MCCC2

Summary

MCCC2 (methylcrotonyl-CoA carboxylase subunit 2, HGNC:6937) is a protein-coding gene on chromosome 5q13.2, encoding Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (Q9HCC0). 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.

This gene encodes the small 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. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 64087 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylcrotonyl-CoA carboxylase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 939 total — 66 pathogenic, 95 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes
• MANE Select transcript: NM_022132

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6937
Approved symbol	MCCC2
Name	methylcrotonyl-CoA carboxylase subunit 2
Location	5q13.2
Locus type	gene with protein product
Status	Approved
Aliases	MCCB, MCCCβ
Ensembl gene	ENSG00000131844
Ensembl biotype	protein_coding
OMIM	609014
Entrez	64087

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 21 protein_coding, 14 retained_intron, 10 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000340941, ENST00000505435, ENST00000505787, ENST00000507169, ENST00000509358, ENST00000509539, ENST00000510895, ENST00000512218, ENST00000629193, ENST00000681968, ENST00000681991, ENST00000682045, ENST00000682175, ENST00000682214, ENST00000682231, ENST00000682438, ENST00000682499, ENST00000682541, ENST00000682640, ENST00000682667, ENST00000682687, ENST00000682727, ENST00000682876, ENST00000683098, ENST00000683163, ENST00000683258, ENST00000683339, ENST00000683403, ENST00000683429, ENST00000683665, ENST00000683789, ENST00000683847, ENST00000683882, ENST00000684024, ENST00000684132, ENST00000684254, ENST00000684310, ENST00000684316, ENST00000684473, ENST00000684474, ENST00000684530, ENST00000684652, ENST00000684686, ENST00000888940, ENST00000888941, ENST00000888942, ENST00000888943, ENST00000935385, ENST00000954856

RefSeq mRNA: 2 — MANE Select: NM_022132 NM_001363147, NM_022132

CCDS: CCDS34184, CCDS93731

Canonical transcript exons

ENST00000340941 — 17 exons

Exon	Start	End
ENSE00000972093	71641003	71641075
ENSE00001504608	71643819	71643895
ENSE00001690220	71592926	71592992
ENSE00002022892	71656743	71658706
ENSE00002063117	71587340	71587554
ENSE00003469021	71635151	71635246
ENSE00003504411	71646211	71646277
ENSE00003520225	71649097	71649253
ENSE00003560687	71599659	71599760
ENSE00003561722	71632121	71632185
ENSE00003572580	71602506	71602633
ENSE00003628776	71634943	71635042
ENSE00003640142	71626640	71626753
ENSE00003641376	71604356	71604468
ENSE00003646186	71650069	71650183
ENSE00003673992	71596280	71596364
ENSE00003677817	71652669	71652754

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 96.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.9792 / max 335.3199, expressed in 1818 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56873	16.0853	1788
56872	11.9276	1752
56874	3.5111	1445
56871	2.9590	1358
56875	2.2731	999
56876	0.2231	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	96.12	gold quality
right adrenal gland cortex	UBERON:0035827	95.81	gold quality
secondary oocyte	CL:0000655	95.67	gold quality
right adrenal gland	UBERON:0001233	95.67	gold quality
right lobe of liver	UBERON:0001114	95.60	gold quality
heart left ventricle	UBERON:0002084	95.58	gold quality
cardiac ventricle	UBERON:0002082	95.48	gold quality
tongue squamous epithelium	UBERON:0006919	95.21	silver quality
left adrenal gland	UBERON:0001234	95.11	gold quality
heart right ventricle	UBERON:0002080	95.11	gold quality
liver	UBERON:0002107	94.82	gold quality
rectum	UBERON:0001052	94.81	gold quality
left adrenal gland cortex	UBERON:0035825	94.68	gold quality
adrenal gland	UBERON:0002369	94.36	gold quality
apex of heart	UBERON:0002098	94.32	gold quality
adrenal cortex	UBERON:0001235	94.24	gold quality
esophagus squamous epithelium	UBERON:0006920	93.98	gold quality
corpus epididymis	UBERON:0004359	93.86	gold quality
ileal mucosa	UBERON:0000331	93.77	gold quality
nephron tubule	UBERON:0001231	93.77	gold quality
epithelium of esophagus	UBERON:0001976	93.77	gold quality
heart	UBERON:0000948	93.57	gold quality
choroid plexus epithelium	UBERON:0003911	93.39	gold quality
gastrocnemius	UBERON:0001388	93.18	gold quality
epithelium of mammary gland	UBERON:0003244	93.14	gold quality
endometrium	UBERON:0001295	93.07	gold quality
mammary duct	UBERON:0001765	92.96	gold quality
muscle of leg	UBERON:0001383	92.95	gold quality
adult mammalian kidney	UBERON:0000082	92.94	gold quality
right atrium auricular region	UBERON:0006631	92.90	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	128.92
E-GEOD-99795	no	267.69
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 15)

• 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 20 amino acids (MCCbeta) were both necessary and sufficient for targeting. Structural requirements for mitochondrial import were defined by site-directed mutagenesis. (PMID:16023992)
• The Kd value of soraphen A for the BC domains of human ACC1 and ACC2 is 1 nM. This high binding affinity is mainly due to the extensive interactions between soraphen A and the human biotin carboxylase domain (PMID:17876819)
• Molecular analyses revealed novel mutations in one of the causative genes, MCCA or MCCB, in all five of the MCC deficiency patients (PMID:17968484)
• 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)
• Mutation in 3-methylcrotonyl CoA carboxylase 2 gene is associated with 3-methylcrotonyl-CoA carboxylase deficiency. (PMID:22264772)
• Novel mutation in MCCC2 gene was identified in Chinese population. (PMID:25382614)
• 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)
• MCCC2 overexpression predicts an unfavorable prognosis and promotes cell proliferation in breast cancer (PMID:30895811)
• Mutations on MCCC1 and MCCC2 genes are the major genetic causes for the increased C5-OH in neonates (PMID:31901042)
• MCCC2 overexpression predicts poorer prognosis and promotes cell proliferation in colorectal cancer. (PMID:32205097)
• [Analysis of MCCC2 gene variant in a pedigree affected with 3-methylcrotonyl coenzyme A carboxylase deficiency]. (PMID:33423264)
• MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer. (PMID:37828426)
• ECHDC2 inhibits the proliferation of gastric cancer cells by binding with NEDD4 to degrade MCCC2 and reduce aerobic glycolysis. (PMID:38783226)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mccc2	ENSDARG00000017571
mus_musculus	Mccc2	ENSMUSG00000021646
rattus_norvegicus	Mccc2	ENSRNOG00000017752
drosophila_melanogaster	Mccc2	FBGN0042083
caenorhabditis_elegans		WBGENE00303021

Paralogs (1): PCCB (ENSG00000114054)

Protein

Protein identifiers

Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial — Q9HCC0 (reviewed: Q9HCC0)

Alternative names: 3-methylcrotonyl-CoA carboxylase 2, 3-methylcrotonyl-CoA carboxylase non-biotin-containing subunit, 3-methylcrotonyl-CoA:carbon dioxide ligase subunit beta

All UniProt accessions (23): A0A0D9SFE9, A0A0S2Z5R4, A0A140VK29, A0A804HHS4, A0A804HIH3, A0A804HIQ3, A0A804HJ24, A0A804HJ31, A0A804HJ84, A0A804HJC1, A0A804HJL2, A0A804HJW2, A0A804HJW5, A0A804HK37, A0A804HKE8, A0A804HKH3, A0A804HKN6, A0A804HL02, A0A804HLJ9, D6R9R1, Q9HCC0, D6RD67, D6RDF7

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Probably a dodecamer composed of six biotin-containing alpha subunits (MCCC1) and six beta (MCCC2) subunits.

Subcellular location. Mitochondrion matrix.

Disease relevance. 3-methylcrotonoyl-CoA carboxylase 2 deficiency (MCC2D) [MIM:210210] 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.

Similarity. Belongs to the AccD/PCCB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCC0-1	1	yes
Q9HCC0-2	2

RefSeq proteins (2): NP_001350076, NP_071415* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011762	COA_CT_N	Domain
IPR011763	COA_CT_C	Domain
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily
IPR034733	AcCoA_carboxyl_beta	Domain
IPR045190	MCCB/AccD1-like	Family

Pfam: PF01039

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (130 total): sequence variant 61, helix 26, strand 22, turn 8, modified residue 6, domain 2, region of interest 2, transit peptide 1, chain 1, splice variant 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
8J73	ELECTRON MICROSCOPY	4.16

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCC0-F1	94.82	0.93

Functional residue map

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

Post-translational modifications (6): 495, 511, 70, 70, 141, 495

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: 276 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_COENZYME_A_METABOLIC_PROCESS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, PRAMOONJAGO_SOX4_TARGETS_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS

GO Biological Process (3): L-leucine catabolic process (GO:0006552), branched-chain amino acid catabolic process (GO:0009083), coenzyme A metabolic process (GO:0015936)

GO Molecular Function (5): methylcrotonoyl-CoA carboxylase activity (GO:0004485), ATP binding (GO:0005524), 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
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
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
CoA carboxylase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound 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

2212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCCC2	MCCC1	Q96RQ3	985
MCCC2	USHBP1	Q8N6Y0	960
MCCC2	MCC	P23508	904
MCCC2	BTD	P43251	811
MCCC2	PCCA	P05165	809
MCCC2	HLCS	P50747	606
MCCC2	IVD	P26440	594
MCCC2	HMGCL	P35914	568
MCCC2	BCKDHB	P21953	548
MCCC2	BCKDHA	P12694	539
MCCC2	ETFA	P13804	514
MCCC2	TUFM	P49411	489
MCCC2	GCN1	Q92616	481
MCCC2	BCAT2	O15382	481
MCCC2	ACACA	Q13085	479

IntAct

100 interactions, top by confidence:

A	B	Type	Score
IFIT1	IFIT3	psi-mi:“MI:0914”(association)	0.920
MCCC1	MCCC2	psi-mi:“MI:0915”(physical association)	0.820
MCCC1	MCCC2	psi-mi:“MI:0407”(direct interaction)	0.820
OPG044	DDX3X	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
ECH1	ECI2	psi-mi:“MI:0914”(association)	0.620
OPG200	IKBKB	psi-mi:“MI:0914”(association)	0.620
RECK	IFNA4	psi-mi:“MI:0914”(association)	0.530
MRPL13	GTPBP10	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
MCCC2	CFTR	psi-mi:“MI:0915”(physical association)	0.520
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
INPPL1	BCR/ABL fusion	psi-mi:“MI:0914”(association)	0.460
UBASH3B	BCR/ABL fusion	psi-mi:“MI:0914”(association)	0.460
HSPB2	MCCC2	psi-mi:“MI:0915”(physical association)	0.370
STK4	IGHA1	psi-mi:“MI:0914”(association)	0.350
STK4	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
ECSIT	NDUFS2	psi-mi:“MI:0914”(association)	0.350
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
L1TD1	MYO1C	psi-mi:“MI:0914”(association)	0.350

BioGRID (188): MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), HMGCL (Co-fractionation), MCCC1 (Co-fractionation), MCCC2 (Affinity Capture-MS), MCCC2 (Two-hybrid), MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), MCCC2 (Affinity Capture-MS), PMPCA (Affinity Capture-MS), MCCC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4A695, A4FV08, A4IHW6, O65084, O73817, O81153, O88958, P23902, P33672, P40112, P46926, P49720, P52410, P62495, P62496, P62497, P62498, Q0VCX5, Q17QL1, Q1W374, Q1W375, Q1W376, Q1W377, Q259G4, Q3MHC2, Q3ULD5, Q4R5Y2, Q503E1, Q5R4C7, Q5R8T8, Q5U2Q7, Q5XIT9, Q5ZIH0, Q64422, Q6IA69, Q6PA43, Q7DLR9, Q7XPW5, Q7ZV22, Q8BWY3

Diamond homologs: A0PXC5, A0RJJ8, A1BI17, A3N2D4, A4IRQ7, A4W6T0, A5FJY2, A5ITM4, A5UY57, A6QHN5, A6T4Y7, A6U2G7, A7GTP6, A7NIE9, A7X3C8, A7Z7K8, A8FG57, A8Z2L6, A9B536, A9VJR3, A9WBQ9, B0BR78, B0RW82, B1HNE3, B1HX17, B1XKV6, B1ZVD6, B3EFW3, B3H2H3, B4SEP9, B7GGS9, B7HFB5, B7HRP1, B7IK00, B7JRX4, B8G381, B9DN96, B9J0A1, B9LE80, C1EUU5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 125 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.

GO biological processes:

GO term	Partners	Fold	FDR
JNK cascade	6	15.0×	3e-03
positive regulation of miRNA transcription	5	13.3×	6e-03
DNA damage response	10	4.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	66
Likely pathogenic	95
Uncertain significance	281
Likely benign	306
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067879	NC_000005.9:g.(?70895466)(70895607_?)del	Pathogenic
1072513	NM_022132.5(MCCC2):c.823del (p.His275fs)	Pathogenic
1073302	NC_000005.9:g.(?70936810)(70936922_?)del	Pathogenic
1073303	NC_000005.9:g.(?70892097)(70892201_?)del	Pathogenic
1073702	NM_022132.5(MCCC2):c.318C>A (p.Tyr106Ter)	Pathogenic
1074648	NM_022132.5(MCCC2):c.970_985del (p.Asn324fs)	Pathogenic
1076539	NM_022132.5(MCCC2):c.76_77del (p.Asp26fs)	Pathogenic
1098284	NM_022132.5(MCCC2):c.592C>T (p.Gln198Ter)	Pathogenic
1392602	NM_022132.5(MCCC2):c.342del (p.Pro115fs)	Pathogenic
1402549	NM_022132.5(MCCC2):c.1144_1147inv (p.Lys382_Lys383delinsPheTer)	Pathogenic
1403091	NM_022132.5(MCCC2):c.1308_1318del (p.Lys436fs)	Pathogenic
1433768	NM_022132.5(MCCC2):c.1546_1547insGGCCGGGCGCGGGGGCTCACGCTTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCACGAGGTCGGGAGATNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTTTGAAGAGG (p.Glu515_Glu516insGlyProGlyAlaGlyAlaHisAlaCysAsnProSerThrLeuGlyGlyArgGlyGlyTrpIleThrArgSerGlyAspXaaXaaXaaXaaLysLysLysLysLysLysLysLysPheGluGlu)	Pathogenic
1455699	NM_022132.5(MCCC2):c.533T>G (p.Leu178Ter)	Pathogenic
1458918	NC_000005.9:g.(?70922457)(70922590_?)del	Pathogenic
1459230	NC_000005.9:g.(?70898323)(70928022_?)del	Pathogenic
1460280	NC_000005.9:g.(?70922447)(70952687_?)del	Pathogenic
1919	NM_022132.5(MCCC2):c.517dup (p.Ser173fs)	Pathogenic
1924	NM_022132.5(MCCC2):c.803G>C (p.Arg268Thr)	Pathogenic
1926	NM_022132.5(MCCC2):c.569A>G (p.His190Arg)	Pathogenic
1928	NM_022132.5(MCCC2):c.1574+1G>A	Pathogenic
1939186	NM_022132.5(MCCC2):c.1234del (p.Glu412fs)	Pathogenic
203809	NM_022132.5(MCCC2):c.1181G>T (p.Arg394Ile)	Pathogenic
2152002	NM_022132.5(MCCC2):c.1150-1G>A	Pathogenic
2426733	NC_000005.9:g.(?70898323)(70900305_?)del	Pathogenic
2426735	NC_000005.9:g.(?70930773)(70930871_?)del	Pathogenic
2426736	NC_000005.9:g.(?70892087)(70892211_?)del	Pathogenic
2426737	NC_000005.9:g.(?70895476)(70900305_?)dup	Pathogenic
2627306	NM_022132.5(MCCC2):c.1131_1132del (p.Phe377_Ser378insTer)	Pathogenic
2700813	NM_022132.5(MCCC2):c.529del (p.Tyr177fs)	Pathogenic
2734731	NM_022132.5(MCCC2):c.282-1G>C	Pathogenic

SpliceAI

3340 predictions. Top by Δscore:

Variant	Effect	Δscore
5:71592920:TTTTA:T	acceptor_loss	1.0000
5:71592921:TTTAG:T	acceptor_loss	1.0000
5:71592922:TTA:T	acceptor_loss	1.0000
5:71592924:A:AG	acceptor_gain	1.0000
5:71592925:G:GG	acceptor_gain	1.0000
5:71592925:GGA:G	acceptor_gain	1.0000
5:71592989:C:G	donor_gain	1.0000
5:71592989:CTAG:C	donor_loss	1.0000
5:71592990:TAGGT:T	donor_loss	1.0000
5:71592991:AGG:A	donor_loss	1.0000
5:71592994:T:A	donor_loss	1.0000
5:71596363:GG:G	donor_gain	1.0000
5:71596364:GG:G	donor_gain	1.0000
5:71599651:C:CA	acceptor_gain	1.0000
5:71599654:TTTA:T	acceptor_loss	1.0000
5:71599657:A:AG	acceptor_gain	1.0000
5:71599657:A:C	acceptor_loss	1.0000
5:71599658:G:GG	acceptor_gain	1.0000
5:71599756:TCAGG:T	donor_gain	1.0000
5:71599758:AGG:A	donor_gain	1.0000
5:71599759:GG:G	donor_gain	1.0000
5:71599759:GGG:G	donor_gain	1.0000
5:71599760:GG:G	donor_gain	1.0000
5:71599761:G:GG	donor_gain	1.0000
5:71599762:TGAG:T	donor_loss	1.0000
5:71599763:GAGTA:G	donor_loss	1.0000
5:71602504:A:AG	acceptor_gain	1.0000
5:71602505:G:GG	acceptor_gain	1.0000
5:71602505:GA:G	acceptor_gain	1.0000
5:71602505:GAGTA:G	acceptor_gain	1.0000

AlphaMissense

3655 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:71649099:T:C	F407L	0.999
5:71649101:T:A	F407L	0.999
5:71649101:T:G	F407L	0.999
5:71646234:C:G	C391W	0.998
5:71649136:C:A	A419D	0.997
5:71656798:A:C	S544R	0.997
5:71656800:T:A	S544R	0.997
5:71656800:T:G	S544R	0.997
5:71641046:A:T	K348I	0.996
5:71643819:G:A	G358E	0.996
5:71650088:T:A	W465R	0.996
5:71650088:T:C	W465R	0.996
5:71602601:C:A	A160D	0.995
5:71626733:T:C	F240L	0.995
5:71626735:C:A	F240L	0.995
5:71626735:C:G	F240L	0.995
5:71643862:C:A	N372K	0.995
5:71643862:C:G	N372K	0.995
5:71646220:T:C	F387L	0.995
5:71646221:T:C	F387S	0.995
5:71646222:T:A	F387L	0.995
5:71646222:T:G	F387L	0.995
5:71649100:T:C	F407S	0.995
5:71604397:T:C	F185L	0.994
5:71604399:T:A	F185L	0.994
5:71604399:T:G	F185L	0.994
5:71626663:C:G	C216W	0.994
5:71641047:A:C	K348N	0.994
5:71641047:A:T	K348N	0.994
5:71643858:G:A	G371E	0.994

dbSNP variants (sampled 300 via entrez): RS1000091126 (5:71628993 A>G), RS1000096718 (5:71621821 A>G), RS1000144748 (5:71610362 C>A,G,T), RS1000163303 (5:71627207 A>G), RS1000183381 (5:71658729 T>C), RS1000183634 (5:71589422 A>C,G), RS1000390124 (5:71596671 G>A), RS1000402528 (5:71589025 T>TA), RS1000431655 (5:71610198 T>C), RS1000463639 (5:71610492 A>G), RS1000578450 (5:71614303 C>T), RS1000582029 (5:71634813 G>A,T), RS1000626929 (5:71617146 A>G), RS1000664866 (5:71611640 T>C), RS1000689777 (5:71647313 A>C,G,T)

Disease associations

OMIM: gene MIM:609014 | disease phenotypes: MIM:210210, MIM:210200, MIM:271150

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylcrotonyl-CoA carboxylase 2 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 (4): 3-methylcrotonyl-CoA carboxylase 2 deficiency (MONDO:0008862), 3-methylcrotonyl-CoA carboxylase deficiency (MONDO:0018950), autism spectrum disorder (MONDO:0005258), spinal muscular atrophy, type IV (MONDO:0010056)

Orphanet (3): 3-methylcrotonyl-CoA carboxylase deficiency (Orphanet:6), Proximal spinal muscular atrophy type 4 (Orphanet:83420), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001051	Seborrheic dermatitis
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:0001596	Alopecia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0001992	Organic aciduria
HP:0001993	Ketoacidosis
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency
HP:0002179	Opisthotonus
HP:0002919	Ketonuria
HP:0003108	Hyperglycinuria
HP:0003202	Skeletal muscle atrophy
HP:0003234	Decreased circulating carnitine concentration
HP:0003353	Propionyl-CoA carboxylase deficiency
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004357	Abnormal circulating leucine concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008953_3	Chromosomal aberration frequency (chromatid type)	6.000000e-06
GCST009391_784	Metabolite levels	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009862	chromatid-type aberration frequency
EFO:0010394	sphingomyelin 18:1 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535309	3-methylcrotonyl CoA carboxylase 2 deficiency (supp.)
C563948	Spinal Muscular Atrophy, Type IV (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067224 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.99	Kd	101.9	nM	CHEMBL5653589
6.99	ED50	101.9	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148729: Binding affinity to human MCCC2 incubated for 45 mins by Kinobead based pull down assay	kd	0.1019	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Acetaminophen	decreases expression	2
Estradiol	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
methylselenic acid	decreases expression	1
beta-lapachone	decreases expression	1
methylparaben	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Irinotecan	decreases expression, affects cotreatment, affects response to substance	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Copper	affects binding, decreases expression	1
Demecolcine	increases expression	1
Dinitrochlorobenzene	affects binding	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651771	Binding	Binding affinity to human MCCC2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder