MMUT

Chr 6AR

methylmalonyl-CoA mutase

NCBI Gene: 4594ENSG00000146085UniProt: P22033

Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key intermediate of the tricarboxylic acid cycle

Primary Disease Associations & Inheritance

Methylmalonic aciduria, mut(0) typeMIM #251000
AR
590
ClinVar variants
175
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— MMUT
🧬
Gene-Disease Validity (ClinGen)
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency · 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
175 Pathogenic / Likely Pathogenic· 210 VUS of 590 total submissions
💊
Clinical Trials
2 active or recruiting trials — 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.
1.23LOEUF
pLI 0.000
Z-score 0.40
OE 0.93 (0.71–1.23)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?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.
0.23Z-score
OE missense 0.97 (0.89–1.05)
401 obs / 414.1 exp
Tolerant

Mild missense constraint

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.0.93 (0.71–1.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.89–1.05)
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.1.00
0≤1.21.6
LoF obs/exp: 35 / 37.7Missense obs/exp: 401 / 414.1Syn Z: 0.01

ClinVar Variant Classifications

590 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic83
Likely Pathogenic92
VUS210
Likely Benign156
Benign21
Conflicting28
83
Pathogenic
92
Likely Pathogenic
210
VUS
156
Likely Benign
21
Benign
28
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
41
12
30
0
83
Likely Pathogenic
23
43
26
0
92
VUS
1
166
38
5
210
Likely Benign
0
2
90
64
156
Benign
0
1
20
0
21
Conflicting
—28
Total6522420469590

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

View in ClinVar →

Protein Context — Lollipop Plot

MMUT · protein map & ClinVar variants

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

Gene2Phenotype Curations

MMUT-related methylmalonic aciduria

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Methylmalonic aciduria, mut(0) type

MIM #251000

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MMUT
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Different mutations in the MMUT gene are associated with the effect of vitamin B12 in a cohort of 266 Chinese patients with mut-type methylmalonic acidemia: A retrospective study.
Yu Y et al.·Mol Genet Genomic Med
2021Cohort
A rare mutation c.1663G > A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients.
Liang L et al.·Orphanet J Rare Dis
2021Cohort
Evaluation of the clinical, biochemical, genotype and prognosis of mut-type methylmalonic acidemia in 365 Chinese cases.
Liang L et al.·J Med Genet
2023Cohort
Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency.
Luciani A et al.·Nat Commun
2020
Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia.
Manoli I et al.·J Inherit Metab Dis
2023Review
Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.
Manoli I et al.·JCI Insight
2024
Identification of a biallelic MMUT variant (p.Thr230Arg) and its global perspective on clinical management.
Mansoor S et al.·Mol Biol Rep
2024Case report
Improved therapeutic efficacy in two mouse models of methylmalonic acidemia (MMA) using a second-generation mRNA therapy.
Coughlan KA et al.·Mol Genet Metab
2024Functional
Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria.
Denley MCS et al.·Commun Biol
2025
Treatment of metabolic disorders using genomic technologies: Lessons from methylmalonic acidemia.
Venturoni LE et al.·J Inherit Metab Dis
2022Review
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
Methylmalonic Acidemia (MMA)

A Prospective Study of Pediatric Participants up to 16 Years of Age With Methylmalonic Acidemia (MMA) Due to Mutations in the MMUT Gene

NOT YET RECRUITING
NCT07432880Genespire SrlStarted 2026-05
Methylmalonic Acidemia

Long-term Follow-up Study of Patients Who Received hLB-001 Gene Therapy

ACTIVE NOT RECRUITING
NCT05506254Alexion Pharmaceuticals, Inc.Started 2022-07-15
hLB-001

External Resources

Links to major genomics databases and tools