MCCC1

Summary

MCCC1 (methylcrotonyl-CoA carboxylase subunit 1, HGNC:6936) is a protein-coding gene on chromosome 3q27.1, encoding Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (Q96RQ3). 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.

This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism.

Source: NCBI Gene 56922 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylcrotonyl-CoA carboxylase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 1,010 total — 86 pathogenic, 83 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6936
Approved symbol	MCCC1
Name	methylcrotonyl-CoA carboxylase subunit 1
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	MCCA, MCCCα
Ensembl gene	ENSG00000078070
Ensembl biotype	protein_coding
OMIM	609010
Entrez	56922

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 16 protein_coding, 7 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000265594, ENST00000464601, ENST00000466650, ENST00000473955, ENST00000476176, ENST00000486226, ENST00000487634, ENST00000489909, ENST00000490284, ENST00000492597, ENST00000495767, ENST00000497830, ENST00000497959, ENST00000908214, ENST00000908215, ENST00000908216, ENST00000908217, ENST00000908218, ENST00000908219, ENST00000908220, ENST00000908221, ENST00000908222, ENST00000908223, ENST00000947200, ENST00000947201, ENST00000947202

RefSeq mRNA: 3 — MANE Select: NM_020166 NM_001293273, NM_001363880, NM_020166

CCDS: CCDS3241, CCDS87170

Canonical transcript exons

ENST00000265594 — 19 exons

Exon	Start	End
ENSE00001869985	183015218	183015566
ENSE00001887323	183099352	183099496
ENSE00002478553	183092409	183092545
ENSE00003508906	183025755	183025804
ENSE00003521212	183052159	183052240
ENSE00003530197	183017266	183017337
ENSE00003567325	183086693	183086788
ENSE00003571952	183070999	183071120
ENSE00003615818	183039026	183039135
ENSE00003619954	183033991	183034077
ENSE00003625514	183020130	183020237
ENSE00003640516	183057311	183057422
ENSE00003645658	183094559	183094605
ENSE00003659985	183072366	183072487
ENSE00003672772	183041567	183041750
ENSE00003680282	183071210	183071357
ENSE00003686499	183037218	183037434
ENSE00003690046	183045413	183045540
ENSE00003747949	183022417	183022554

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 96.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.6508 / max 293.3452, expressed in 1808 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45781	8.1485	1740
45780	6.2607	1679
45782	0.5196	289
45778	0.3929	194
45784	0.2329	84
45779	0.0962	28

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	96.69	gold quality
metanephros cortex	UBERON:0010533	95.18	gold quality
right lobe of liver	UBERON:0001114	95.17	gold quality
right lung	UBERON:0002167	94.66	gold quality
right adrenal gland cortex	UBERON:0035827	94.25	gold quality
colonic epithelium	UBERON:0000397	94.12	gold quality
adrenal tissue	UBERON:0018303	93.97	gold quality
adult mammalian kidney	UBERON:0000082	93.59	gold quality
right adrenal gland	UBERON:0001233	93.51	gold quality
right uterine tube	UBERON:0001302	93.51	gold quality
pancreas	UBERON:0001264	93.35	gold quality
left ovary	UBERON:0002119	93.26	gold quality
left adrenal gland cortex	UBERON:0035825	93.18	gold quality
body of stomach	UBERON:0001161	93.16	gold quality
left adrenal gland	UBERON:0001234	93.16	gold quality
left lobe of thyroid gland	UBERON:0001120	93.07	gold quality
right ovary	UBERON:0002118	92.92	gold quality
right lobe of thyroid gland	UBERON:0001119	92.91	gold quality
tibial nerve	UBERON:0001323	92.85	gold quality
heart left ventricle	UBERON:0002084	92.79	gold quality
left ventricle myocardium	UBERON:0006566	92.78	gold quality
liver	UBERON:0002107	92.73	gold quality
sural nerve	UBERON:0015488	92.70	gold quality
adrenal cortex	UBERON:0001235	92.63	gold quality
cardiac ventricle	UBERON:0002082	92.62	gold quality
thyroid gland	UBERON:0002046	92.58	gold quality
adrenal gland	UBERON:0002369	92.51	gold quality
skin of abdomen	UBERON:0001416	92.47	gold quality
adenohypophysis	UBERON:0002196	92.37	gold quality
calcaneal tendon	UBERON:0003701	92.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	20.67

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP63

miRNA regulators (miRDB)

14 targeting MCCC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-323B-3P	99.14	68.89	725
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-2115-5P	98.66	68.07	1191
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-7973	96.48	65.54	502

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• factors other than the genotype at the MCCA and MCCB loci have a major influence on the phenotype of MCC deficiency (PMID:16010683)
• The amino-termini containing 39 (MCCalpha) or 20 amino acids (MCCbeta) were both necessary and sufficient for targeting. Structural requirements for mitochondrial import were defined by site-directed mutagenesis. (PMID:16023992)
• Molecular analyses revealed novel mutations in one of the causative genes, MCCA or MCCB, in all five of the MCC deficiency patients (PMID:17968484)
• A family with 3-methylcrotonyl-CoA carboxylase deficiency with different clinical features is described. (PMID:19339287)
• analysis of a novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency (PMID:19706617)
• identified two novel MCCA and four novel MCCB mutant alleles from five MCC-deficient patients (PMID:21071250)
• study reports eight different mutant alleles of MCCC1 or MCCC2 including six novel mutations in Korean patients with 3-methylcrotonyl-CoA carboxylase (MCC) deficiency (PMID:22150417)
• 3-methylcrotonyl-CoA carboxylase inhibition has a role in increased excretion of 3-hydroxyisovaleric acid in valproate-treated patients (PMID:22189597)
• Mutation in 3-methylcrotonyl CoA carboxylase 1 gene is associated with 3-methylcrotonyl-CoA carboxylase deficiency. (PMID:22264772)
• This study demonistrated that Mainland China demonstrates that MCCC1/LAMP3 (rs11711441) is associated with a lower risk of Parkinson’s disease. (PMID:23496138)
• Four new point mutations were detected in the MCCC1 gene in patients with maternal 3-methylcrotonyl coenzyme deficiency. (PMID:24078573)
• Novel mutations in MCCC1 gene were identified in Chinese population. The expression profiles of two splice mutations (c.639+2T>A and c.639+5G>T) were also characterized. (PMID:25382614)
• Our study provides strong support for the susceptibility role of RAB7L1/NUCKS1 rs823118 and MCCC1 rs12637471 in sporadic Parkinson’s disease in a Han Chinese population (PMID:26914237)
• This study reports data mainly obtained from the Portuguese newborn screening program collected over a ten-year period. Analysis of the MCCC1 and MCCC2 genes yielded 26 previously unreported mutations and a variant of clinically unknown significance. (PMID:27601257)
• MCCC1 plays an essential role in virus-triggered, MAVS-mediated activation of NF-kappaB signaling. (PMID:27629939)
• Mutation in the methylcrotonoyl-CoA carboxylase gene is associated with 3-Methylcrotonyl-CoA carboxylase deficiency leading to feeding difficulties and vomiting. (PMID:31730530)
• Mutations on MCCC1 and MCCC2 genes are the major genetic causes for the increased C5-OH in neonates (PMID:31901042)
• SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson’s disease in southern Chinese population. (PMID:32652860)
• Association study of MCCC1/LAMP3 and DGKQ variants with Parkinson’s disease in patients of Malay ancestry. (PMID:33559030)
• Methylcrotonyl-CoA carboxylase subunit 1 (MCCA) regulates multidrug resistance in multiple myeloma. (PMID:37805164)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mccc1	ENSDARG00000102538
mus_musculus	Mccc1	ENSMUSG00000027709
rattus_norvegicus	Mccc1	ENSRNOG00000013293
drosophila_melanogaster	Mccc1	FBGN0039877
caenorhabditis_elegans		WBGENE00009319

Paralogs (4): ACACB (ENSG00000076555), PC (ENSG00000173599), PCCA (ENSG00000175198), ACACA (ENSG00000278540)

Protein

Protein identifiers

Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial — Q96RQ3 (reviewed: Q96RQ3)

Alternative names: 3-methylcrotonyl-CoA carboxylase 1, 3-methylcrotonyl-CoA carboxylase biotin-containing subunit, 3-methylcrotonyl-CoA:carbon dioxide ligase subunit alpha

All UniProt accessions (9): Q96RQ3, A0A0S2Z693, E9PG35, E9PHF7, F2Z2Z7, F2Z3E2, F8WDI3, F8WF46, G5E9X5

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Probably a dodecamer composed of six biotin-containing alpha subunits (MCCC1) and six beta (MCCC2) subunits. Interacts (via the biotin carboxylation domain) with SIRT4.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Acetylated.

Disease relevance. 3-methylcrotonoyl-CoA carboxylase 1 deficiency (MCC1D) [MIM:210200] An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-leucine degradation; (S)-3-hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 2/3.

RefSeq proteins (3): NP_001280202, NP_001350809, NP_064551* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR001882	Biotin_BS	Binding_site
IPR005479	CPAse_ATP-bd	Domain
IPR005481	BC-like_N	Domain
IPR005482	Biotin_COase_C	Domain
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR011054	Rudment_hybrid_motif	Homologous_superfamily
IPR011761	ATP-grasp	Domain
IPR011764	Biotin_carboxylation_dom	Domain
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR050856	Biotin_carboxylase_complex	Family

Pfam: PF00289, PF00364, PF02785, PF02786

Catalyzed reactions (Rhea), 1 shown:

• 3-methylbut-2-enoyl-CoA + hydrogencarbonate + ATP = 3-methyl-(2E)-glutaconyl-CoA + ADP + phosphate + H(+) (RHEA:13589)

UniProt features (124 total): strand 39, sequence variant 39, helix 24, binding site 6, modified residue 5, turn 4, domain 3, transit peptide 1, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
8XL6	ELECTRON MICROSCOPY	2.29
8XL8	ELECTRON MICROSCOPY	2.36
8JAW	ELECTRON MICROSCOPY	2.51
8JAK	ELECTRON MICROSCOPY	2.52
8J7D	ELECTRON MICROSCOPY	2.7
8J4Z	ELECTRON MICROSCOPY	2.73
8XL7	ELECTRON MICROSCOPY	2.85
8J99	ELECTRON MICROSCOPY	2.87
8JXL	ELECTRON MICROSCOPY	2.98
8JXN	ELECTRON MICROSCOPY	3.2
8JXM	ELECTRON MICROSCOPY	3.49
8K2V	ELECTRON MICROSCOPY	3.52
8J78	ELECTRON MICROSCOPY	3.88
2EJM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RQ3-F1	87.53	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 339

Ligand- & substrate-binding residues (6): 282; 322; 163; 205; 211–212; 255

Post-translational modifications (5): 237, 494, 581, 581, 681

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-196780	Biotin transport and metabolism
R-HSA-3371599	Defective HLCS causes multiple carboxylase deficiency
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9909438	3-Methylcrotonyl-CoA carboxylase deficiency
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-3323169	Defects in biotin (Btn) metabolism
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-9865118	Diseases of branched-chain amino acid catabolism

MSigDB gene sets: 234 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, YANG_BREAST_CANCER_ESR1_LASER_DN, CAFFAREL_RESPONSE_TO_THC_UP, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, LANDIS_ERBB2_BREAST_PRENEOPLASTIC_DN, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS, NADLER_OBESITY_DN, GOBP_AMINO_ACID_CATABOLIC_PROCESS, BURTON_ADIPOGENESIS_6, CAFFAREL_RESPONSE_TO_THC_24HR_5_DN

GO Biological Process (3): L-leucine catabolic process (GO:0006552), biotin metabolic process (GO:0006768), branched-chain amino acid catabolic process (GO:0009083)

GO Molecular Function (8): biotin carboxylase activity (GO:0004075), methylcrotonoyl-CoA carboxylase activity (GO:0004485), ATP binding (GO:0005524), biotin binding (GO:0009374), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), methylcrotonoyl-CoA carboxylase complex (GO:1905202)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Metabolism	2
Diseases of metabolism	2
Metabolism of water-soluble vitamins and cofactors	1
Defects in biotin (Btn) metabolism	1
Metabolism of amino acids and derivatives	1
Diseases of branched-chain amino acid catabolism	1
Metabolism of vitamins and cofactors	1
Defects in vitamin and cofactor metabolism	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heterocyclic compound binding	2
cytoplasm	2
L-leucine metabolic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
sulfur compound metabolic process	1
monocarboxylic acid metabolic process	1
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
ligase activity, forming carbon-nitrogen bonds	1
CoA carboxylase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
vitamin binding	1
monocarboxylic acid binding	1
sulfur compound binding	1
cation binding	1
nucleoside phosphate binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1
catalytic complex	1

Protein interactions and networks

STRING

1952 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCCC1	MCCC2	Q9HCC0	985
MCCC1	HLCS	P50747	934
MCCC1	MCC	P23508	917
MCCC1	CCDC62	Q6P9F0	774
MCCC1	BTD	P43251	774
MCCC1	ACMSD	Q8TDX5	762
MCCC1	GAK	O14976	690
MCCC1	HIP1R	O75146	667
MCCC1	SYT12	Q8IV01	663
MCCC1	TMEM175	Q9BSA9	659
MCCC1	LRRK2	Q5S007	659
MCCC1	STK39	Q9UEW8	647
MCCC1	DGKQ	P52824	636
MCCC1	SYT11	Q9BT88	630
MCCC1	SNCA	P37840	620

