2-methylbutyryl-CoA dehydrogenase deficiency

Summary

2-methylbutyryl-CoA dehydrogenase deficiency (MONDO:0012392) is a disease caused by ACADSB (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ACADSB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 306
• Phenotypes (HPO): 9
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0035019	Elevated circulating C5 acylcarnitine concentration	Frequent (30-79%)
HP:0033220	2-ethylhydracylic aciduria	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001531	Failure to thrive in infancy	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000717	Autism	Very rare (<1-4%)
HP:0000750	Delayed speech and language development	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	2-methylbutyryl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0012392
MeSH	C566487
OMIM	610006
Orphanet	79157
NCIT	C98863
UMLS	C1864912
MedGen	355324
GARD	0010322
Is cancer (heuristic)	no

Also known as: 2-methylbutyric aciduria · 2-methylbutyryl-CoA dehydrogenase deficiency · 2-methylbutyrylglycinuria · butyryl-CoA dehydrogenase deficiency · developmental delay due to 2-methylbutyryl-CoA dehydrogenase deficiency · SBCAD deficiency · short branched-chain acyl-CoA dehydrogenase deficiency · short/branched-chain acyl-coA dehydrogenase deficiency

Data availability: 306 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › 2-methylbutyryl-CoA dehydrogenase deficiency

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxyisobutyryl-CoA hydrolase deficiency, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, propionic acidemia, isobutyryl-CoA dehydrogenase deficiency, combined malonic and methylmalonic acidemia, multiple carboxylase deficiency, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, 3-methylglutaconic aciduria, 3-methylcrotonyl-CoA carboxylase 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

306 retrieved; paginated sample, class counts are floors:

137 uncertain significance, 58 likely benign, 45 benign, 21 likely pathogenic, 19 conflicting classifications of pathogenicity, 13 pathogenic, 10 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1481374	NM_001609.4(ACADSB):c.923G>A (p.Cys308Tyr)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678478	NM_001609.4(ACADSB):c.478del (p.Ala160fs)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2153596	NM_001609.4(ACADSB):c.275C>G (p.Ser92Ter)	ACADSB	Pathogenic	criteria provided, multiple submitters, no conflicts
2632051	NM_001609.4(ACADSB):c.1116C>A (p.Tyr372Ter)	ACADSB	Pathogenic	criteria provided, single submitter
281177	NM_001609.4(ACADSB):c.295C>T (p.Gln99Ter)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2828858	NM_001609.4(ACADSB):c.356del (p.Leu119fs)	ACADSB	Pathogenic	criteria provided, single submitter
2828859	NM_001609.4(ACADSB):c.878dup (p.Gly293_Arg294insTer)	ACADSB	Pathogenic	criteria provided, single submitter
2899530	NM_001609.4(ACADSB):c.1172del (p.Gly391fs)	ACADSB	Pathogenic	criteria provided, single submitter
299075	NM_001609.4(ACADSB):c.621G>A (p.Trp207Ter)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3682850	NM_001609.4(ACADSB):c.548G>A (p.Ser183Asn)	ACADSB	Pathogenic	criteria provided, single submitter
4278338	NM_001609.4(ACADSB):c.1128+2T>G	ACADSB	Pathogenic	criteria provided, single submitter
448980	NM_001609.4(ACADSB):c.303+3A>G	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4806895	NM_001609.4(ACADSB):c.653T>C (p.Leu218Pro)	ACADSB	Pathogenic	criteria provided, single submitter
4814191	NM_001609.4(ACADSB):c.454A>T (p.Lys152Ter)	ACADSB	Pathogenic	criteria provided, single submitter
577108	NM_001609.4(ACADSB):c.655G>A (p.Val219Met)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
583673	NC_000010.11:g.(?123034356)(123041379_?)del	ACADSB	Pathogenic	criteria provided, single submitter
659271	NM_001609.4(ACADSB):c.375dup (p.Glu126fs)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
664690	NM_001609.4(ACADSB):c.1165A>G (p.Met389Val)	ACADSB	Pathogenic	criteria provided, multiple submitters, no conflicts
859736	NM_001609.4(ACADSB):c.653dup (p.Val219fs)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9199	NM_001609.4(ACADSB):c.1228G>A (p.Gly410Ser)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9200	NM_001609.4(ACADSB):c.763C>T (p.Leu255Phe)	ACADSB	Pathogenic	criteria provided, single submitter
9203	NM_001609.4(ACADSB):c.1159G>A (p.Glu387Lys)	ACADSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3244863	NC_000010.10:g.(?122842033)(124813281_?)del	CUZD1	Pathogenic	criteria provided, single submitter
1032758	NM_001609.4(ACADSB):c.1228+1G>A	ACADSB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066905	NM_001609.4(ACADSB):c.1128+1G>A	ACADSB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068211	NM_001609.4(ACADSB):c.1128+1_1128+3del	ACADSB	Likely pathogenic	criteria provided, single submitter
1698867	NM_001609.4(ACADSB):c.824del (p.Ile275fs)	ACADSB	Likely pathogenic	criteria provided, single submitter
2572604	NM_001609.4(ACADSB):c.746del (p.Pro249fs)	ACADSB	Likely pathogenic	no assertion criteria provided
2628744	NM_001609.4(ACADSB):c.1053C>A (p.Tyr351Ter)	ACADSB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2786901	NM_001609.4(ACADSB):c.901-2A>G	ACADSB	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ACADSB	Definitive	Autosomal recessive	2-methylbutyryl-CoA dehydrogenase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACADSB	Orphanet:79157	2-methylbutyryl-CoA dehydrogenase deficiency
IKZF5	Orphanet:168629	Autosomal thrombocytopenia with normal platelets

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACADSB	HGNC:91	ENSG00000196177	P45954	Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial	gencc,clinvar
IKZF5	HGNC:14283	ENSG00000095574	Q9H5V7	Zinc finger protein Pegasus	clinvar
CUZD1	HGNC:17937	ENSG00000138161	Q86UP6	CUB and zona pellucida-like domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACADSB	Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial	Short and branched chain specific acyl-CoA dehydrogenase that catalyzes the proR-proR stereospecific alpha,beta-dehydrogenation of fatty acyl-CoA thioesters using the electron transfer flavoprotein (ETF) as their physiologic electron accep…
IKZF5	Zinc finger protein Pegasus	Transcriptional repressor that binds the core 5’GNNTGTNG-3’ DNA consensus sequence.
CUZD1	CUB and zona pellucida-like domain-containing protein 1	Localized to zymogen granules, where it functions in trypsinogen activation.

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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACADSB	Other/Unknown	no		Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C
IKZF5	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF
CUZD1	Other/Unknown	no		CUB_dom, ZP_dom, Sperma_CUB_dom_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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	2
biceps brachii	1
liver	1
right lobe of liver	1
C1 segment of cervical spinal cord	1
endothelial cell	1
islet of Langerhans	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACADSB	273	ubiquitous	marker	right lobe of liver, liver, biceps brachii
IKZF5	262	ubiquitous	marker	endothelial cell, body of pancreas, C1 segment of cervical spinal cord
CUZD1	130	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACADSB	2,259
IKZF5	965
CUZD1	768

Intra-cohort edges

A	B	Sources
ACADSB	IKZF5	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACADSB	P45954	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CUZD1	Q86UP6	79.43
IKZF5	Q9H5V7	54.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Branched-chain amino acid catabolism	1	475.8×	0.011	ACADSB
Mitochondrial protein degradation	1	114.2×	0.022	ACADSB
Metabolism of amino acids and derivatives	1	67.6×	0.025	ACADSB
Metabolism of proteins	1	12.4×	0.086	ACADSB
Metabolism	1	11.6×	0.086	ACADSB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
trypsinogen activation	1	5617.3×	0.001	CUZD1
L-isoleucine catabolic process	1	936.2×	0.004	ACADSB
fatty acid metabolic process	1	64.6×	0.036	ACADSB
cell division	1	15.4×	0.109	CUZD1
cell adhesion	1	12.5×	0.109	CUZD1
negative regulation of transcription by RNA polymerase II	1	5.9×	0.187	IKZF5
regulation of transcription by RNA polymerase II	1	3.9×	0.236	IKZF5

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
ACADSB	0	0
IKZF5	0	0
CUZD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	ACADSB, IKZF5, CUZD1

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)
ACADSB	0	—
IKZF5	0	—
CUZD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan