MCCC2

Chr 5AR

methylcrotonyl-CoA carboxylase subunit 2

Also known as: MCCB, MCCCbeta

NCBI Gene: 64087 ENSG00000131844 OMIM: 609014

The protein functions as the small subunit of 3-methylcrotonyl-CoA carboxylase, which catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA in leucine catabolism within the mitochondrial matrix. Mutations cause 3-methylcrotonyl-CoA carboxylase 2 deficiency through autosomal recessive inheritance, resulting in impaired leucine breakdown and 3-methylcrotonylglycinuria.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, May 2018]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.901 OMIM phenotype

Clinical Summary— MCCC2

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Gene-Disease Validity (ClinGen)

3-methylcrotonyl-CoA carboxylase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

219 unique Pathogenic / Likely Pathogenic· 282 VUS of 937 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MCCC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 2.04

OE 0.63 (0.45–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.31Z-score

OE missense 0.95 (0.86–1.05)

298 obs / 313.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.45–0.90)

0≤0.351.4

Missense OE?0.95 (0.86–1.05)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 22 / 35.0Missense obs/exp: 298 / 313.2Syn Z: 0.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMCCC2-related 3-methylcrotonyl-CoA carboxylase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.80top 25%

GOF

0.5562th %ile

LOF

0.2582th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

937 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65

Likely Pathogenic154

VUS282

Likely Benign313

Benign62

Conflicting40

Pathogenic

154

Likely Pathogenic

282

VUS

313

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	6	22	0	65
Likely Pathogenic	100	50	4	0	154
VUS	2	210	54	16	282
Likely Benign	0	2	157	154	313
Benign	0	0	59	3	62
Conflicting	—				40
Total	139	268	296	173	916

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

7 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap MCCC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →