3-methylcrotonyl-CoA carboxylase 1 deficiency

Summary

3-methylcrotonyl-CoA carboxylase 1 deficiency (MONDO:0008861) is a disease caused by MCCC1 (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Causal gene: MCCC1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 862
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylcrotonyl-CoA carboxylase 1 deficiency
Mondo ID	MONDO:0008861
MeSH	C535308
OMIM	210200
DOID	DOID:0080579
GARD	0005665
Is cancer (heuristic)	no

Also known as: 3 Alpha methylcrotonylglycinuria 1 · 3 alpha methylcrotonylglycinuria 1 · 3 Methylcrotonyl-CoA carboxylase 1 deficiency · 3 Methylcrotonyl-CoA carboxylase deficiency · 3 methylcrotonylglycinuria · 3-MCC deficiency · 3-Methylcrotonyl-Coa carboxylase 1 deficiency · 3-methylcrotonyl-CoA carboxylase 1 deficiency · 3-Methylcrotonyl-Coa carboxylase deficiency · 3-methylcrotonyl-CoA carboxylase deficiency caused by mutation in MCCC1 · 3-Methylcrotonyl-Coenzyme A carboxylase deficiency · 3-methylcrotonylglycinuria · 3-methylcrotonylglycinuria I · Bmcc deficiency · deficiency of methylcrotonoyl-Coa carboxylase · MCC 1 deficiency · MCC deficiency · MCC1 deficiency · MCC1D · MCCC1 3-methylcrotonyl-CoA carboxylase deficiency (+4 more)

Data availability: 862 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

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 › urea cycle disorder › 3-methylcrotonyl-CoA carboxylase 1 deficiency

Related subtypes (2): citrullinemia, urea cycle disorder or inherited hyperammonemia

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:

267 likely benign, 152 uncertain significance, 58 likely pathogenic, 54 pathogenic, 34 pathogenic/likely pathogenic, 15 benign, 14 conflicting classifications of pathogenicity, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066544	NM_020166.5(MCCC1):c.2T>C (p.Met1Thr)	LOC129938008	Pathogenic	criteria provided, single submitter
1067048	NM_020166.5(MCCC1):c.639+5G>T	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069008	NC_000003.11:g.(?182817140)(182817228_?)del	MCCC1	Pathogenic	criteria provided, single submitter
1069009	NC_000003.11:g.(?182733206)(182733374_?)del	MCCC1	Pathogenic	criteria provided, single submitter
1069056	NM_020166.5(MCCC1):c.313C>T (p.Gln105Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070232	NM_020166.5(MCCC1):c.123C>A (p.Tyr41Ter)	MCCC1	Pathogenic	criteria provided, single submitter
1071001	NM_020166.5(MCCC1):c.762-2_762-1del	MCCC1	Pathogenic	criteria provided, single submitter
1072424	NM_020166.5(MCCC1):c.1268-2A>G	MCCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074168	NM_020166.5(MCCC1):c.1205T>G (p.Leu402Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076555	NM_020166.5(MCCC1):c.556del (p.Gln186fs)	MCCC1	Pathogenic	criteria provided, single submitter
1217132	NM_020166.5(MCCC1):c.1790dup (p.Tyr597Ter)	MCCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323270	NM_020166.5(MCCC1):c.1254_1255del (p.Gly419fs)	MCCC1	Pathogenic	criteria provided, single submitter
1352407	NC_000003.11:g.(?182790144)(182817385_?)del	MCCC1	Pathogenic	criteria provided, single submitter
1363034	NM_020166.5(MCCC1):c.804del (p.Val269fs)	MCCC1	Pathogenic	criteria provided, single submitter
1364122	NM_020166.5(MCCC1):c.1132C>T (p.Gln378Ter)	MCCC1	Pathogenic	criteria provided, single submitter
1370608	NM_020166.5(MCCC1):c.1908C>G (p.Tyr636Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1394199	NM_020166.5(MCCC1):c.435del (p.Gly146fs)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407057	NM_020166.5(MCCC1):c.1853_1856del (p.Ile618fs)	MCCC1	Pathogenic	criteria provided, single submitter
1411435	NM_020166.5(MCCC1):c.1129_1130del (p.Leu377fs)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1431460	NM_020166.5(MCCC1):c.221_224del (p.Gln74fs)	MCCC1	Pathogenic	criteria provided, single submitter
1438722	NM_020166.5(MCCC1):c.310C>T (p.Gln104Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453669	NM_020166.5(MCCC1):c.635del (p.Gly212fs)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456726	NM_020166.5(MCCC1):c.1792del (p.Tyr597_Leu598insTer)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457124	NM_020166.5(MCCC1):c.1651A>T (p.Arg551Ter)	MCCC1	Pathogenic	criteria provided, single submitter
1457334	NM_020166.5(MCCC1):c.951_952del (p.Ala318fs)	MCCC1	Pathogenic	criteria provided, single submitter
1457467	NM_020166.5(MCCC1):c.1264C>T (p.Gln422Ter)	MCCC1	Pathogenic	criteria provided, single submitter
1458008	NM_020166.5(MCCC1):c.534_535delinsTT (p.Glu179Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458455	NM_020166.5(MCCC1):c.1074G>A (p.Trp358Ter)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458456	NM_020166.5(MCCC1):c.539G>T (p.Gly180Val)	MCCC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458732	NM_020166.5(MCCC1):c.1333C>T (p.Gln445Ter)	MCCC1	Pathogenic	criteria provided, single submitter

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
MCCC1	Definitive	Autosomal recessive	3-methylcrotonyl-CoA carboxylase 1 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MCCC1	Orphanet:6	3-methylcrotonyl-CoA carboxylase deficiency
ALG3	Orphanet:79321	ALG3-CDG

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
MCCC1	HGNC:6936	ENSG00000078070	Q96RQ3	Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial	gencc,clinvar
ALG3	HGNC:23056	ENSG00000214160	Q92685	Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCCC1	Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial	Biotin-attachment 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.
ALG3	Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase	Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCCC1	Other/Unknown	no		Biotin_lipoyl, Biotin_BS, CPAse_ATP-bd
ALG3	Enzyme (other)	yes	2.4.1.258	Glycosyltransferase_ALG3

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
right lobe of liver	2
body of pancreas	1
metanephros cortex	1
mucosa of transverse colon	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCCC1	286	ubiquitous	marker	body of pancreas, metanephros cortex, right lobe of liver
ALG3	208	ubiquitous	marker	mucosa of transverse colon, stromal cell of endometrium, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCCC1	2,322
ALG3	1,320

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCCC1	Q96RQ3	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG3	Q92685	89.05

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
Defective ALG3 causes CDG-1d	1	5710.0×	0.002	ALG3
Diseases of metabolism	2	80.4×	0.002	MCCC1, ALG3
3-Methylcrotonyl-CoA carboxylase deficiency	1	2855.0×	0.002	MCCC1
Defects in biotin (Btn) metabolism	1	1142.0×	0.004	MCCC1
Diseases of branched-chain amino acid catabolism	1	951.7×	0.004	MCCC1
Defective HLCS causes multiple carboxylase deficiency	1	815.7×	0.004	MCCC1
Biotin transport and metabolism	1	519.1×	0.006	MCCC1
Diseases associated with N-glycosylation of proteins	1	317.2×	0.007	ALG3
Defects in vitamin and cofactor metabolism	1	300.5×	0.007	MCCC1
Branched-chain amino acid catabolism	1	237.9×	0.008	MCCC1
Disease	2	13.1×	0.011	MCCC1, ALG3
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.016	ALG3
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.017	MCCC1
Diseases of glycosylation	1	65.6×	0.022	ALG3
Metabolism of vitamins and cofactors	1	58.3×	0.023	MCCC1
Metabolism of amino acids and derivatives	1	33.8×	0.037	MCCC1
Asparagine N-linked glycosylation	1	30.1×	0.039	ALG3
Post-translational protein modification	1	9.6×	0.113	ALG3
Metabolism of proteins	1	6.2×	0.163	ALG3
Metabolism	1	5.8×	0.165	MCCC1

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
biotin metabolic process	1	2106.5×	0.002	MCCC1
L-leucine catabolic process	1	1203.7×	0.002	MCCC1
branched-chain amino acid catabolic process	1	526.6×	0.003	MCCC1
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.003	ALG3
protein N-linked glycosylation	1	131.7×	0.008	ALG3

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
MCCC1	0	0
ALG3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MCCC1	2	Binding:2
ALG3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG3	2.4.1.258	dolichyl-P-Man:Man5GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase

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	1	ALG3
E	Difficult family or no structure, no drug	1	MCCC1

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)
MCCC1	2	—
ALG3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan