MCCC1

Chr 3AR

methylcrotonyl-CoA carboxylase subunit 1

Also known as: MCC-B, MCCA, MCCCalpha

NCBI Gene: 56922 ENSG00000078070 UniProt: Q96RQ3 OMIM: 609010

This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase, which catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA as part of leucine catabolism. Biallelic mutations cause 3-methylcrotonyl-CoA carboxylase 1 deficiency, an autosomal recessive disorder of leucine metabolism. The pathogenic mechanism involves loss of enzyme function leading to impaired leucine breakdown.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.901 OMIM phenotype

Clinical Summary— MCCC1

🧬

Gene-Disease Validity (ClinGen)

3-methylcrotonyl-CoA carboxylase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

219 unique Pathogenic / Likely Pathogenic· 320 VUS of 1015 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — MCCC1

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 2.03

OE 0.64 (0.46–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.54Z-score

OE missense 0.92 (0.85–1.01)

371 obs / 401.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.46–0.90)

0≤0.351.4

Missense OE?0.92 (0.85–1.01)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 24 / 37.4Missense obs/exp: 371 / 401.6Syn Z: -0.46

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMCCC1-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.

0.74top 25%

GOF

0.6052th %ile

LOF

0.2874th %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

1015 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic86

Likely Pathogenic133

VUS320

Likely Benign364

Benign53

Conflicting41

Pathogenic

133

Likely Pathogenic

320

VUS

364

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	66	4	16	0	86
Likely Pathogenic	105	22	6	0	133
VUS	5	273	31	11	320
Likely Benign	0	22	154	188	364
Benign	0	3	49	1	53
Conflicting	—				41
Total	176	324	256	200	997

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap MCCC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →