3-methylcrotonyl-CoA carboxylase 2 deficiency

Summary

3-methylcrotonyl-CoA carboxylase 2 deficiency (MONDO:0008862) is a disease caused by MCCC2 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: MCCC2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 772
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylcrotonyl-CoA carboxylase 2 deficiency
Mondo ID	MONDO:0008862
MeSH	C535309
OMIM	210210
DOID	DOID:0080580
UMLS	C1859499
MedGen	347898
GARD	0009151
Is cancer (heuristic)	no

Also known as: 3 alpha methylcrotonyl-CoA carboxylase 2 deficiency · 3 alpha methylcrotonylglycinuria 2 · 3-Methylcrotonyl-CoA carboxylase 2 deficiency · 3-methylcrotonyl-CoA carboxylase deficiency caused by mutation in MCCC2 · MCC 2 deficiency · MCC2D · MCCC2 3-methylcrotonyl-CoA carboxylase deficiency · methylcrotonylglycinuria type 2

Data availability: 772 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: 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 › 3-methylcrotonyl-CoA carboxylase deficiency › 3-methylcrotonyl-CoA carboxylase 2 deficiency

Related subtypes (1): 3-methylcrotonyl-CoA carboxylase 1 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:

232 likely benign, 153 uncertain significance, 74 likely pathogenic, 49 pathogenic, 43 pathogenic/likely pathogenic, 29 conflicting classifications of pathogenicity, 17 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067700	NM_022132.5(MCCC2):c.1149+1G>A	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067879	NC_000005.9:g.(?70895466)(70895607_?)del	MCCC2	Pathogenic	criteria provided, single submitter
1072513	NM_022132.5(MCCC2):c.823del (p.His275fs)	MCCC2	Pathogenic	criteria provided, single submitter
1073302	NC_000005.9:g.(?70936810)(70936922_?)del	MCCC2	Pathogenic	criteria provided, single submitter
1073303	NC_000005.9:g.(?70892097)(70892201_?)del	MCCC2	Pathogenic	criteria provided, single submitter
1073702	NM_022132.5(MCCC2):c.318C>A (p.Tyr106Ter)	MCCC2	Pathogenic	criteria provided, single submitter
1074648	NM_022132.5(MCCC2):c.970_985del (p.Asn324fs)	MCCC2	Pathogenic	criteria provided, single submitter
1076539	NM_022132.5(MCCC2):c.76_77del (p.Asp26fs)	MCCC2	Pathogenic	criteria provided, single submitter
1098284	NM_022132.5(MCCC2):c.592C>T (p.Gln198Ter)	MCCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323271	NM_022132.5(MCCC2):c.127C>T (p.Gln43Ter)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324702	NM_022132.5(MCCC2):c.351_353del (p.Gly118del)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1392602	NM_022132.5(MCCC2):c.342del (p.Pro115fs)	MCCC2	Pathogenic	criteria provided, single submitter
1402549	NM_022132.5(MCCC2):c.1144_1147inv (p.Lys382_Lys383delinsPheTer)	MCCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1403091	NM_022132.5(MCCC2):c.1308_1318del (p.Lys436fs)	MCCC2	Pathogenic	criteria provided, single submitter
1419078	NM_022132.5(MCCC2):c.230C>G (p.Ser77Ter)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433768	NM_022132.5(MCCC2):c.1546_1547insGGCCGGGCGCGGGGGCTCACGCTTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCACGAGGTCGGGAGATNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTTTGAAGAGG (p.Glu515_Glu516insGlyProGlyAlaGlyAlaHisAlaCysAsnProSerThrLeuGlyGlyArgGlyGlyTrpIleThrArgSerGlyAspXaaXaaXaaXaaLysLysLysLysLysLysLysLysPheGluGlu)	MCCC2	Pathogenic	criteria provided, single submitter
1453800	NM_022132.5(MCCC2):c.689del (p.Asn230fs)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455699	NM_022132.5(MCCC2):c.533T>G (p.Leu178Ter)	MCCC2	Pathogenic	criteria provided, single submitter
1458918	NC_000005.9:g.(?70922457)(70922590_?)del	MCCC2	Pathogenic	criteria provided, single submitter
1459230	NC_000005.9:g.(?70898323)(70928022_?)del	MCCC2	Pathogenic	criteria provided, single submitter
1460280	NC_000005.9:g.(?70922447)(70952687_?)del	MCCC2	Pathogenic	criteria provided, single submitter
1477647	NM_022132.5(MCCC2):c.1189C>G (p.Pro397Ala)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1483421	NM_022132.5(MCCC2):c.1208A>G (p.Asn403Ser)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1487464	NM_022132.5(MCCC2):c.281+5G>A	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1520993	NM_022132.5(MCCC2):c.384-2A>G	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1521043	NM_022132.5(MCCC2):c.1054G>A (p.Gly352Arg)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1521051	NM_022132.5(MCCC2):c.1149+1G>T	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1521913	NM_022132.5(MCCC2):c.739-2A>G	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167279	NM_022132.5(MCCC2):c.994C>T (p.Arg332Ter)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705095	NM_022132.5(MCCC2):c.1570G>A (p.Ala524Thr)	MCCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
MCCC2	Definitive	Autosomal recessive	3-methylcrotonyl-CoA carboxylase 2 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCCC2	Orphanet:6	3-methylcrotonyl-CoA carboxylase deficiency
BDP1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
MCCC2	HGNC:6937	ENSG00000131844	Q9HCC0	Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial	gencc,clinvar
BDP1	HGNC:13652	ENSG00000145734	A6H8Y1	Transcription factor TFIIIB component B’’ homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCCC2	Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial	Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.
BDP1	Transcription factor TFIIIB component B’’ homolog	General activator of RNA polymerase III transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCCC2	Other/Unknown	no		COA_CT_N, COA_CT_C, ClpP/crotonase-like_dom_sf
BDP1	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, TFIIIB_B’’_Myb

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
left ventricle myocardium	1
right adrenal gland cortex	1
secondary oocyte	1
calcaneal tendon	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCCC2	272	ubiquitous	marker	left ventricle myocardium, right adrenal gland cortex, secondary oocyte
BDP1	134	ubiquitous	marker	sural nerve, calcaneal tendon, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCCC2	2,500
BDP1	1,581

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCCC2	Q9HCC0	14
BDP1	A6H8Y1	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
3-Methylcrotonyl-CoA carboxylase deficiency	1	2855.0×	0.006	MCCC2
Defects in biotin (Btn) metabolism	1	1142.0×	0.006	MCCC2
Diseases of branched-chain amino acid catabolism	1	951.7×	0.006	MCCC2
Defective HLCS causes multiple carboxylase deficiency	1	815.7×	0.006	MCCC2
Biotin transport and metabolism	1	519.1×	0.008	MCCC2
Defects in vitamin and cofactor metabolism	1	300.5×	0.010	MCCC2
Branched-chain amino acid catabolism	1	237.9×	0.010	MCCC2
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.010	BDP1
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.010	BDP1
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.010	BDP1
RNA Polymerase III Transcription Initiation	1	167.9×	0.010	BDP1
RNA Polymerase III Transcription	1	163.1×	0.010	BDP1
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.011	BDP1
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.016	MCCC2
Metabolism of vitamins and cofactors	1	58.3×	0.023	MCCC2
Diseases of metabolism	1	40.2×	0.031	MCCC2
Metabolism of amino acids and derivatives	1	33.8×	0.035	MCCC2
Gene expression (Transcription)	1	8.9×	0.121	BDP1
Disease	1	6.5×	0.155	MCCC2
Metabolism	1	5.8×	0.165	MCCC2

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
RNA polymerase III preinitiation complex assembly	1	8426.0×	5e-04	BDP1
coenzyme A metabolic process	1	1685.2×	0.001	MCCC2
L-leucine catabolic process	1	1203.7×	0.001	MCCC2
branched-chain amino acid catabolic process	1	526.6×	0.002	MCCC2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MCCC2	0	0
BDP1	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
MCCC2	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	MCCC2, BDP1

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)
MCCC2	1	—
BDP1	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
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns