Cobalamin C disease: genes and variants
Cobalamin C disease is linked to 2 analyzed proteins (MMACHC and MMADHC). 41 DNA variants are known to cause it; 102 more are uncertain, and 2 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Cobalamin C disease
MMACHC: Cyanocobalamin reductase / alkylcobalamin dealkylase
It processes intracellular cobalamin so that vitamin B12 can be converted into the active cofactors needed for methionine synthase and methylmalonyl-CoA mutase. Biallelic loss causes cblC disease, with combined methylmalonic acidemia and homocystinuria and highly variable neurologic and systemic manifestations.
40 disease-causing and 102 uncertain variants in MMACHC are linked to Cobalamin C disease.
MMADHC: Cobalamin trafficking protein CblD
It directs intracellular cobalamin toward the methylcobalamin and adenosylcobalamin pathways needed for methionine and methylmalonyl-CoA metabolism. Biallelic pathogenic variants cause cblD disease, producing isolated or combined methylmalonic acidemia and homocystinuria.
1 disease-causing and 0 uncertain variants in MMADHC are linked to Cobalamin C disease.
Known disease-causing variants in Cobalamin C disease
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| MMACHC G147D | 147 | Disease-causing (★★) | |
| MMACHC G155R | 155 | Disease-causing (★★) | |
| MMACHC G156D | 156 | Disease-causing (★★) | |
| MMACHC G162W | 162 | Disease-causing (★★) | |
| MMACHC R189S | 189 | Disease-causing (★★) | |
| MMACHC R206P | 206 | Disease-causing (★★) | |
| MMACHC L116P | 116 | Disease-causing (★★) | |
| MMACHC Y130C | 130 | Disease-causing (★★) | |
| MMACHC Y130H | 130 | Disease-causing (★★) | |
| MMACHC R161Q | 161 | Disease-causing (★★) | |
| MMACHC R161L | 161 | Disease-causing (★★) | |
| MMACHC R161G | 161 | Disease-causing (★★) | |
| MMACHC R189C | 189 | Disease-causing (★★) | |
| MMACHC R206Q | 206 | Disease-causing (★★) | |
| MMACHC M1R | 1 | Disease-causing (★★) | |
| MMACHC M1T | 1 | Disease-causing (★★) | |
| MMACHC M1I | 1 | Disease-causing (★★) | |
| MMACHC M1V | 1 | Disease-causing (★★) | |
| MMACHC A117P | 117 | Disease-causing (★★) | |
| MMACHC H151R | 151 | Disease-causing (★★) | |
| MMACHC L193P | 193 | Disease-causing (★★) | |
| MMACHC Q27R | 27 | Disease-causing (★★) | |
| MMACHC R61P | 61 | Disease-causing (★★) | |
| MMACHC E92D | 92 | Disease-causing (★★) | |
| MMACHC L116V | 116 | Disease-causing (★) | |
| MMACHC G147S | 147 | Disease-causing (★) | |
| MMACHC G156S | 156 | Disease-causing (★) | |
| MMACHC G162R | 162 | Disease-causing (★) | |
| MMACHC R189L | 189 | Disease-causing (★) | |
| MMACHC L116M | 116 | Disease-causing (★) | |
| MMACHC H122Q | 122 | Disease-causing (★) | |
| MMACHC G147R | 147 | Disease-causing (★) | |
| MMACHC M1L | 1 | Disease-causing (★) | |
| MMACHC H122L | 122 | Disease-causing (★) | |
| MMACHC I150K | 150 | Disease-causing (★) | |
| MMACHC R132L | 132 | Disease-causing (★) | |
| MMACHC Y215H | 215 | Disease-causing (★) | |
| MMACHC R206W | 206 | Disease-causing | |
| MMACHC G155E | 155 | Disease-causing | |
| MMACHC R189H | 189 | Disease-causing | |
| MMADHC Y249C | 249 | Disease-causing |
Uncertain variants in Cobalamin C disease that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| MMACHC L193F | 193 | Uncertain | +7: in a 3D region that tolerates change poorly (2R); L193P at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.856 | |
| MMACHC H122N | 122 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; H122Q at the same position is pathogenic; REVEL 0.885 |
Which prediction tools work for Cobalamin C disease
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- REVEL: 96 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: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 85 out of 100
- SIFT: 79 out of 100
- phyloP: 67 out of 100
Diseases related to Cobalamin C disease
- Disorders of Intracellular Cobalamin Metabolism, also linked to MMACHC and MMADHC
- Methylmalonic aciduria and homocystinuria type cblD, also linked to MMADHC
Frequently asked questions
Which genes are linked to Cobalamin C disease?
In CATVariant, Cobalamin C disease is linked to 2 analyzed proteins: MMACHC (Cyanocobalamin reductase / alkylcobalamin dealkylase) and MMADHC (Cobalamin trafficking protein CblD).
How many genetic variants are linked to Cobalamin C disease?
145 variants: 41 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 102 are of uncertain significance or have conflicting reports.
Which uncertain variants in Cobalamin C disease look disease-causing?
2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MMACHC L193F and MMACHC H122N. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Cobalamin C disease?
Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.85, based on 29 disease-causing and 11 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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