MMUT

Summary

MMUT (methylmalonyl-CoA mutase, HGNC:7526) is a protein-coding gene on chromosome 6p12.3, encoding Methylmalonyl-CoA mutase, mitochondrial (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.

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.

Source: NCBI Gene 4594 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 1,242 total — 220 pathogenic, 134 likely-pathogenic
• Phenotypes (HPO): 54
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7526
Approved symbol	MMUT
Name	methylmalonyl-CoA mutase
Location	6p12.3
Locus type	gene with protein product
Status	Approved
Aliases	MCM
Ensembl gene	ENSG00000146085
Ensembl biotype	protein_coding
OMIM	609058
Entrez	4594

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 20 protein_coding

ENST00000274813, ENST00000878060, ENST00000878061, ENST00000878062, ENST00000878063, ENST00000878064, ENST00000878065, ENST00000878066, ENST00000878067, ENST00000878068, ENST00000878069, ENST00000878070, ENST00000878071, ENST00000878072, ENST00000878073, ENST00000953754, ENST00000953755, ENST00000953756, ENST00000953757, ENST00000953758

RefSeq mRNA: 1 — MANE Select: NM_000255 NM_000255

CCDS: CCDS4924

Canonical transcript exons

ENST00000274813 — 13 exons

Exon	Start	End
ENSE00000973845	49457691	49458058
ENSE00000973851	49444639	49444754
ENSE00000973852	49441840	49441971
ENSE00000973854	49435456	49435623
ENSE00000973855	49430360	49431856
ENSE00001139009	49440206	49440353
ENSE00001139024	49447670	49447785
ENSE00001139030	49448816	49448927
ENSE00001139037	49451466	49451714
ENSE00001139044	49453585	49453756
ENSE00001139050	49456080	49456237
ENSE00001167247	49459082	49459505
ENSE00001926852	49463103	49463253

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9632 / max 144.0618, expressed in 1782 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73909	11.6960	1779
73910	0.7844	512
73908	0.4829	225

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	97.92	gold quality
oocyte	CL:0000023	96.99	gold quality
nephron tubule	UBERON:0001231	96.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.68	gold quality
pancreatic ductal cell	CL:0002079	96.62	gold quality
colonic mucosa	UBERON:0000317	96.52	gold quality
endothelial cell	CL:0000115	96.48	gold quality
liver	UBERON:0002107	96.15	gold quality
jejunal mucosa	UBERON:0000399	96.11	gold quality
cervix squamous epithelium	UBERON:0006922	95.96	gold quality
secondary oocyte	CL:0000655	95.70	gold quality
buccal mucosa cell	CL:0002336	95.56	gold quality
kidney epithelium	UBERON:0004819	95.45	gold quality
biceps brachii	UBERON:0001507	95.33	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.17	gold quality
left ventricle myocardium	UBERON:0006566	95.06	gold quality
heart right ventricle	UBERON:0002080	94.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.69	gold quality
right lobe of liver	UBERON:0001114	94.66	gold quality
renal medulla	UBERON:0000362	94.65	gold quality
renal glomerulus	UBERON:0000074	94.56	gold quality
pigmented layer of retina	UBERON:0001782	94.47	gold quality
metanephric glomerulus	UBERON:0004736	94.47	gold quality
myocardium	UBERON:0002349	94.46	gold quality
retina	UBERON:0000966	94.44	gold quality
squamous epithelium	UBERON:0006914	94.26	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.22	gold quality
esophagus squamous epithelium	UBERON:0006920	94.14	gold quality
bronchial epithelial cell	CL:0002328	93.93	gold quality
cranial nerve II	UBERON:0000941	93.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, MYC, SP1, TP53

miRNA regulators (miRDB)

95 targeting MMUT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Analysis of the prevalence and distribution of MCM mutations throughout the coding sequence in relation to the enzyme structure. (PMID:15643616)
• The MUT gene was sequenced in 160 patients with mut methylmalonic acidemia (MMA). Sequence analysis identified mutations in 96% of disease alleles. (PMID:16281286)
• p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut(-) phenotype. (PMID:17113806)
• A case report is presented of kidney transplantation in MUT. (PMID:17401587)
• Mutations in methylmalonyl-CoA mutase is associated with methylmalonic acidemia (PMID:17410422)
• Novel mutation of the MCM gene (R727X)identified in a Japanese girl causing mild presentation of methylmalonic acidemia during infancy. (PMID:17445044)
• Long-term outcome in methylmalonic acidurias is influenced by the underlying genetic defects in MCM/MMAA/MMAB. (PMID:17597648)
• Crystal structure and mutagenesis of MUT: insight into the causes of metylamalonic aciduria. (PMID:17728257)
• Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. (PMID:17957493)
• Methylmalonyl-CoA Mutase intronic variations causing aberrantly spliced messenger RNA is associated with propionic and methylmalonic acidemia. (PMID:17966092)
• early hyperammonemia can lead to significant brain damage in methylmalonic acidemia (PMID:18940555)
• Mitochondrial dysfunction in MUT is reported. (PMID:19088183)
• Seventeen MUT gene mutations were detected in 14 of the 21 methylmalonic acidemia patients, among them 8 mutations were novel. (PMID:19806564)
• CPS1, MUT, NOX4, and DPEP1 is associated with plasma homocysteine in healthy Women. (PMID:20031578)
• Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (PMID:20876572)
• MMAA acts as a chaperone of human MCM protein. (PMID:21138732)
• Pathogenicity of the human truncation mutant results from its inability to sequester adenosyltransferase (AdoCbl) for direct transfer to methylmalonyl-CoA mutase, resulting in holoenzyme formation and disease. (PMID:21604717)
• This work reveals that Mexican patients with MMA have new (p.V136F) as well as worldwide and hispanic reported mutations. The mutation R108C is the most frequent change (40% of total alleles) mainly in patients from Leon, Guanajuato (PMID:23045948)
• The contribution of Glu338 in human MCM to adenosylcobalamin Co-C bond labilization and catalysis was evaluated by substituting the residue with a glutamine, aspartate, or alanine. The MCM variants showed 16-, 330-, and 12-fold reductions in k(cat). (PMID:23311430)
• Using alanine-scanning mutagenesis, we demonstrate that the switch III motif is critical for bidirectional signal transmission of the GTPase-activating protein activity of MCM and the chaperone functions of MeaB in the MeaB-MCM complex. (PMID:23873214)
• This is the first description of a homozygous mutation in the N-terminal extended segment of the MCM apoenzyme. (PMID:24330302)
• Mutations in MUT cause methylmalonic acidemia. (PMID:24406457)
• data stratify MUT missense mutations into categories of biochemical defects, including (1) reduced protein level due to misfolding, (2) increased thermolability, (3) impaired enzyme activity, and (4) reduced cofactor response in substrate turnover (PMID:25125334)
• Five different known mutations in either MUT or MMACHC genes were identified in seven of the eight Chinese patients with methyl malonic acidemia. (PMID:25982642)
• 3 Patients with Isolated methylmalonic acidemia lacked methylmalonyl-CoA mutase (MCM) activity and had no MCM band, patients with the cobalamin defects had high MCM activity levels and an intense MCM band at about 83 kDa, in comparison to those in their parents. (PMID:26370686)
• a novel splice site mutation in intron 12 of the MUT gene is a potential highly pathogenic allele via inhibition of alternative splicing leading to Methylmalonic aciduria. (PMID:26449400)
• In methylmalonic acidemia,a total of 10 novel MUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. (PMID:26454439)
• we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants (PMID:26830710)
• Two novel mutations of the MUT gene, including c.581C>T (p.P194L) and c.1219A>T (p.N407Y), are associated with methylmalonic academia in a Chinese family. (PMID:27060300)
• Study identified 41 novel mutations in patients with methylmalonic aciduria (MMA); most of them were missense mutations. The absence of MUT protein in most of the patient cell lines, suggesting protein instability as a major mechanism of deficiency in mut-type MMA. (PMID:27167370)
• A total of 54 different mutations in MUT were identified in 48 patients; 16 novel mutations were identified… In five patients, the NGS panel did not confirm the diagnosis made by complementation analysis. One of these patients was found to carry 2 novel mutations (PMID:27233228)
• localization of hMMAA and its colocalization with hMCM in human (PMID:28943303)
• The gene therapy method has been described for restoring the methylmalonyl-CoA mutase activity in vitro in fibroblasts from methylmalonic aciduria patients. (PMID:29265583)
• Three novel variants of the MUT gene have been identified in patients with methylmalonic aciduria. (PMID:30098236)
• Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation. (PMID:30913280)
• These data demonstrate durable functional benefit of hMUT mRNA and support development of this new class of therapy for a devastating, pediatric disorder. (PMID:31303505)
• Our study identified a novel, deleterious, heterozygous missense mutation in MUT gene in a couple and helps to consider the genetic counselling and prenatal diagnosis more seriously for this family with clinical phenotypes of organic acidemia. (PMID:32013889)
• Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase. (PMID:32659443)
• Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress. (PMID:32679819)
• Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut. (PMID:32754920)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmut	ENSDARG00000060554
mus_musculus	Mmut	ENSMUSG00000023921
rattus_norvegicus	Mmut	ENSRNOG00000050843
caenorhabditis_elegans		WBGENE00014202

Paralogs (1): MMAA (ENSG00000151611)

Protein

Protein identifiers

Methylmalonyl-CoA mutase, mitochondrial — P22033 (reviewed: P22033)

Alternative names: Methylmalonyl-CoA isomerase

All UniProt accessions (2): P22033, A0A024RD82

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Homodimer. Interacts (the apoenzyme form) with MMAA; the interaction is GTP dependent.

Subcellular location. Mitochondrion matrix. Mitochondrion. Cytoplasm.

Disease relevance. Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (MAMM) [MIM:251000] An often fatal disorder of organic acid metabolism. Common clinical features include lethargy, vomiting, failure to thrive, hypotonia, neurological deficit and early death. Two forms of the disease are distinguished by the presence (mut-) or absence (mut0) of residual enzyme activity. Mut0 patients have more severe neurological manifestations of the disease than do MUT- patients. MAMM is unresponsive to vitamin B12 therapy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. During catalysis, accumulation of oxidized inactive cofactor hydroxocobalamin (OH2Cbl) leads to loss of MMUT activity. Interaction with MMAA decreases the rate of OH2Cbl formation and promotes the replacement of OH2Cbl by the active cofactor adenosylcobalamin (AdoCbl), thereby restoring MMUT activity. Inhibited by itaconyl-CoA, a metabolite that inactivates the coenzyme B12 cofactor. Inhibited by malyl-coA. Inhibited at high concentration of substrate.

Similarity. Belongs to the methylmalonyl-CoA mutase family.

RefSeq proteins (1): NP_000246* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006098	MMCoA_mutase_a_cat	Domain
IPR006099	MeMalonylCoA_mutase_a/b_cat	Domain
IPR006158	Cobalamin-bd	Domain
IPR006159	Acid_CoA_mut_C	Domain
IPR016176	Cbl-dep_enz_cat	Homologous_superfamily
IPR036724	Cobalamin-bd_sf	Homologous_superfamily
IPR058549	MeMalonylCoA_mutase_a/b_site	Conserved_site

Pfam: PF01642, PF02310

Enzyme classification (BRENDA):

• EC 5.4.99.2 — methylmalonyl-CoA mutase (BRENDA: 31 organisms, 36 substrates, 31 inhibitors, 38 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(R)-2-METHYLMALONYL-COA	0.0279–0.364	7
SUCCINYL-COA	0.025–0.3474	7
ADENOSYLCOBALAMIN	0.0002–0.0086	5
(R)-2-METHYL-3-OXOPROPANOYL-COA	0.085–1.5	4
(R,S)-METHYLMALONYL-COA	0.11–0.13	2
(R/S)-2-METHYL-3-OXOPROPANOYL-COA	0.06–0.2	2
METHYLMALONYL-CARBA(DETHIA)-COENZYME A	0.136	2
METHYLMALONYL-COA	0.133–0.357	2
4-CARBOXY-2-OXOBUTANOYL-COA	0.132	1
SUCCINYL-DICARBA(DETHIA)-COA	2.2	1
(R)-METHYLMALONYL-COA	—	0

Catalyzed reactions (Rhea), 1 shown:

• (R)-methylmalonyl-CoA = succinyl-CoA (RHEA:22888)

UniProt features (234 total): sequence variant 143, helix 37, strand 22, binding site 9, modified residue 7, turn 7, sequence conflict 6, transit peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8DYL	X-RAY DIFFRACTION	1.9
2XIJ	X-RAY DIFFRACTION	1.95
2XIQ	X-RAY DIFFRACTION	1.95
8DYJ	X-RAY DIFFRACTION	2.2
3BIC	X-RAY DIFFRACTION	2.6
8GJU	X-RAY DIFFRACTION	2.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22033-F1	92.72	0.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 304–306; 627 (axial binding residue); 50; 96–99; 106–110; 216–218; 228; 255; 265

Post-translational modifications (7): 89, 212, 335, 343, 481, 595, 602

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-3359475	Defective MMAA causes MMA, cblA type
R-HSA-3359478	Defective MUT causes MMAM
R-HSA-71032	Propionyl-CoA catabolism
R-HSA-9759218	Cobalamin (Cbl) metabolism
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-3296469	Defects in cobalamin (B12) metabolism
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-5668914	Diseases of metabolism
R-HSA-77289	Mitochondrial Fatty Acid Beta-Oxidation
R-HSA-8978868	Fatty acid metabolism
R-HSA-9759774	Diseases of mitochondrial beta oxidation
R-HSA-9759785	Diseases of propionyl-CoA catabolism

MSigDB gene sets: 350 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, IWANAGA_E2F1_TARGETS_INDUCED_BY_SERUM, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_HOMOCYSTEINE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, chr6p12

GO Biological Process (7): post-embryonic development (GO:0009791), obsolete propionate metabolic process, methylmalonyl pathway (GO:0019678), positive regulation of GTPase activity (GO:0043547), homocysteine metabolic process (GO:0050667), succinyl-CoA biosynthetic process (GO:1901290), sulfur compound metabolic process (GO:0006790), small molecule metabolic process (GO:0044281)

GO Molecular Function (11): GTPase activity (GO:0003924), methylmalonyl-CoA mutase activity (GO:0004494), cobalamin binding (GO:0031419), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), modified amino acid binding (GO:0072341), catalytic activity (GO:0003824), protein binding (GO:0005515), isomerase activity (GO:0016853), intramolecular transferase activity (GO:0016866)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Metabolism	2
Diseases of metabolism	2
Defects in cobalamin (B12) metabolism	1
Diseases of propionyl-CoA catabolism	1
Mitochondrial Fatty Acid Beta-Oxidation	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Defects in vitamin and cofactor metabolism	1
Disease	1
Fatty acid metabolism	1
Metabolism of lipids	1
Diseases of mitochondrial beta oxidation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	2
binding	2
multicellular organism development	1
multicellular organismal process	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
sulfur amino acid metabolic process	1
non-proteinogenic amino acid metabolic process	1
succinyl-CoA metabolic process	1
acyl-CoA biosynthetic process	1
ribonucleoside triphosphate phosphatase activity	1
intramolecular transferase activity	1
vitamin binding	1
tetrapyrrole binding	1
heterocyclic compound binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
molecular_function	1
catalytic activity	1
isomerase activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMUT	MMAB	Q96EY8	973
MMUT	MMAA	Q8IVH4	968
MMUT	MMADHC	Q9H3L0	955
MMUT	MTR	Q99707	944
MMUT	LMBRD1	Q9NUN5	931
MMUT	MCEE	Q96PE7	921
MMUT	MMACHC	Q9Y4U1	910
MMUT	PCCB	P05166	907
MMUT	PCCA	P05165	887
MMUT	SDHC	Q99643	880
MMUT	AGO2	Q9UKV8	839
MMUT	CBL	P22681	838
MMUT	CCK	P06307	814
MMUT	GAPDH	P00354	810
MMUT	TCN2	P20062	806

IntAct

54 interactions, top by confidence:

A	B	Type	Score
GRPEL2	DBT	psi-mi:“MI:0914”(association)	0.710
MMAA	MMUT	psi-mi:“MI:0407”(direct interaction)	0.670
MMAA	MMUT	psi-mi:“MI:0915”(physical association)	0.670
	MMUT	psi-mi:“MI:0883”(gtpase reaction)	0.620
	MMUT	psi-mi:“MI:0407”(direct interaction)	0.610
	MMUT	psi-mi:“MI:0915”(physical association)	0.610
	MMUT	psi-mi:“MI:0883”(gtpase reaction)	0.610
MMUT	MMUT	psi-mi:“MI:0407”(direct interaction)	0.560
MMUT		psi-mi:“MI:0915”(physical association)	0.560
MMUT	HTT	psi-mi:“MI:0915”(physical association)	0.560
CRYZ	MMUT	psi-mi:“MI:0914”(association)	0.560

BioGRID (69): MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Affinity Capture-MS), MUT (Proximity Label-MS), MUT (Affinity Capture-MS), MUT (Proximity Label-MS), MUT (Affinity Capture-MS)

ESM2 similar proteins: A4ILL5, A4IT51, A6T0H8, B0CIM5, B2S8A9, B2U7E6, B9JYR4, C0RGH3, C0SPC0, I3VE77, O30372, O62137, O62140, O74935, O86028, O87009, P16332, P22033, P97562, Q1LJV5, Q2YNV6, Q471I2, Q474N8, Q48440, Q4L1M7, Q57160, Q57FQ9, Q59677, Q5L1E2, Q5RFN2, Q5SJP8, Q6F4M8, Q7KML2, Q7MGQ1, Q8DDP0, Q8G340, Q8GMG6, Q8HXX1, Q8MI68, Q8RQQ0

Diamond homologs: A7IQE5, I3VE77, O86028, P11653, P16332, P22033, P26947, P27253, P65488, P9WJK4, P9WJK5, Q05065, Q23381, Q3IZ90, Q3J4D7, Q49115, Q59677, Q5RFN2, Q5Z110, Q8HXX1, Q8MI68, Q9GK13, A7IQE6, I3VE74, Q1LRY0, Q5KUG0, Q146L7, Q59268, Q87L95, P11652, P65486, P9WJK6, P9WJK7, Q05064, Q59676, P61191, P80078, Q24SG7, Q890S0, Q8RHY7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MMUT	“down-regulates quantity”	(S)-methylmalonyl-CoA(5-)	“chemical modification”
MMUT	“up-regulates quantity”	succinyl-CoA(5-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1242 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	220
Likely pathogenic	134
Uncertain significance	311
Likely benign	384
Benign	33

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100707	NM_000255.4(MMUT):c.323G>A (p.Arg108His)	Pathogenic
1027373	NM_000255.4(MMUT):c.438T>A (p.Tyr146Ter)	Pathogenic
1068338	NM_000255.4(MMUT):c.1540C>A (p.Gln514Lys)	Pathogenic
1069591	NM_000255.4(MMUT):c.1658del (p.Val553fs)	Pathogenic
1070207	NM_000255.4(MMUT):c.920_923del (p.Phe307fs)	Pathogenic
1073042	NM_000255.4(MMUT):c.2194dup (p.Ala732fs)	Pathogenic
1073471	NM_000255.4(MMUT):c.656del (p.Asn219fs)	Pathogenic
1073633	NM_000255.4(MMUT):c.481G>A (p.Gly161Arg)	Pathogenic
1075803	NM_000255.4(MMUT):c.1463dup (p.Val489fs)	Pathogenic
1176511	NM_000255.4(MMUT):c.1230_1235del (p.Ile411_Ile412del)	Pathogenic
1323284	NM_000255.4(MMUT):c.1240G>T (p.Glu414Ter)	Pathogenic
1350287	NM_000255.4(MMUT):c.2098del (p.Met700fs)	Pathogenic
1353016	NM_000255.4(MMUT):c.426del (p.His143fs)	Pathogenic
1363286	NM_000255.4(MMUT):c.2122C>T (p.Gln708Ter)	Pathogenic
1366923	NM_000255.4(MMUT):c.443C>T (p.Ser148Leu)	Pathogenic
1381246	NM_000255.4(MMUT):c.1677-1G>T	Pathogenic
1387856	NM_000255.4(MMUT):c.1569del (p.Ser524fs)	Pathogenic
1406625	NM_000255.4(MMUT):c.976A>T (p.Arg326Ter)	Pathogenic
1409739	NM_000255.4(MMUT):c.1342G>T (p.Glu448Ter)	Pathogenic
1411936	NC_000006.11:g.(?49399441)(49427179_?)del	Pathogenic
1415456	NM_000255.4(MMUT):c.1880dup (p.His627fs)	Pathogenic
1417592	NM_000255.4(MMUT):c.1645dup (p.Leu549fs)	Pathogenic
1424166	NM_000255.4(MMUT):c.1070C>G (p.Ser357Ter)	Pathogenic
1424311	NM_000255.4(MMUT):c.1513del (p.Ile505fs)	Pathogenic
1435188	NM_000255.4(MMUT):c.1679del (p.Cys560fs)	Pathogenic
1441625	NM_000255.4(MMUT):c.522_523insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCAGTGTGGCGATTCCTCAGGGATCTAGAACTAGAAATACCATTTGACCCAGCCATCCCATTACTGGGTATATACCAAAATTCTTTTT (p.Asp175delinsPhePhePhePhePhePheXaaXaaXaaXaaGlnCysGlyAspSerSerGlyIleTer)	Pathogenic
1452615	NM_000255.4(MMUT):c.754-1G>C	Pathogenic
1452874	NM_000255.4(MMUT):c.626dup (p.Pro209_Lys210insTer)	Pathogenic
1453449	NM_000255.4(MMUT):c.1274G>A (p.Trp425Ter)	Pathogenic
1453607	NM_000255.4(MMUT):c.1147_1148del (p.Gln383fs)	Pathogenic

SpliceAI

2451 predictions. Top by Δscore:

Variant	Effect	Δscore
6:49435451:AATAC:A	donor_loss	1.0000
6:49435452:ATAC:A	donor_loss	1.0000
6:49435453:TAC:T	donor_loss	1.0000
6:49435454:ACC:A	donor_loss	1.0000
6:49435455:C:A	donor_loss	1.0000
6:49435466:A:AC	donor_gain	1.0000
6:49435620:GAGT:G	acceptor_gain	1.0000
6:49435621:AGTC:A	acceptor_loss	1.0000
6:49435622:GT:G	acceptor_gain	1.0000
6:49435622:GTCTA:G	acceptor_loss	1.0000
6:49435623:TCTAA:T	acceptor_loss	1.0000
6:49435624:C:CA	acceptor_loss	1.0000
6:49435624:C:CC	acceptor_gain	1.0000
6:49435633:C:CT	acceptor_gain	1.0000
6:49435634:A:T	acceptor_gain	1.0000
6:49440200:TAGTA:T	donor_loss	1.0000
6:49440201:AGTAC:A	donor_loss	1.0000
6:49440202:GTA:G	donor_loss	1.0000
6:49440203:TAC:T	donor_loss	1.0000
6:49440204:ACC:A	donor_loss	1.0000
6:49440205:CCTGG:C	donor_loss	1.0000
6:49440349:GAACC:G	acceptor_gain	1.0000
6:49440350:AACC:A	acceptor_gain	1.0000
6:49440351:ACC:A	acceptor_gain	1.0000
6:49440352:CC:C	acceptor_gain	1.0000
6:49440352:CCC:C	acceptor_gain	1.0000
6:49440353:CC:C	acceptor_gain	1.0000
6:49440354:C:CC	acceptor_gain	1.0000
6:49440354:C:T	acceptor_gain	1.0000
6:49440354:CTGA:C	acceptor_loss	1.0000

AlphaMissense

4914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:49435564:G:C	S672R	1.000
6:49435564:G:T	S672R	1.000
6:49435566:T:G	S672R	1.000
6:49440209:G:C	F651L	1.000
6:49440209:G:T	F651L	1.000
6:49440211:A:G	F651L	1.000
6:49440285:C:T	G626D	1.000
6:49440288:T:A	D625V	1.000
6:49451642:G:C	H386D	1.000
6:49456198:G:C	H265D	1.000
6:49456205:A:C	S262R	1.000
6:49456205:A:T	S262R	1.000
6:49456207:T:G	S262R	1.000
6:49457773:T:A	E224V	1.000
6:49457775:C:A	K223N	1.000
6:49457775:C:G	K223N	1.000
6:49457785:T:A	D220V	1.000
6:49457787:A:C	N219K	1.000
6:49457787:A:T	N219K	1.000
6:49457790:T:A	Q218H	1.000
6:49457790:T:G	Q218H	1.000
6:49458037:A:T	V136D	1.000
6:49459139:A:G	Y110H	1.000
6:49459154:A:G	W105R	1.000
6:49459154:A:T	W105R	1.000
6:49435526:A:G	L685P	0.999
6:49435598:G:T	A661D	0.999
6:49435599:C:G	A661P	0.999
6:49440211:A:C	F651V	0.999
6:49440211:A:T	F651I	0.999

dbSNP variants (sampled 300 via entrez): RS1000149535 (6:49450959 G>T), RS1000292361 (6:49457804 T>C), RS1000301144 (6:49443136 G>A), RS1000408623 (6:49458158 C>G,T), RS1000516548 (6:49449362 T>C), RS1000518085 (6:49463222 C>T), RS1000570197 (6:49463383 C>A,T), RS1000650403 (6:49432422 C>T), RS1000661730 (6:49432103 G>A), RS1000937032 (6:49432967 T>C), RS1001004933 (6:49438592 C>A), RS1001166648 (6:49438818 T>C), RS1001237774 (6:49431227 T>C,G), RS1001304087 (6:49432623 G>A,T), RS1001337103 (6:49437043 C>T)

Disease associations

OMIM: gene MIM:609058 | disease phenotypes: MIM:251000, MIM:613070, MIM:614876, MIM:614877

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	Definitive	Autosomal recessive
vitamin B12-unresponsive methylmalonic acidemia type mut0	Supportive	Autosomal recessive
vitamin B12-unresponsive methylmalonic acidemia type mut-	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	Definitive	AR

Mondo (7): methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (MONDO:0009612), methylmalonic acidemia (MONDO:0002012), acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (MONDO:0013111), peroxisome biogenesis disorder 8A (Zellweger) (MONDO:0013942), peroxisome biogenesis disorder 8B (MONDO:0013943), vitamin B12-unresponsive methylmalonic acidemia type mut0 (MONDO:0017360), vitamin B12-unresponsive methylmalonic acidemia type mut- (MONDO:0019267)

Orphanet (4): Vitamin B12-unresponsive methylmalonic acidemia (Orphanet:27), Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (Orphanet:217371), Neonatal adrenoleukodystrophy (Orphanet:44), Zellweger syndrome (Orphanet:912)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000124	Renal tubular dysfunction
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001638	Cardiomyopathy
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001970	Tubulointerstitial nephritis
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002014	Diarrhea

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000483_6	Folate pathway vitamin levels	5.000000e-08
GCST002087_4	Homocysteine levels	2.000000e-10
GCST006110_38	Nose morphology	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004620	vitamin B12 measurement
EFO:0004578	homocysteine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C565390	Methylmalonic Aciduria due to Methylmalonyl-CoA Mutase Deficiency (supp.)
C537358	Methylmalonic acidemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, increases expression	3
Valproic Acid	affects expression, decreases methylation, increases expression	3
deoxynivalenol	decreases expression	2
adefovir	affects expression, increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, decreases expression	2
Zidovudine	increases expression, affects expression	2
Cyclosporine	decreases expression, affects cotreatment	2
Aflatoxin B1	decreases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression, decreases expression	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases expression	1
antibiotic G 418	affects expression, affects activity, affects cotreatment, increases reaction	1
sodium arsenite	increases expression	1
ochratoxin A	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
nefazodone	affects cotreatment, decreases expression	1
hydroxycobalamin(c-lactam)	decreases activity	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Atazanavir Sulfate	affects cotreatment, decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases abundance, increases expression	1
Calcitriol	increases expression	1

Cellosaurus cell lines

209 cell lines: 205 finite cell line, 2 transformed cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0D81	WG1681	Finite cell line	Male
CVCL_0F56	WG1130	Finite cell line	Female
CVCL_B3UE	WG2181	Finite cell line
CVCL_B3UF	WG2408	Finite cell line
CVCL_B3UG	WG2662	Finite cell line
CVCL_B3VZ	WG3163	Finite cell line
CVCL_B3WM	WG1958	Finite cell line	Female
CVCL_B3WN	WG2113	Finite cell line
CVCL_B3WP	WG2328	Finite cell line
CVCL_B3Y1	WG1713	Finite cell line

Clinical trials (associated diseases)

23 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02426775	PHASE3	COMPLETED	Carglumic Acid in Methylmalonic Acidemia and Propionic Acidemia
NCT07163364	PHASE3	NOT_YET_RECRUITING	A Study to Evaluate the Effects and Safety of Hydroxocobalamin in Participants With Combined Methylmalonic Academia (cblC Type)
NCT01341379	PHASE2	WITHDRAWN	Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate
NCT01597440	PHASE2	TERMINATED	Long-term Outcome of N-Carbamylglutamate Treatment in Propionic Acidemia and Methylmalonic Acidemia
NCT01599286	PHASE2	COMPLETED	Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
NCT04732429	PHASE2	TERMINATED	Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia
NCT04836494	PHASE1	TERMINATED	A First in Human, Dose Escalation Study to Evaluate the Safety and Tolerability of BBP-671 in Healthy Volunteers and Patients With Propionic Acidemia or Methylmalonic Acidemia
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03810690	PHASE1/PHASE2	WITHDRAWN	Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia
NCT04581785	PHASE1/PHASE2	TERMINATED	Gene Therapy With hLB-001 in Pediatric Patients With Severe Methylmalonic Acidemia
NCT04899310	PHASE1/PHASE2	TERMINATED	A Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia
NCT05295433	PHASE1/PHASE2	RECRUITING	An Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in Other Clinical Studies of mRNA-3705
NCT05778877	PHASE1/PHASE2	WITHDRAWN	A Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of SEL-302 in Pediatric Subjects With MMA
NCT00078078	Not specified	RECRUITING	Clinical and Laboratory Study of Methylmalonic Acidemia
NCT01289158	Not specified	UNKNOWN	Combined Malonic and Methylmalonic Aciduria (CMAMMA): Gene Identification and Outcome Study
NCT03484767	Not specified	COMPLETED	The MaP Study: Mapping the Patient Journey in MMA and PA
NCT04176523	Not specified	RECRUITING	Understanding the Long-Term Management of Organic Acidemia Patients With CARBAGLU®: A Mixed Methods Approach
NCT05040178	Not specified	RECRUITING	An Observational Study of Carbaglu® for the Treatment of MMA and PA in Adults and Pediatrics
NCT05330039	Not specified	COMPLETED	Characterization of Intestinal Microbiota in Children With Inborn Errors of Metabolism (IEM)
NCT05438485	Not specified	TERMINATED	Natural History Study of Patients With Methylmalonic Acidemia and Propionic Acidemia
NCT05506254	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Patients Who Received hLB-001 Gene Therapy
NCT06664840	Not specified	NOT_YET_RECRUITING	MyRareDiet A Novel Diet Tracking Tool
NCT07432880	Not specified	NOT_YET_RECRUITING	A Prospective Study of Pediatric Participants up to 16 Years of Age With Methylmalonic Acidemia (MMA) Due to Mutations in the MMUT Gene