MCCC2 (Q9HCC0) variants and mutations
MCCC2 (also known as Q9HCC0) is a human protein-coding gene encoding a methylcrotonoyl-CoA carboxylase beta chain, mitochondrial protein. It partners with MCCC1 to catalyze an essential carboxylation step in mitochondrial leucine catabolism. Biallelic pathogenic variants cause 3-methylcrotonyl-CoA carboxylase deficiency, which can produce hypoglycemia, acidosis, neurologic symptoms, or remain clinically mild. This analysis covers 940 MCCC2 variants and mutations. Of these, 78% have computational variant effect predictions. Disease context includes 3-methylcrotonyl-CoA carboxylase 2 deficiency, Isolated 3-methylcrotonyl-CoA carboxylase deficiency, and 3-methylcrotonyl-CoA carboxylase deficiency. Example MCCC2 variants include W2C, W2R, and W2G.
Variant analysis overview
- Gene: MCCC2
- Protein: Q9HCC0
- UniProt accession: Q9HCC0
- Organism: Homo sapiens
- Variants analyzed: 940
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 747 unspecified-consequence records; 121 missense variants; 4 stop-gained variants; 53 synonymous variants; 1 in-frame deletions; 7 frameshift variants; 2 splice-region variants; 5 substitution
- Prediction scores: 733 variants have prediction scores (78% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: 3-methylcrotonyl-CoA carboxylase 2 deficiency, Isolated 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, hereditary disease, autism spectrum disorder, spinal muscular atrophy, type IV, Parkinson disease, multiple sclerosis, lysosomal storage disease, Alzheimer disease, neurodegenerative disease, hepatocellular carcinoma.
Protein structure and variant hotspots
- Protein features: 2 domains; 6 post-translational modification sites.
- Structural context: 698 variants have structural context.
- PTM context: 6 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable MCCC2 variants
Examples include W2C, W2R, W2G, W2L, W2*, A3S, A3T, A3D. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- W2C (p.Trp2Cys), rs727504007, ClinGen CA234243, ClinVar RCV000153470, ExAC rs727504007, REVEL 0.60, CADD 24.10, Uncertain significance, not provided
- W2R (p.Trp2Arg), gnomAD 5-71587429-T-C, REVEL 0.52, CADD 23.40
- W2G (p.Trp2Gly), gnomAD 5-71587429-T-G, REVEL 0.60, CADD 23.70
- W2L (p.Trp2Leu), gnomAD 5-71587430-G-T, REVEL 0.41, CADD 20.10
- W2* (p.Trp2Ter), gnomAD 5-71587430-G-A, CADD 36.00
- A3S (p.Ala3Ser), TOPMed rs1245728864, gnomAD rs1245728864, REVEL 0.21, CADD 16.00
- A3T (p.Ala3Thr), gnomAD 5-71587432-G-A, REVEL 0.25, CADD 18.20
- A3D (p.Ala3Asp), gnomAD 5-71587433-C-A, REVEL 0.39, CADD 21.00
- A3V (p.Ala3Val), gnomAD 5-71587433-C-T, REVEL 0.35, CADD 21.10
- A3A (p.Ala3Ala), gnomAD 5-71587434-C-G, CADD 6.37
- V4A (p.Val4Ala), Ensembl rs2112250739
- V4I (p.Val4Ile), gnomAD rs1355867067, REVEL 0.14, CADD 4.65
- V4F (p.Val4Phe), gnomAD 5-71587435-G-T, REVEL 0.24, CADD 5.92
- V4D (p.Val4Asp), gnomAD 5-71587436-T-A, REVEL 0.34, CADD 11.20
- V4V (p.Val4Val), rs777349189, gnomAD 5-71587437-C-T, CADD 5.50
- L5L (p.Leu5Leu), rs954414863, gnomAD 5-71587438-C-T, CADD 7.63
- L5M (p.Leu5Met), gnomAD 5-71587438-C-A, REVEL 0.24, CADD 11.70
- L5P (p.Leu5Pro), gnomAD 5-71587439-T-C, REVEL 0.43, CADD 16.20
- L5Q (p.Leu5Gln), gnomAD 5-71587439-T-A, REVEL 0.46, CADD 15.50
- R6K (p.Arg6Lys), Ensembl rs1215578653, REVEL 0.45, CADD 20.70
- R6G (p.Arg6Gly), gnomAD 5-71587441-A-G, REVEL 0.54, CADD 22.80
- R6M (p.Arg6Met), gnomAD 5-71587442-G-T, REVEL 0.50, CADD 23.20
- L7S (p.Leu7Ser), gnomAD 5-71587445-T-C, REVEL 0.31, CADD 12.50
- L7L (p.Leu7Leu), gnomAD 5-71587446-A-G, CADD 6.66
- A8P (p.Ala8Pro), TOPMed rs1204608472, gnomAD rs1204608472, REVEL 0.43, CADD 10.40
- A8T (p.Ala8Thr), cosmic curated COSV10811, TOPMed rs1204608472, gnomAD rs1204608472, REVEL 0.28, CADD 7.91
- A8S (p.Ala8Ser), gnomAD 5-71587447-G-T, REVEL 0.33, CADD 7.74
- A8D (p.Ala8Asp), gnomAD 5-71587448-C-A, REVEL 0.60, CADD 9.31
- A8V (p.Ala8Val), gnomAD 5-71587448-C-T, REVEL 0.28, CADD 11.30
- L9M (p.Leu9Met), gnomAD 5-71587450-C-A, REVEL 0.27, CADD 17.90
- L9Q (p.Leu9Gln), gnomAD 5-71587451-T-A, REVEL 0.50, CADD 21.20
- L9R (p.Leu9Arg), gnomAD 5-71587451-T-G, REVEL 0.55, CADD 17.40
- L9P (p.Leu9Pro), gnomAD 5-71587451-T-C, REVEL 0.53, CADD 21.50
- L9L (p.Leu9Leu), gnomAD 5-71587452-G-T, CADD 7.38
- R10G (p.Arg10Gly), ExAC rs746669042, TOPMed rs746669042, gnomAD rs746669042
- R10W (p.Arg10Trp), ExAC rs746669042, TOPMed rs746669042, gnomAD rs746669042, REVEL 0.32, CADD 13.70, Uncertain significance, not specified
- R10R (p.Arg10Arg), rs746669042, gnomAD 5-71587453-C-A, CADD 7.60
- R10L (p.Arg10Leu), gnomAD 5-71587454-G-T, REVEL 0.39, CADD 15.40
- R10Q (p.Arg10Gln), gnomAD 5-71587454-G-A, REVEL 0.29, CADD 17.50
- P11L (p.Pro11Leu), rs986973442, ClinGen CA120016443, ClinVar RCV000998393, TOPMed rs986973442, REVEL 0.36, CADD 8.66, Uncertain significance, not provided
- P11Q (p.Pro11Gln), TOPMed rs986973442, gnomAD rs986973442, REVEL 0.34, CADD 6.52, Uncertain significance
- P11T (p.Pro11Thr), gnomAD 5-71587456-C-A, REVEL 0.27, CADD 11.70
- P11S (p.Pro11Ser), gnomAD 5-71587456-C-T, REVEL 0.32, CADD 12.20
- P11P (p.Pro11Pro), rs770765635, gnomAD 5-71587458-G-A, CADD 7.13
- C12Y (p.Cys12Tyr), gnomAD rs1190101205, REVEL 0.40, CADD 12.90
- p.Cys12 Pro20del, gnomAD 5-71587453-CGGCCG, CADD 13.70
- C12R (p.Cys12Arg), gnomAD 5-71587459-T-C, REVEL 0.26, CADD 14.60
- C12S (p.Cys12Ser), gnomAD 5-71587459-T-A, REVEL 0.27, CADD 13.10
- C12F (p.Cys12Phe), gnomAD 5-71587460-G-T, REVEL 0.36, CADD 13.60
- A13G (p.Ala13Gly), rs2530684146, ClinGen CA360001639, ClinVar RCV003057475, Uncertain significance, 3-methylcrotonyl-CoA carboxylase 2 deficiency
- A13T (p.Ala13Thr), gnomAD 5-71587462-G-A, REVEL 0.15, CADD 8.43
- A13S (p.Ala13Ser), gnomAD 5-71587462-G-T, REVEL 0.14, CADD 5.78
- A13D (p.Ala13Asp), gnomAD 5-71587463-C-A, REVEL 0.24, CADD 13.30
- A13V (p.Ala13Val), gnomAD 5-71587463-C-T, REVEL 0.22, CADD 13.20
- A13A (p.Ala13Ala), gnomAD 5-71587464-C-T, CADD 8.85
- R14H (p.Arg14His), Ensembl rs1007270449, REVEL 0.35, CADD 22.10
- R14C (p.Arg14Cys), gnomAD 5-71587465-C-T, REVEL 0.34, CADD 22.20
- R14S (p.Arg14Ser), gnomAD 5-71587465-C-A, REVEL 0.39, CADD 16.20
- R14L (p.Arg14Leu), gnomAD 5-71587466-G-T, REVEL 0.32, CADD 21.80
- R14R (p.Arg14Arg), rs1018412147, gnomAD 5-71587467-C-A, CADD 8.36
- A15T (p.Ala15Thr), gnomAD 5-71587468-G-A, REVEL 0.28, CADD 10.70
- A15S (p.Ala15Ser), gnomAD 5-71587468-G-T, REVEL 0.27, CADD 8.78
- A15G (p.Ala15Gly), gnomAD 5-71587469-C-G, REVEL 0.28, CADD 14.20
- A15D (p.Ala15Asp), gnomAD 5-71587469-C-A, REVEL 0.37, CADD 17.60
- A15V (p.Ala15Val), gnomAD 5-71587469-C-T, REVEL 0.28, CADD 13.00
- A15A (p.Ala15Ala), gnomAD 5-71587470-C-T, CADD 6.46
- S16P (p.Ser16Pro), gnomAD 5-71587471-T-C, REVEL 0.30, CADD 9.62
- S16Y (p.Ser16Tyr), gnomAD 5-71587472-C-A, REVEL 0.29, CADD 17.10
- S16F (p.Ser16Phe), gnomAD 5-71587472-C-T, REVEL 0.28, CADD 15.20
- S16S (p.Ser16Ser), gnomAD 5-71587473-T-C, CADD 6.25
- P17A (p.Pro17Ala), ExAC rs780891559, TOPMed rs780891559, gnomAD rs780891559
- P17L (p.Pro17Leu), ExAC rs746257649, gnomAD rs746257649, REVEL 0.22, CADD 4.31
- P17S (p.Pro17Ser), ExAC rs780891559, TOPMed rs780891559, gnomAD rs780891559, REVEL 0.26, CADD 6.41
- P17T (p.Pro17Thr), ExAC rs780891559, TOPMed rs780891559, gnomAD rs780891559, REVEL 0.23, CADD 3.75
- P17R (p.Pro17Arg), gnomAD 5-71587475-C-G, REVEL 0.22, CADD 4.78
- P17H (p.Pro17His), gnomAD 5-71587475-C-A, REVEL 0.20, CADD 10.00
- P17P (p.Pro17Pro), rs1390205513, gnomAD 5-71587476-C-G, CADD 6.72
- A18P (p.Ala18Pro), gnomAD 5-71587473-TC-T, CADD 14.40
- A18S (p.Ala18Ser), gnomAD 5-71587477-G-T, REVEL 0.20, CADD 5.13
- A18T (p.Ala18Thr), gnomAD 5-71587477-G-A, REVEL 0.20, CADD 8.64
- A18D (p.Ala18Asp), gnomAD 5-71587478-C-A, REVEL 0.26, CADD 15.50
- A18V (p.Ala18Val), gnomAD 5-71587478-C-T, REVEL 0.23, CADD 15.30
- A18A (p.Ala18Ala), rs747327321, gnomAD 5-71587479-C-G, CADD 3.04
- G19R (p.Gly19Arg), ExAC rs775893873, gnomAD rs775893873, REVEL 0.21, CADD 6.10
- G19W (p.Gly19Trp), gnomAD 5-71587480-G-T, REVEL 0.43, CADD 11.10
- G19V (p.Gly19Val), gnomAD 5-71587481-G-T, REVEL 0.27, CADD 8.39
- G19G (p.Gly19Gly), gnomAD 5-71587482-G-T, CADD 7.00
- P20L (p.Pro20Leu), TOPMed rs1397527099, gnomAD rs1397527099, REVEL 0.28, CADD 0.66
- P20S (p.Pro20Ser), rs371336335, ClinGen CA3297656, cosmic curated COSV60155, ClinVar RCV001154159, REVEL 0.22, CADD 6.25, Uncertain significance, 3-methylcrotonyl-CoA carboxylase 2 deficiency; Inborn genetic diseases; not prov
- P20T (p.Pro20Thr), gnomAD 5-71587483-C-A, REVEL 0.21, CADD 5.00
- P20Q (p.Pro20Gln), gnomAD 5-71587484-C-A, REVEL 0.33, CADD 0.29
- P20P (p.Pro20Pro), gnomAD 5-71587485-G-A, CADD 12.10
- R21C (p.Arg21Cys), rs1744805925, ClinGen CA360001844, ClinVar RCV003352389, TOPMed rs1744805925, REVEL 0.73, CADD 27.60, Uncertain significance, Inborn genetic diseases
- R21S (p.Arg21Ser), gnomAD 5-71587486-C-A, REVEL 0.69, CADD 23.60
- R21L (p.Arg21Leu), gnomAD 5-71587487-G-T, REVEL 0.77, CADD 25.60
- R21P (p.Arg21Pro), gnomAD 5-71587487-G-C, REVEL 0.67, CADD 23.80
- R21H (p.Arg21His), gnomAD 5-71587487-G-A, REVEL 0.60, CADD 26.00
- R21R (p.Arg21Arg), gnomAD 5-71587488-C-T, CADD 9.35
- A22V (p.Ala22Val), gnomAD rs1326660260, REVEL 0.26, CADD 15.70
- A22S (p.Ala22Ser), gnomAD 5-71587489-G-T, REVEL 0.17, CADD 4.91
- A22T (p.Ala22Thr), gnomAD 5-71587489-G-A, REVEL 0.21, CADD 7.93
- A22D (p.Ala22Asp), gnomAD 5-71587490-C-A, REVEL 0.26, CADD 15.20
- A22A (p.Ala22Ala), gnomAD 5-71587491-C-G, CADD 13.10
- Y23C (p.Tyr23Cys), rs1238687077, ClinGen CA360001925, ClinVar RCV003499030, TOPMed rs1238687077, REVEL 0.80, CADD 28.10, Likely pathogenic, 3-methylcrotonyl-CoA carboxylase 2 deficiency
- Y23S (p.Tyr23Ser), rs1238687077, ClinGen CA360001907, ClinVar RCV003067403, ClinVar RCV003083339, REVEL 0.74, CADD 24.50, Conflicting interpretations, Inborn genetic diseases; 3-methylcrotonyl-CoA carboxylase 2 deficiency
- Y23H (p.Tyr23His), gnomAD 5-71587492-T-C, REVEL 0.70, CADD 27.70
- H24Q (p.His24Gln), rs374686220, ClinGen CA360001963, ClinVar RCV000625574, ESP rs374686220, REVEL 0.59, CADD 22.30, Uncertain significance, 3-methylcrotonyl-CoA carboxylase 2 deficiency
- H24Y (p.His24Tyr), Ensembl rs1744806774, REVEL 0.43, CADD 22.30
- H24T (p.His24Thr), gnomAD 5-71587494-TC-T, CADD 26.70
- H24N (p.His24Asn), gnomAD 5-71587495-C-A, REVEL 0.55, CADD 23.50
- H24D (p.His24Asp), gnomAD 5-71587495-C-G, REVEL 0.76, CADD 23.70
- H24R (p.His24Arg), gnomAD 5-71587496-A-G, REVEL 0.55, CADD 23.60
- H24L (p.His24Leu), gnomAD 5-71587496-A-T, REVEL 0.68, CADD 24.10
- H24H (p.His24His), rs374686220, gnomAD 5-71587497-C-T, CADD 12.00
- G25E (p.Gly25Glu), Ensembl rs1561813665, REVEL 0.59, CADD 21.80
- G25V (p.Gly25Val), NCI-TCGA TCGA novel, REVEL 0.53, CADD 21.10, Variant assessed as somatic; moderate impact.
