MMACHC

Chr 1AR

metabolism of cobalamin associated C

Also known as: cblC

NCBI Gene: 25974 ENSG00000132763 UniProt: Q9Y4U1 OMIM: 609831

The protein encoded by MMACHC is involved in the binding and intracellular trafficking of cobalamin (vitamin B12), with its C-terminal region showing similarity to bacterial proteins involved in cobalamin uptake. Mutations cause methylmalonic aciduria and homocystinuria, cblC type, inherited in an autosomal recessive pattern. The pathogenic mechanism involves defective cobalamin processing leading to impaired methylmalonyl-CoA mutase and methionine synthase function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.751 OMIM phenotype

Clinical Summary— MMACHC

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Gene-Disease Validity (ClinGen)

methylmalonic aciduria and homocystinuria type cblC · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

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

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ClinVar Variants

187 unique Pathogenic / Likely Pathogenic· 216 VUS of 677 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — MMACHC

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-1.08Z-score

OE missense 1.23 (1.10–1.38)

213 obs / 173.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.21 (0.84–1.75)

0≤0.351.4

Missense OE?1.23 (1.10–1.38)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 18 / 14.8Missense obs/exp: 213 / 173.2Syn Z: -1.65

ClinVar Variant Classifications

677 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78

Likely Pathogenic109

VUS216

Likely Benign208

Benign24

Conflicting36

Pathogenic

109

Likely Pathogenic

216

VUS

208

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	59	12	6	1	78
Likely Pathogenic	69	37	2	1	109
VUS	18	148	49	1	216
Likely Benign	1	4	58	145	208
Benign	0	1	21	2	24
Conflicting	—				36
Total	147	202	136	150	671

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap MMACHC — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →