MMUT

Chr 6AR

methylmalonyl-CoA mutase

Also known as: MCM, MUT

NCBI Gene: 4594 ENSG00000146085 UniProt: P22033 OMIM: 609058

The MMUT gene encodes methylmalonyl-CoA mutase, a vitamin B12-dependent mitochondrial enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in the tricarboxylic acid cycle. Mutations cause methylmalonic aciduria (mut0 type), an autosomal recessive disorder typically presenting in the neonatal period with metabolic acidosis, hyperammonemia, and failure to thrive. The gene shows tolerance to loss-of-function variants (LOEUF 1.232), consistent with recessive inheritance where heterozygous carriers are unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Methylmalonic aciduria, mut(0) typeMIM #251000

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.23

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — MMUT

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.23LOEUF

pLI 0.000

Z-score 0.40

OE 0.93 (0.71–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.23Z-score

OE missense 0.97 (0.89–1.05)

401 obs / 414.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.93 (0.71–1.23)

0≤0.351.4

Missense OE?0.97 (0.89–1.05)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 35 / 37.7Missense obs/exp: 401 / 414.1Syn Z: 0.01

Background carrier burden — how many people carry a rare variant somewhere in MMUT?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 69

935 rare PASS variants

Rare truncating (LoF)

1 in 730

173 rare PASS variants

Rare synonymous (reference)

1 in 270

292 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MMUT. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 87	1 in 890
South Asian	~43k	1 in 69	1 in 400
Remaining (unassigned)	~30k	1 in 56	1 in 770
European (Finnish)	~27k	1 in 210	1 in 3,800
Admixed American	~22k	1 in 58	1 in 570
African / African American	~21k	1 in 48	1 in 470
East Asian	~20k	1 in 71	1 in 270
Ashkenazi Jewish	~13k	1 in 640	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 72	1 in 480

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.