.6×	0.014	ACSF3
ROS and RNS production in phagocytes	1	167.9×	0.014	CYBA
Detoxification of Reactive Oxygen Species	1	150.3×	0.014	CYBA
VEGFA-VEGFR2 Pathway	1	69.6×	0.023	CYBA
Fatty acid metabolism	1	65.6×	0.023	ACSF3
RAC2 GTPase cycle	1	63.4×	0.023	CYBA
RAC3 GTPase cycle	1	59.5×	0.023	CYBA
RAC1 GTPase cycle	1	30.5×	0.041	CYBA
Metabolism of lipids	1	15.8×	0.072	ACSF3
Neutrophil degranulation	1	11.5×	0.091	CYBA
Metabolism	1	5.8×	0.165	ACSF3

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
negative regulation of glomerular filtration by angiotensin	1	8426.0×	0.002	CYBA
smooth muscle hypertrophy	1	8426.0×	0.002	CYBA
malonate catabolic process	1	8426.0×	0.002	ACSF3
cytochrome complex assembly	1	4213.0×	0.002	CYBA
cellular response to L-glutamine	1	2106.5×	0.004	CYBA
positive regulation of mucus secretion	1	1685.2×	0.004	CYBA
positive regulation of toll-like receptor 2 signaling pathway	1	1053.2×	0.005	CYBA
positive regulation of defense response to bacterium	1	936.2×	0.005	CYBA
response to aldosterone	1	842.6×	0.005	CYBA
hydrogen peroxide biosynthetic process	1	702.2×	0.005	CYBA
respiratory burst	1	648.1×	0.005	CYBA
mucus secretion	1	648.1×	0.005	CYBA
cellular response to phorbol 13-acetate 12-myristate	1	648.1×	0.005	CYBA
positive regulation of reactive oxygen species biosynthetic process	1	561.7×	0.005	CYBA
superoxide metabolic process	1	495.6×	0.005	CYBA
regulation of release of sequestered calcium ion into cytosol	1	468.1×	0.005	CYBA
cellular response to angiotensin	1	468.1×	0.005	CYBA
positive regulation of superoxide anion generation	1	443.5×	0.005	CYBA
long-chain fatty-acyl-CoA biosynthetic process	1	421.3×	0.005	ACSF3
superoxide anion generation	1	337.0×	0.006	CYBA
cellular response to gamma radiation	1	300.9×	0.006	CYBA
response to interleukin-1	1	255.3×	0.007	CYBA
response to nutrient levels	1	183.2×	0.009	CYBA
fatty acid biosynthetic process	1	175.5×	0.009	ACSF3
positive regulation of smooth muscle cell proliferation	1	165.2×	0.009	CYBA
response to activity	1	162.0×	0.009	CYBA
positive regulation of phagocytosis	1	159.0×	0.009	CYBA
cellular response to glucose stimulus	1	133.8×	0.011	CYBA
positive regulation of endothelial cell proliferation	1	115.4×	0.012	CYBA
cellular response to mechanical stimulus	1	108.0×	0.012	CYBA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYBA	0	0
ACSF3	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
CYBA	1	Binding:1
ACSF3	1	Binding:1

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	2	CYBA, ACSF3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CYBA	1	—
ACSF3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.