IntAct

146 interactions, top by confidence:

A	B	Type	Score
IFIT1	IFIT3	psi-mi:“MI:0914”(association)	0.920
ARPC5	ARPC1B	psi-mi:“MI:0914”(association)	0.890
MCCC1	MCCC2	psi-mi:“MI:0915”(physical association)	0.820
MCCC1	MCCC2	psi-mi:“MI:0407”(direct interaction)	0.820
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FECH	PGRMC1	psi-mi:“MI:0914”(association)	0.700
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
ECI2	ECH1	psi-mi:“MI:0914”(association)	0.620
ECH1	ECI2	psi-mi:“MI:0914”(association)	0.620
OXCT2	MCCC1	psi-mi:“MI:0915”(physical association)	0.620
GCAT	NDUFS6	psi-mi:“MI:0914”(association)	0.530
ECH1	ECI2	psi-mi:“MI:0914”(association)	0.530
TUFM	ZMYM6	psi-mi:“MI:0914”(association)	0.530
OXCT2	HSPD1	psi-mi:“MI:0914”(association)	0.530
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
NPB	CST4	psi-mi:“MI:0914”(association)	0.530
ARHGEF26	CPS1	psi-mi:“MI:0914”(association)	0.530
TUFM	MTIF2	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
ATPAF2	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
RPUSD3	HSPD1	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530

BioGRID (224): MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Co-fractionation), MCCC1 (Affinity Capture-MS), MCCC1 (Proximity Label-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U2WCB2, A6NK44, A6QLI6, A8XX92, A9NNH7, B9FK36, O42764, P05165, P07997, P08680, P0DTA4, P13196, P13446, P14882, P16635, P22557, P43090, P54889, Q19842, Q28CR0, Q2KIZ3, Q2QMG2, Q42523, Q42777, Q4KLB0, Q4WHU1, Q502D1, Q553V2, Q5I0C3, Q5R557, Q5R7K1, Q5R9R9, Q612F5, Q63147, Q6CDR5, Q6JQN1, Q759G5, Q872T7, Q8K370, Q91ZA3

Diamond homologs: A0A0H3JRU9, A0A4P8DJE6, A2C2S8, A5H0J2, A6ZMR9, B3LM95, B8G187, B9HBA8, B9N843, C0H419, C7GRE4, C8ZF72, D3DJ41, D3DJ42, E9Q4Z2, I3R7G3, O00763, O04983, O17732, O27179, O27939, O30019, O34544, O52058, O93918, P05115, P05165, P06959, P0A509, P0DTA4, P10802, P11154, P11497, P11498, P13187, P14882, P24182, P29337, P32327, P32528

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 174 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Aerobic respiration and respiratory electron transport	9	6.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	6	38.6×	7e-06
mitochondrial respiratory chain complex I assembly	6	16.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1010 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	86
Likely pathogenic	83
Uncertain significance	320
Likely benign	352
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069008	NC_000003.11:g.(?182817140)(182817228_?)del	Pathogenic
1069009	NC_000003.11:g.(?182733206)(182733374_?)del	Pathogenic
1070232	NM_020166.5(MCCC1):c.123C>A (p.Tyr41Ter)	Pathogenic
1071001	NM_020166.5(MCCC1):c.762-2_762-1del	Pathogenic
1072424	NM_020166.5(MCCC1):c.1268-2A>G	Pathogenic
1076555	NM_020166.5(MCCC1):c.556del (p.Gln186fs)	Pathogenic
1217132	NM_020166.5(MCCC1):c.1790dup (p.Tyr597Ter)	Pathogenic
1323270	NM_020166.5(MCCC1):c.1254_1255del (p.Gly419fs)	Pathogenic
1352407	NC_000003.11:g.(?182790144)(182817385_?)del	Pathogenic
1363034	NM_020166.5(MCCC1):c.804del (p.Val269fs)	Pathogenic
1364122	NM_020166.5(MCCC1):c.1132C>T (p.Gln378Ter)	Pathogenic
1407057	NM_020166.5(MCCC1):c.1853_1856del (p.Ile618fs)	Pathogenic
1431460	NM_020166.5(MCCC1):c.221_224del (p.Gln74fs)	Pathogenic
1457124	NM_020166.5(MCCC1):c.1651A>T (p.Arg551Ter)	Pathogenic
1457334	NM_020166.5(MCCC1):c.951_952del (p.Ala318fs)	Pathogenic
1457467	NM_020166.5(MCCC1):c.1264C>T (p.Gln422Ter)	Pathogenic
1458732	NM_020166.5(MCCC1):c.1333C>T (p.Gln445Ter)	Pathogenic
167269	NM_020166.5(MCCC1):c.1526del (p.Cys509fs)	Pathogenic
1900449	NM_020166.5(MCCC1):c.220C>T (p.Gln74Ter)	Pathogenic
1926425	NC_000003.12:g.183057423del	Pathogenic
1931	NM_020166.5(MCCC1):c.1594G>C (p.Asp532His)	Pathogenic
1935	NM_020166.5(MCCC1):c.1380T>G (p.Ile460Met)	Pathogenic
193913	NM_020166.5(MCCC1):c.1114C>T (p.Gln372Ter)	Pathogenic
196495	NM_020166.5(MCCC1):c.205A>T (p.Lys69Ter)	Pathogenic
1999431	NM_020166.5(MCCC1):c.762-2A>G	Pathogenic
2018112	NM_020166.5(MCCC1):c.393del (p.Leu132fs)	Pathogenic
2024095	NM_020166.5(MCCC1):c.827_828del (p.Asp275_Cys276insTer)	Pathogenic
203798	NM_020166.5(MCCC1):c.1193_1194del (p.Val398fs)	Pathogenic
203800	NM_020166.5(MCCC1):c.2085del (p.Val697fs)	Pathogenic
2153665	NM_020166.5(MCCC1):c.272del (p.Met91fs)	Pathogenic

SpliceAI

3269 predictions. Top by Δscore:

Variant	Effect	Δscore
3:183022411:CATTA:C	donor_loss	1.0000
3:183022412:ATTAC:A	donor_loss	1.0000
3:183022413:TTA:T	donor_loss	1.0000
3:183022414:TAC:T	donor_loss	1.0000
3:183022415:A:AT	donor_loss	1.0000
3:183022416:C:CG	donor_loss	1.0000
3:183022550:TCAAT:T	acceptor_gain	1.0000
3:183022551:CAAT:C	acceptor_gain	1.0000
3:183022551:CAATC:C	acceptor_gain	1.0000
3:183022552:AAT:A	acceptor_gain	1.0000
3:183022553:AT:A	acceptor_gain	1.0000
3:183022554:TC:T	acceptor_loss	1.0000
3:183022555:C:CC	acceptor_gain	1.0000
3:183022555:C:CG	acceptor_loss	1.0000
3:183022564:A:AC	acceptor_gain	1.0000
3:183022564:A:C	acceptor_gain	1.0000
3:183039024:A:AC	donor_gain	1.0000
3:183039025:C:CC	donor_gain	1.0000
3:183039133:CTC:C	acceptor_gain	1.0000
3:183039134:TC:T	acceptor_gain	1.0000
3:183039134:TCCTG:T	acceptor_loss	1.0000
3:183039135:CC:C	acceptor_gain	1.0000
3:183039135:CCTG:C	acceptor_loss	1.0000
3:183039136:C:CC	acceptor_gain	1.0000
3:183039137:T:A	acceptor_loss	1.0000
3:183041561:CTTTA:C	donor_loss	1.0000
3:183041562:TTTA:T	donor_loss	1.0000
3:183041563:TTA:T	donor_loss	1.0000
3:183041564:TACCT:T	donor_loss	1.0000
3:183041565:A:AG	donor_loss	1.0000

AlphaMissense

4784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:183045527:A:C	F323L	0.987
3:183045527:A:T	F323L	0.987
3:183045529:A:G	F323L	0.987
3:183071043:G:C	F239L	0.987
3:183071043:G:T	F239L	0.987
3:183071045:A:G	F239L	0.987
3:183057353:A:C	S277R	0.979
3:183057353:A:T	S277R	0.979
3:183057355:T:G	S277R	0.979
3:183071057:C:G	A235P	0.979
3:183017312:A:T	V668E	0.976
3:183034061:A:C	F537L	0.974
3:183034061:A:T	F537L	0.974
3:183034063:A:G	F537L	0.974
3:183034008:A:G	L555P	0.970
3:183022493:A:G	L598P	0.967
3:183037274:A:G	L513P	0.967
3:183037277:G:T	A512D	0.967
3:183037281:C:G	A511P	0.965
3:183071112:C:A	R216S	0.965
3:183071112:C:G	R216S	0.965
3:183071235:T:A	K205I	0.965
3:183045497:G:C	F333L	0.964
3:183045497:G:T	F333L	0.964
3:183045499:A:G	F333L	0.964
3:183037278:C:G	A512P	0.962
3:183041649:G:C	F395L	0.962
3:183041649:G:T	F395L	0.962
3:183041651:A:G	F395L	0.962
3:183039100:C:G	A435P	0.961

dbSNP variants (sampled 300 via entrez): RS1000018589 (3:183103035 G>A), RS1000024673 (3:183114967 T>C), RS1000028989 (3:183072827 C>A,T), RS1000035579 (3:183091558 A>G), RS1000038618 (3:183018536 G>A), RS1000063758 (3:183027908 C>G,T), RS1000092423 (3:183066881 G>T), RS1000107659 (3:183116458 C>T), RS1000144992 (3:183025117 G>A), RS1000159824 (3:183107792 C>T), RS1000187676 (3:183035072 C>A), RS1000229056 (3:183100411 C>G), RS1000252828 (3:183094172 C>G), RS1000265287 (3:183047602 T>C), RS1000294374 (3:183098615 A>G)

Disease associations

OMIM: gene MIM:609010 | disease phenotypes: MIM:210200

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylcrotonyl-CoA carboxylase 1 deficiency	Definitive	Autosomal recessive
3-methylcrotonyl-CoA carboxylase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
3-methylcrotonyl-CoA carboxylase deficiency	Definitive	AR

Mondo (2): 3-methylcrotonyl-CoA carboxylase 1 deficiency (MONDO:0008861), 3-methylcrotonyl-CoA carboxylase deficiency (MONDO:0018950)

Orphanet (1): 3-methylcrotonyl-CoA carboxylase deficiency (Orphanet:6)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001531	Failure to thrive in infancy
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0001992	Organic aciduria
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency
HP:0002104	Apnea
HP:0002179	Opisthotonus
HP:0002919	Ketonuria
HP:0003581	Adult onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004357	Abnormal circulating leucine concentration
HP:0004911	Episodic metabolic acidosis
HP:0006573	Acute hepatic steatosis
HP:0008281	Acute hyperammonemia
HP:0008872	Feeding difficulties in infancy
HP:0033111	3-hydroxyisovaleric aciduria
HP:0033596	Elevated urinary 3-methylcrotonylglycine level

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000959_6	Parkinson’s disease	8.000000e-12
GCST001126_4	Parkinson’s disease	3.000000e-10
GCST002544_15	Parkinson’s disease	2.000000e-21
GCST003158_3	Subjective response to lithium treatment	9.000000e-07
GCST003922_1	Parkinson’s disease	3.000000e-08
GCST003984_7	Parkinson’s disease	3.000000e-14
GCST004902_44	Parkinson’s disease	2.000000e-30
GCST009325_96	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-34
GCST010049_3	Parkinson’s disease	8.000000e-17
GCST010991_37	Parkinson’s disease	2.000000e-11
GCST012020_599	Serum metabolite levels	8.000000e-18
GCST012021_47	Serum metabolite levels	8.000000e-18
GCST012046_3	Fasting insulin	8.000000e-07
GCST012496_2	Lung function (FVC)	6.000000e-06
GCST90002388_204	Lymphocyte count	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0004587	lymphocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535308	3-methylcrotonyl CoA carboxylase 1 deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196116 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
sodium arsenite	increases expression, decreases expression, increases abundance	2
Air Pollutants	decreases expression, affects methylation, increases abundance	2
Estradiol	decreases expression, affects cotreatment, increases expression	2
bisphenol F	increases expression	1
bisphenol A	decreases expression	1
glycidyl methacrylate	decreases expression	1
sulforaphane	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression	1
periodate-oxidized adenosine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Caffeine	decreases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Manganese	increases abundance, increases expression	1
Ozone	affects methylation, increases abundance	1
Phenobarbital	affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6124256	Binding	Binding affinity to MCCC1 in human HepG2 cells assessed as reduction in pronase-mediated MCCC1 degradation at 40 to 80 uM preincubated for 1 hr followed by pronase addition measured after 10 mins by DARTS assay	Corosolic acid and its derivatives targeting MCCC1 against insulin resistance and their hypoglycemic effect on type 2 diabetic mice. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9JY	Ubigene HEK293 MCCC1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	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