MMACHC

Chr 1AR

metabolism of cobalamin associated C

Also known as: cblC

NCBI Gene: 25974ENSG00000132763UniProt: Q9Y4U1

The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Methylmalonic aciduria and homocystinuria, cblC typeMIM #277400
AR
181
ClinVar variants
68
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— MMACHC
🧬
Gene-Disease Validity (ClinGen)
methylmalonic aciduria and homocystinuria type cblC · 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
68 Pathogenic / Likely Pathogenic· 71 VUS of 181 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.75LOEUF
pLI 0.000
Z-score -0.76
OE 1.21 (0.84–1.75)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.08Z-score
OE missense 1.23 (1.10–1.38)
213 obs / 173.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.21 (0.84–1.75)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.23 (1.10–1.38)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.26
0≤1.21.6
LoF obs/exp: 18 / 14.8Missense obs/exp: 213 / 173.2Syn Z: -1.65

ClinVar Variant Classifications

181 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic32
VUS71
Likely Benign13
Benign12
Conflicting17
36
Pathogenic
32
Likely Pathogenic
71
VUS
13
Likely Benign
12
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
6
18
1
36
Likely Pathogenic
13
11
7
1
32
VUS
11
21
39
0
71
Likely Benign
0
2
6
5
13
Benign
0
1
9
2
12
Conflicting
—17
Total3541799181

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

View in ClinVar →

Protein Context — Lollipop Plot

MMACHC · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MMACHC-related methylmalonic aciduria and homocystinuria, cblC type

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Methylmalonic aciduria and homocystinuria, cblC type

MIM #277400

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MMACHC
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cobalamin C defect: natural history, pathophysiology, and treatment.
Martinelli D et al.·J Inherit Metab Dis
2011Review
Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review.
Arhip L et al.·Orphanet J Rare Dis
2024Review
Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria.
Hu S et al.·BMC Med Genet
2018
Intracellular processing of vitamin B(12) by MMACHC (CblC).
Hannibal L et al.·Vitam Horm
2022Review
Clinical and electroencephalogram characteristics of methylmalonic acidemia with MMACHC and MUT gene mutations.
Yuan Y et al.·BMC Pediatr
2024
The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.
Demaret T et al.·Mol Genet Metab
2024Cohort
Clinical and molecular spectrum of patients with methylmalonic acidemia and homocysteinemia complicated by cardiovascular manifestations.
Zhao W et al.·Orphanet J Rare Dis
2025Cohort
Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review.
Wang C et al.·Eur J Med Genet
2019Review
Inherited defects of cobalamin metabolism.
Watkins D et al.·Vitam Horm
2022
Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type.
Hao L et al.·Mol Genet Metab
2025Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Rare DiseasesAlbinismIntellectual Disability

Implementation of Long-read Sequencing for the Diagnosis of Rare Diseases.

NOT YET RECRUITING
NCT07400913University Hospital, BordeauxStarted 2026-02
Long-read sequencing

External Resources

Links to major genomics databases and tools