- G25R (p.Gly25Arg), gnomAD 5-71587496-A-AC, CADD 28.70
- G25W (p.Gly25Trp), gnomAD 5-71587498-G-T, REVEL 0.69, CADD 24.50
- G25G (p.Gly25Gly), gnomAD 5-71587500-G-T, CADD 13.80
- D26E (p.Asp26Glu), ExAC rs774475879, TOPMed rs774475879, gnomAD rs774475879, Likely benign
- D26T (p.Asp26Thr), gnomAD 5-71587497-CG-C, CADD 25.60
- D26Y (p.Asp26Tyr), gnomAD 5-71587501-G-T, REVEL 0.79, CADD 29.40
- D26N (p.Asp26Asn), gnomAD 5-71587501-G-A, REVEL 0.53, CADD 25.20
- D26G (p.Asp26Gly), gnomAD 5-71587502-A-G, REVEL 0.52, CADD 23.20
- D26D (p.Asp26Asp), rs774475879, gnomAD 5-71587503-C-T, CADD 13.80
- S27L (p.Ser27Leu), gnomAD rs1252575701, REVEL 0.33, CADD 20.60
- S27P (p.Ser27Pro), gnomAD 5-71587504-T-C, REVEL 0.45, CADD 14.80
- S27* (p.Ser27Ter), gnomAD 5-71587505-C-A, CADD 35.00
- S27S (p.Ser27Ser), gnomAD 5-71587506-G-T, CADD 11.90
- V28L (p.Val28Leu), gnomAD 5-71587507-G-T, REVEL 0.43, CADD 21.80
- V28M (p.Val28Met), gnomAD 5-71587507-G-A, REVEL 0.54, CADD 19.90
- V28A (p.Val28Ala), gnomAD 5-71587508-T-C, REVEL 0.39, CADD 21.20
- V28E (p.Val28Glu), gnomAD 5-71587508-T-A, REVEL 0.48, CADD 23.60
- V28V (p.Val28Val), gnomAD 5-71587509-G-A, CADD 14.30
- A29S (p.Ala29Ser), gnomAD 5-71587510-G-T, REVEL 0.43, CADD 21.20
- A29T (p.Ala29Thr), gnomAD 5-71587510-G-A, REVEL 0.44, CADD 22.40
- A29D (p.Ala29Asp), gnomAD 5-71587511-C-A, REVEL 0.56, CADD 21.40
- A29V (p.Ala29Val), gnomAD 5-71587511-C-T, REVEL 0.45, CADD 21.60
- A29A (p.Ala29Ala), gnomAD 5-71587512-C-T, CADD 12.20
- S30L (p.Ser30Leu), gnomAD rs1483894663, REVEL 0.20, CADD 17.30
- S30T (p.Ser30Thr), gnomAD 5-71587513-T-A, REVEL 0.17, CADD 5.17
- S30* (p.Ser30Ter), gnomAD 5-71587514-C-A, CADD 34.00
- S30S (p.Ser30Ser), rs559384926, gnomAD 5-71587515-G-C, CADD 9.09
- L31V (p.Leu31Val), gnomAD rs1248946124, REVEL 0.29, CADD 15.30
- L31L (p.Leu31Leu), rs1248946124, gnomAD 5-71587516-C-T, CADD 8.74
- L31M (p.Leu31Met), gnomAD 5-71587516-C-A, REVEL 0.49, CADD 20.70
- G32D (p.Gly32Asp), NCI-TCGA Cosmic COSV6015, REVEL 0.57, CADD 22.50, Variant assessed as somatic; moderate impact.
- G32S (p.Gly32Ser), gnomAD 5-71587519-G-A, REVEL 0.54, CADD 22.60
- G32C (p.Gly32Cys), gnomAD 5-71587519-G-T, REVEL 0.73, CADD 27.50
- G32V (p.Gly32Val), gnomAD 5-71587520-G-T, REVEL 0.70, CADD 22.60
- G32G (p.Gly32Gly), rs1436793904, gnomAD 5-71587521-C-T, CADD 11.10
- T33A (p.Thr33Ala), TOPMed rs1182092562, gnomAD rs1182092562, REVEL 0.48, CADD 22.30, Uncertain significance, Inborn genetic diseases
- T33I (p.Thr33Ile), rs2112251506, ClinGen CA360002246, ClinVar RCV001904852, Ensembl rs2112251506, REVEL 0.55, CADD 23.00, Uncertain significance, 3-methylcrotonyl-CoA carboxylase 2 deficiency
- T33P (p.Thr33Pro), TOPMed rs1182092562, gnomAD rs1182092562, Uncertain significance
- T33N (p.Thr33Asn), gnomAD 5-71587523-C-A, REVEL 0.41, CADD 19.10
- T33T (p.Thr33Thr), gnomAD 5-71587524-C-T, CADD 6.47
- Q34* (p.Gln34Ter), rs1413464990, ClinGen CA360002247, ClinVar RCV003470071, TOPMed rs1413464990, CADD 33.00, Pathogenic
- Q34R (p.Gln34Arg), gnomAD rs1479186286
- Q34K (p.Gln34Lys), gnomAD 5-71587525-C-A, REVEL 0.33, CADD 9.35
- Q34H (p.Gln34His), gnomAD 5-71587527-G-T, REVEL 0.33, CADD 10.80
- Q34Q (p.Gln34Gln), rs1320538722, gnomAD 5-71587527-G-A, CADD 6.50
- P35A (p.Pro35Ala), ExAC rs767675836, TOPMed rs767675836, gnomAD rs767675836
- P35L (p.Pro35Leu), rs925336033, ClinGen CA120016524, ClinVar RCV002679882, TOPMed rs925336033, REVEL 0.14, CADD 4.61, Uncertain significance, Inborn genetic diseases
- P35S (p.Pro35Ser), ExAC rs767675836, TOPMed rs767675836, gnomAD rs767675836, REVEL 0.24, CADD 8.25
- P35T (p.Pro35Thr), rs767675836, ClinGen CA360002287, ClinVar RCV002304505, REVEL 0.16, CADD 5.59, Uncertain significance, 3-methylcrotonyl-CoA carboxylase 2 deficiency
- P35Q (p.Pro35Gln), gnomAD 5-71587529-C-A, REVEL 0.15, CADD 6.86
- P35R (p.Pro35Arg), gnomAD 5-71587529-C-G, REVEL 0.30, CADD 13.40
- P35P (p.Pro35Pro), rs1365918358, gnomAD 5-71587530-G-A, CADD 6.68
- D36G (p.Asp36Gly), TOPMed rs1467574687, gnomAD rs1467574687, REVEL 0.76, CADD 26.10
- D36V (p.Asp36Val), TOPMed rs1467574687, gnomAD rs1467574687, REVEL 0.84, CADD 25.80
- D36Y (p.Asp36Tyr), gnomAD 5-71587531-G-T, REVEL 0.78, CADD 26.30
- D36H (p.Asp36His), gnomAD 5-71587531-G-C, REVEL 0.74, CADD 26.00
- D36D (p.Asp36Asp), gnomAD 5-71587533-C-T, CADD 10.60
- L37* (p.Leu37Ter), rs2530684724, ClinVar RCV004574835, Likely pathogenic
- L37L (p.Leu37Leu), gnomAD 5-71587534-T-C, CADD 6.57
- L37S (p.Leu37Ser), gnomAD 5-71587535-T-C, REVEL 0.19, CADD 12.40
- L37F (p.Leu37Phe), gnomAD 5-71587536-G-T, REVEL 0.28, CADD 17.40
- G38D (p.Gly38Asp), Ensembl rs1160233617, REVEL 0.14, CADD 16.50
- G38S (p.Gly38Ser), gnomAD rs1165933854, REVEL 0.18, CADD 11.90
- G38A (p.Gly38Ala), gnomAD 5-71587535-TG-T, CADD 22.90
Public MCCC2 analysis runs
- MCCC2 analysis run — MCCC2 (940 variants) — completed 2026-08-20