3-methylcrotonyl-CoA carboxylase 1 deficiency: genes and variants
3-methylcrotonyl-CoA carboxylase 1 deficiency is linked to 1 analyzed protein (MCCC1). 21 DNA variants are known to cause it; 210 more are uncertain, and 4 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to 3-methylcrotonyl-CoA carboxylase 1 deficiency
MCCC1: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial
It provides one subunit of mitochondrial methylcrotonyl-CoA carboxylase, an enzyme required for leucine degradation. Biallelic loss-of-function variants cause 3-methylcrotonyl-CoA carboxylase deficiency, with clinical severity ranging from asymptomatic biochemical abnormalities to metabolic decompensation.
21 disease-causing and 210 uncertain variants in MCCC1 are linked to 3-methylcrotonyl-CoA carboxylase 1 deficiency.
Known disease-causing variants in 3-methylcrotonyl-CoA carboxylase 1 deficiency
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| MCCC1 G180V | 180 | ATP-grasp | Disease-causing (★★) |
| MCCC1 A289V | 289 | ATP-grasp | Disease-causing (★★) |
| MCCC1 T465I | 465 | Biotin carboxylation | Disease-causing (★★) |
| MCCC1 R66C | 66 | Biotin carboxylation | Disease-causing (★★) |
| MCCC1 E288G | 288 | ATP-grasp | Disease-causing (★★) |
| MCCC1 I434M | 434 | Biotin carboxylation | Disease-causing (★★) |
| MCCC1 R444H | 444 | Biotin carboxylation | Disease-causing (★★) |
| MCCC1 M1V | 1 | Disease-causing (★★) | |
| MCCC1 R421W | 421 | Biotin carboxylation | Disease-causing (★★) |
| MCCC1 C276R | 276 | ATP-grasp | Disease-causing (★) |
| MCCC1 R385G | 385 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 A435T | 435 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 L437P | 437 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 M1T | 1 | Disease-causing (★) | |
| MCCC1 E366K | 366 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 E59G | 59 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 P152L | 152 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 Y430C | 430 | Biotin carboxylation | Disease-causing (★) |
| MCCC1 S535F | 535 | Disease-causing (★) | |
| MCCC1 I460M | 460 | Biotin carboxylation | Disease-causing |
| MCCC1 D532H | 532 | Disease-causing |
Uncertain variants in 3-methylcrotonyl-CoA carboxylase 1 deficiency that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| MCCC1 R444C | 444 | Biotin carboxylation | Conflicting reports (★) | +7: in a 3D region that tolerates change poorly (3R); R444H at the same position is pathogenic; seen in 8.2e-06 of gnomAD DNA copies; REVEL 0.904 |
| MCCC1 C276G | 276 | ATP-grasp | Uncertain (★) | +7: in a 3D region that tolerates change poorly (3R); C276R at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.982 |
| MCCC1 R66H | 66 | Biotin carboxylation | Uncertain (★) | +7: in a 3D region that tolerates change poorly (1R); R66C at the same position is pathogenic; seen in 6.8e-06 of gnomAD DNA copies; REVEL 0.827 |
| MCCC1 A435V | 435 | Biotin carboxylation | Uncertain (★) | +6: 3 other pathogenic changes within 3 positions; A435T at the same position is pathogenic; REVEL 0.918 |
Which prediction tools work for 3-methylcrotonyl-CoA carboxylase 1 deficiency
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- SIFT: 95 out of 100
- REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaGenome (regulatory): 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 85 out of 100
- phyloP: 74 out of 100
- AlphaGenome (splicing): 53 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Diseases related to 3-methylcrotonyl-CoA carboxylase 1 deficiency
- Methylcrotonyl-CoA carboxylase deficiency, also linked to MCCC1
Frequently asked questions
Which genes are linked to 3-methylcrotonyl-CoA carboxylase 1 deficiency?
In CATVariant, 3-methylcrotonyl-CoA carboxylase 1 deficiency is linked to 1 analyzed protein: MCCC1 (Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial).
How many genetic variants are linked to 3-methylcrotonyl-CoA carboxylase 1 deficiency?
240 variants: 21 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 210 are of uncertain significance or have conflicting reports.
Which uncertain variants in 3-methylcrotonyl-CoA carboxylase 1 deficiency look disease-causing?
4 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MCCC1 R444C, MCCC1 C276G, MCCC1 R66H and MCCC1 A435V. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for 3-methylcrotonyl-CoA carboxylase 1 deficiency?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 19 disease-causing and 16 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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