MMAA

Summary

MMAA (metabolism of cobalamin associated A, HGNC:18871) is a protein-coding gene on chromosome 4q31.21, encoding Methylmalonic aciduria type A protein, mitochondrial (Q8IVH4). GTPase, binds and hydrolyzes GTP.

The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria.

Source: NCBI Gene 166785 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylmalonic aciduria, cblA type (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 653 total — 59 pathogenic, 60 likely-pathogenic
• Phenotypes (HPO): 33
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_172250

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18871
Approved symbol	MMAA
Name	metabolism of cobalamin associated A
Location	4q31.21
Locus type	gene with protein product
Status	Approved
Aliases	cblA
Ensembl gene	ENSG00000151611
Ensembl biotype	protein_coding
OMIM	607481
Entrez	166785

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000503730, ENST00000504710, ENST00000506919, ENST00000511969, ENST00000541599, ENST00000647947, ENST00000648388, ENST00000648441, ENST00000649156, ENST00000649173, ENST00000649704, ENST00000679563, ENST00000679930, ENST00000868254, ENST00000868255, ENST00000917257, ENST00000945623

RefSeq mRNA: 2 — MANE Select: NM_172250 NM_001375644, NM_172250

CCDS: CCDS3766

Canonical transcript exons

ENST00000649156 — 7 exons

Exon	Start	End
ENSE00001000639	145651062	145651147
ENSE00003538048	145639075	145639578
ENSE00003669947	145642363	145642485
ENSE00003717678	145653994	145654143
ENSE00003746539	145645986	145646156
ENSE00003832437	145619385	145619407
ENSE00003846290	145655147	145660033

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.3805 / max 55.9687, expressed in 1462 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49918	3.3642	1462
49919	0.0163	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.04	gold quality
oocyte	CL:0000023	95.87	gold quality
tibialis anterior	UBERON:0001385	90.99	gold quality
pancreatic ductal cell	CL:0002079	88.40	gold quality
epithelial cell of pancreas	CL:0000083	87.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.49	gold quality
deltoid	UBERON:0001476	87.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.73	gold quality
right lobe of liver	UBERON:0001114	86.38	gold quality
liver	UBERON:0002107	86.22	gold quality
islet of Langerhans	UBERON:0000006	85.66	gold quality
endothelial cell	CL:0000115	85.61	gold quality
buccal mucosa cell	CL:0002336	84.03	gold quality
ileal mucosa	UBERON:0000331	81.80	gold quality
right testis	UBERON:0004534	81.79	gold quality
mucosa of transverse colon	UBERON:0004991	81.64	gold quality
rectum	UBERON:0001052	81.02	gold quality
left testis	UBERON:0004533	80.92	gold quality
biceps brachii	UBERON:0001507	80.46	gold quality
jejunal mucosa	UBERON:0000399	80.15	gold quality
testis	UBERON:0000473	79.84	gold quality
kidney epithelium	UBERON:0004819	79.54	gold quality
adrenal tissue	UBERON:0018303	79.41	gold quality
cortical plate	UBERON:0005343	79.35	gold quality
esophagus squamous epithelium	UBERON:0006920	79.35	gold quality
upper leg skin	UBERON:0004262	79.07	gold quality
pancreas	UBERON:0001264	78.69	gold quality
gastrocnemius	UBERON:0001388	78.66	gold quality
monocyte	CL:0000576	78.57	gold quality
adult mammalian kidney	UBERON:0000082	78.56	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.06

Regulation

Is transcription factor: no

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 12)

• A candidate gene for mutations (deletion, insertion, stop-codon, missense)in cblA patient cells was identified as MMAA on chromosome 4q31.1-2. It encodes a predicted protein of 418 AA. (PMID:12438653)
• The 503delC mutation is prevalent in Japanese patients with methylmalonic acidemia. (PMID:15308131)
• DNA from 37 cblA patients was analyzed for deleterious mutations in the MMAA gene by DNA sequencing of exons and flanking sequences (PMID:15523652)
• Long-term outcome in methylmalonic acidurias is influenced by the underlying genetic defects in MCM/MMAA/MMAB. (PMID:17597648)
• Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. (PMID:17957493)
• Spondylocostal dysostosis associated with MMAA is presented in a young boy. (PMID:19371216)
• 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)
• Ten novel mutational MMAA variants have been identified in patients with methylmalonic aciduria. (PMID:23026888)
• A novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic academia was identified. The deletion in exon 4 of the MMAA gene (c.674 delA) is a pathogenic allele via a nucleotide frame shift resulting in a stop codon and termination of protein synthesis 38 nucleotides (12 amino acids) downstream of the deletion. (PMID:28536607)
• localization of hMMAA and its colocalization with hMCM in human (PMID:28943303)
• The two siblings were associated with the MMAA c.365T>C variant. (PMID:29996803)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmaa	ENSDARG00000060383
mus_musculus	Mmaa	ENSMUSG00000037022
rattus_norvegicus	Mmaa	ENSRNOG00000011618
caenorhabditis_elegans		WBGENE00020169

Paralogs (1): MMUT (ENSG00000146085)

Protein

Protein identifiers

Methylmalonic aciduria type A protein, mitochondrial — Q8IVH4 (reviewed: Q8IVH4)

All UniProt accessions (6): Q8IVH4, A0A3B3IRG3, A0A3B3ITP4, A0A7P0TAV9, D6RIS5, Q495G5

UniProt curated annotations — full annotation on UniProt →

Function. GTPase, binds and hydrolyzes GTP. Involved in intracellular vitamin B12 metabolism, mediates the transport of cobalamin (Cbl) into mitochondria for the final steps of adenosylcobalamin (AdoCbl) synthesis. Functions as a G-protein chaperone that assists AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase (MMUT). Plays a dual role as both a protectase and a reactivase for MMUT. Protects MMUT from progressive inactivation by oxidation by decreasing the rate of the formation of the oxidized inactive cofactor hydroxocobalamin (OH2Cbl). Additionally acts a reactivase by promoting the replacement of OH2Cbl by the active cofactor AdoCbl, restoring the activity of MMUT in the presence and hydrolysis of GTP.

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

Subcellular location. Mitochondrion. Cytoplasm.

Tissue specificity. Widely expressed. Highest expression is observed in liver and skeletal muscle.

Disease relevance. Methylmalonic aciduria, cblA type (MACA) [MIM:251100] An autosomal recessive disorder of methylmalonate and cobalamin metabolism due to defective synthesis of adenosylcobalamin. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. GTPase activity is stimulated by MMUT.

Similarity. Belongs to the SIMIBI class G3E GTPase family. ArgK/MeaB subfamily.

RefSeq proteins (2): NP_001362573, NP_758454* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005129	GTPase_ArgK	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF03308

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (74 total): sequence variant 39, helix 13, strand 11, turn 4, binding site 3, mutagenesis site 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2WWW	X-RAY DIFFRACTION	2.64
8GJU	X-RAY DIFFRACTION	2.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVH4-F1	78.71	0.58

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 (3): 150–158; 292; 328–330

Mutagenesis-validated functional residues (2):

Position	Phenotype
290	abolishes binding to gtp and gtpase activity; when associated with a-292.
292	abolishes binding to gtp and gtpase activity; when associated with a-290.

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: 174 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_COBALAMIN_METABOLIC_PROCESS, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, REACTOME_MITOCHONDRIAL_FATTY_ACID_BETA_OXIDATION, BASAKI_YBX1_TARGETS_DN, GOCC_MITOCHONDRIAL_MATRIX, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, GOMF_GTPASE_ACTIVITY, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, REACTOME_METABOLISM_OF_VITAMINS_AND_COFACTORS, MATSUDA_NATURAL_KILLER_DIFFERENTIATION, TCANNTGAY_SREBP1_01, DELACROIX_RARG_BOUND_MEF

GO Biological Process (2): cobalamin metabolic process (GO:0009235), succinyl-CoA biosynthetic process (GO:1901290)

GO Molecular Function (8): GTPase activity (GO:0003924), GTP binding (GO:0005525), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), molecular carrier activity (GO:0140104), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

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
binding	2
cellular anatomical structure	2
cytoplasm	2
tetrapyrrole metabolic process	1
succinyl-CoA metabolic process	1
acyl-CoA biosynthetic process	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMAA	MMAB	Q96EY8	990
MMAA	MMADHC	Q9H3L0	983
MMAA	LMBRD1	Q9NUN5	975
MMAA	MMUT	P22033	968
MMAA	MMACHC	Q9Y4U1	947
MMAA	MCEE	Q96PE7	911
MMAA	MTR	Q99707	883
MMAA	MTRR	Q9UBK8	883
MMAA	CD320	Q9NPF0	875
MMAA	CBL	P22681	851
MMAA	SPR	P35270	649
MMAA	KRT13	P13646	633
MMAA	PCCB	P05166	618
MMAA	ABCD4	O14678	571
MMAA	PCCA	P05165	504

IntAct

19 interactions, top by confidence:

A	B	Type	Score
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
	MMAA	psi-mi:“MI:0883”(gtpase reaction)	0.620
	MMUT	psi-mi:“MI:0883”(gtpase reaction)	0.610
	MMAA	psi-mi:“MI:0407”(direct interaction)	0.610
MMAA	MMAA	psi-mi:“MI:0407”(direct interaction)	0.560
	MMAA	psi-mi:“MI:0407”(direct interaction)	0.440
MMAA	H1-1	psi-mi:“MI:0915”(physical association)	0.400
	MMUT	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
GIGYF1	DYNC1I1	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): MMAA (Synthetic Lethality), MMAA (Proximity Label-MS), MMAA (Affinity Capture-MS), MMAA (Affinity Capture-MS), MMAA (Affinity Capture-MS), MMAA (Affinity Capture-MS), MMAA (Co-crystal Structure), MMAA (Reconstituted Complex), MUT (Reconstituted Complex), MUT (Affinity Capture-Western)

ESM2 similar proteins: A0FKE6, A2YQ56, A5GUB0, A7F582, A8XGZ9, C4QXA5, F4JYE9, K3VH30, O13861, O14172, O22436, O42644, O49472, O50046, O80842, O82497, O82626, P16127, P25306, P54886, P93648, Q0WW55, Q22111, Q40545, Q40546, Q43117, Q5R4M8, Q5XF33, Q5XF80, Q69UZ3, Q6NKX1, Q84MA1, Q84W56, Q8BH55, Q8C7H1, Q8H1F6, Q8IVH4, Q8L607, Q8LEA0, Q8TGA0

Diamond homologs: A4YF54, A8XGZ9, O58012, P27254, P37895, P63578, P9WPZ0, P9WPZ1, Q05072, Q22111, Q5KUG0, Q5MFW3, Q8C7H1, Q8IVH4, Q9V225, O28980, Q146L7, Q1LRY0, Q5Z110, A0RUR8, A4T7D7, B1M9D7, A7IQE5, I3VE74, I3VE77, O86028, P11653, P16332, P22033, P27253, P65488, P9WJK4, P9WJK5, Q05065, Q23381, Q3J4D7, Q59677, Q5RFN2, Q8HXX1, Q8MI68

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	60
Uncertain significance	246
Likely benign	204
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1350506	NM_172250.3(MMAA):c.898C>T (p.Arg300Ter)	Pathogenic
1374022	NM_172250.3(MMAA):c.127_134dup (p.Ser46fs)	Pathogenic
1450413	NM_172250.3(MMAA):c.468dup (p.Ser157fs)	Pathogenic
1455574	NM_172250.3(MMAA):c.795_796dup (p.Pro266fs)	Pathogenic
1459643	NC_000004.11:g.(?146575136)(146576596_?)del	Pathogenic
1950525	NM_172250.3(MMAA):c.443T>A (p.Leu148Ter)	Pathogenic
1954560	NM_172250.3(MMAA):c.1117G>T (p.Glu373Ter)	Pathogenic
1975237	NM_172250.3(MMAA):c.1216_1229GCA[2]GACTTCTTTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGCAGCAGACTTCTT[1] (p.Leu410delinsPhePhePhePhePhePhePheXaaXaaXaaXaaIleArgProProArgProProLysValLeuGlyLeuGlnAlaTer)	Pathogenic
1999235	NM_172250.3(MMAA):c.170del (p.Leu57fs)	Pathogenic
2003201	NM_172250.3(MMAA):c.940del (p.Arg314fs)	Pathogenic
2025789	NM_172250.3(MMAA):c.817C>T (p.Gln273Ter)	Pathogenic
203814	NM_172250.3(MMAA):c.387C>A (p.Tyr129Ter)	Pathogenic
203815	NM_172250.3(MMAA):c.593_596del (p.Thr198fs)	Pathogenic
203816	NM_172250.3(MMAA):c.988C>T (p.Arg330Ter)	Pathogenic
2044227	NM_172250.3(MMAA):c.713_714del (p.Ile238fs)	Pathogenic
2057282	NM_172250.3(MMAA):c.184_185del (p.Lys62fs)	Pathogenic
218969	NM_172250.3(MMAA):c.64C>T (p.Arg22Ter)	Pathogenic
218970	NM_172250.3(MMAA):c.161G>A (p.Trp54Ter)	Pathogenic
218972	NM_172250.3(MMAA):c.358C>T (p.Gln120Ter)	Pathogenic
218973	NM_172250.3(MMAA):c.397C>T (p.Gln133Ter)	Pathogenic
218974	NM_172250.3(MMAA):c.503del (p.Thr168fs)	Pathogenic
218976	NM_172250.3(MMAA):c.650T>A (p.Leu217Ter)	Pathogenic
225189	NM_172250.3(MMAA):c.1025T>G (p.Met342Arg)	Pathogenic
2676600	NM_172250.3(MMAA):c.54del (p.Ala19fs)	Pathogenic
2676607	NM_172250.3(MMAA):c.260_267dup (p.Tyr90fs)	Pathogenic
2734674	NM_172250.3(MMAA):c.388del (p.His130fs)	Pathogenic
2764322	NM_172250.3(MMAA):c.1124del (p.Val375fs)	Pathogenic
2828093	NM_172250.3(MMAA):c.386dup (p.Tyr129Ter)	Pathogenic
2849547	NM_172250.3(MMAA):c.325G>T (p.Glu109Ter)	Pathogenic
2859780	NM_172250.3(MMAA):c.851del (p.Asp284fs)	Pathogenic

SpliceAI

1550 predictions. Top by Δscore:

Variant	Effect	Δscore
4:145653989:TTTA:T	acceptor_loss	1.0000
4:145653991:TAG:T	acceptor_loss	1.0000
4:145653992:A:AG	acceptor_gain	1.0000
4:145653992:AG:A	acceptor_gain	1.0000
4:145653993:G:GT	acceptor_gain	1.0000
4:145653993:GG:G	acceptor_gain	1.0000
4:145653993:GGGT:G	acceptor_gain	1.0000
4:145654144:G:GC	donor_loss	1.0000
4:145654144:G:GG	donor_gain	1.0000
4:145654145:T:G	donor_loss	1.0000
4:145655267:A:T	donor_gain	1.0000
4:145655294:G:GT	donor_gain	1.0000
4:145655295:A:T	donor_gain	1.0000
4:145619403:GGCGG:G	donor_gain	0.9900
4:145619404:GCGG:G	donor_gain	0.9900
4:145619404:GCGGG:G	donor_gain	0.9900
4:145642333:ATT:A	acceptor_gain	0.9900
4:145644195:A:T	donor_gain	0.9900
4:145645984:AG:A	acceptor_gain	0.9900
4:145645985:GG:G	acceptor_gain	0.9900
4:145645985:GGA:G	acceptor_gain	0.9900
4:145645985:GGAT:G	acceptor_gain	0.9900
4:145645985:GGATC:G	acceptor_gain	0.9900
4:145646153:GTTG:G	donor_gain	0.9900
4:145646156:GGT:G	donor_loss	0.9900
4:145646157:G:GA	donor_loss	0.9900
4:145646158:T:G	donor_loss	0.9900
4:145646159:GA:G	donor_loss	0.9900
4:145646160:A:AT	donor_loss	0.9900
4:145653982:T:TA	acceptor_gain	0.9900

AlphaMissense

2687 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:145646000:G:C	D193H	0.998
4:145646001:A:C	D193A	0.998
4:145646013:T:C	M197T	0.998
4:145646049:G:C	R209T	0.998
4:145654001:A:T	K276I	0.998
4:145654002:A:C	K276N	0.998
4:145654002:A:T	K276N	0.998
4:145642371:G:T	G150W	0.997
4:145642372:G:A	G150E	0.997
4:145646001:A:T	D193V	0.997
4:145646010:G:C	R196P	0.997
4:145646049:G:T	R209M	0.997
4:145646156:G:C	G245R	0.997
4:145642387:G:A	G155E	0.996
4:145642390:A:T	K156I	0.996
4:145642456:C:A	A178D	0.996
4:145642462:A:G	D180G	0.996
4:145645998:G:A	G192D	0.996
4:145646001:A:G	D193G	0.996
4:145651062:G:A	G245D	0.996
4:145642392:T:C	S157P	0.995
4:145646002:T:A	D193E	0.995
4:145646002:T:G	D193E	0.995
4:145646005:A:C	K194N	0.995
4:145646005:A:T	K194N	0.995
4:145646013:T:G	M197R	0.995
4:145646014:G:A	M197I	0.995
4:145646014:G:C	M197I	0.995
4:145646014:G:T	M197I	0.995
4:145651086:T:A	V253D	0.995

dbSNP variants (sampled 300 via entrez): RS1000037172 (4:145658444 ATG>A), RS1000174508 (4:145655664 A>G), RS1000226779 (4:145622649 A>C), RS1000264801 (4:145648027 T>G), RS1000319683 (4:145649386 C>T), RS1000419059 (4:145654886 ATAAAT>A), RS1000456413 (4:145642185 A>G,T), RS1000496096 (4:145619940 T>C), RS1000798304 (4:145619700 A>G), RS1000850210 (4:145637254 T>A,C), RS1000882062 (4:145655448 G>A), RS1000893058 (4:145633866 C>T), RS10009151 (4:145644478 C>G), RS1001116618 (4:145620729 T>A), RS1001133765 (4:145659957 T>A,C)

Disease associations

OMIM: gene MIM:607481 | disease phenotypes: MIM:251100, MIM:251000, MIM:251110, MIM:116200

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonic aciduria, cblA type	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
methylmalonic aciduria, cblA type	Definitive	AR

Mondo (5): methylmalonic aciduria, cblA type (MONDO:0009613), methylmalonic acidemia (MONDO:0002012), methylmalonic aciduria, cblB type (MONDO:0009614), microcephaly (MONDO:0001149), cataract (MONDO:0005129)

Orphanet (3): Vitamin B12-responsive methylmalonic acidemia (Orphanet:28), Vitamin B12-responsive methylmalonic acidemia type cblA (Orphanet:79310), Vitamin B12-responsive methylmalonic acidemia type cblB (Orphanet:79311)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001337	Tremor
HP:0001348	Brisk reflexes
HP:0001508	Failure to thrive
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0001946	Ketosis
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002098	Respiratory distress
HP:0002154	Hyperglycinemia
HP:0002240	Hepatomegaly
HP:0002912	Methylmalonic acidemia
HP:0002919	Ketonuria
HP:0003145	Decreased circulating adenosylcobalamin concentration
HP:0003210	Decreased methylmalonyl-CoA mutase activity
HP:0003593	Infantile onset
HP:0008872	Feeding difficulties in infancy
HP:0012120	Methylmalonic aciduria
HP:0031962	Elevated serum anion gap

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003469_6	Response to cognitive-behavioural therapy in anxiety disorder	5.000000e-06
GCST010725_4	Malaria	4.000000e-10
GCST010725_84	Malaria	7.000000e-11
GCST010725_89	Malaria	7.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, affects expression	4
entinostat	decreases expression, affects cotreatment	2
Cisplatin	decreases expression, increases expression	2
Nickel	increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3UL	WG2664	Finite cell line
CVCL_RG94	WG1761	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00312299	PHASE4	COMPLETED	Posterior Capsule Opacification Study
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00347243	PHASE4	COMPLETED	Wavefront Analisys and Contrast Sensitivity of Spherical and Aspherical Intraocular Lenses
NCT00347503	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients
NCT00348244	PHASE4	COMPLETED	Ketorolac vs. Steroid in the Prevention of CME
NCT00348270	PHASE4	COMPLETED	Comparison of the Quality of Vision Provided by AMO Tecnis Z9000 and Alcon Laboratories MA60 Acrysof Posterior Chamber Intraocular Lenses
NCT00348582	PHASE4	COMPLETED	Acular LS vs. Nevanac in Post op Inflammation Following Cataract Surgery
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT00349583	PHASE4	COMPLETED	Efficacy of Topical Cyclosporine Versus Tears for Improving Visual Outcomes Following Multifocal IOL Implantation
NCT00355446	PHASE4	COMPLETED	Bioavailability of Bimatoprost Ophthalmic Solution in Human Aqueous.
NCT00386438	PHASE4	COMPLETED	Efficacy of Honan Balloon in Intraocular Pressure Reduction Before Phacoemulsification
NCT00392275	PHASE4	COMPLETED	Penetrance of Third Generation Fluoroquinolones in Eyes With Functioning Filtering Blebs
NCT00428363	PHASE4	COMPLETED	Effect of Optic Edge Design in a Silicone Intraocular Lens on Posterior Capsule Opacification
NCT00449267	PHASE4	COMPLETED	Aurolab Hydrophobic Foldable Intraocular Lens Study
NCT00459303	PHASE4	COMPLETED	Comparison of Functional Vision Provided by AMO Tecnis Z9000 and Alcon SA60AT Acrysof
NCT00469690	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients: Trough Drug Effects
NCT00576485	PHASE4	COMPLETED	Spherical Aberration and Contrast Sensitivity in IOLs
NCT00612729	PHASE4	COMPLETED	Light Filters in Intraocular Lenses (IOLs) and Its Influence on Colour and Contrast Vision.
NCT00612781	PHASE4	COMPLETED	Yellow Versus White Study
NCT00630019	PHASE4	COMPLETED	Ocular Tissue Levels of 1.5% Levofloxacin Ophthalmic Solution Compared to an Active Comparator
NCT00673803	PHASE4	COMPLETED	Influence of Two Different Preloaded Intraocular Lens (IOLs) on Posterior Capsule Opacification
NCT00684138	PHASE4	COMPLETED	ACRYSOF® ReSTOR® Aspheric +3.0 D Add Power Intraocular Lens (IOL)
NCT00698724	PHASE4	COMPLETED	Comparing Optical Coherence Tomography (OCT) and Visual Acuity Outcomes in Subjects Undergoing Cataract Surgery, Who Receive Xibrom Ophthalmic Solution and Standard Presurgical Care vs. Xibrom Ophthalmic Solution Plus Prednisolone Acetate 1% and Standard Presurgical Care
NCT00710905	PHASE4	TERMINATED	Visual Function With Contralateral AcrySof® ReSTOR® Aspheric SN6AD1 and SN6AD3
NCT00710931	PHASE4	COMPLETED	Visual Function With Bilateral AcrySof® ReSTOR® Aspheric SN6AD1
NCT00711347	PHASE4	COMPLETED	Intraoperative Floppy Iris Syndrome
NCT00712244	PHASE4	COMPLETED	DisCoVisc Versus DuoVisc, Healon5 and AmVisc Plus
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00719732	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof ReSTOR Aspheric +3
NCT00721253	PHASE4	COMPLETED	Visual Outcomes of Subjects Bilaterally Implanted With ReSTOR Aspheric +4 vs. Tecnis or Acri.LISA
NCT00731640	PHASE4	COMPLETED	Contralateral ReSTOR / Monofocal or Phakic Eye
NCT00732030	PHASE4	COMPLETED	Low Cylinder Toric
NCT00758199	PHASE4	COMPLETED	Determination of Optimum Duration of Treatment With Bromfenac (Xibrom) Eyedrops Following Cataract Surgery
NCT00760058	PHASE4	WITHDRAWN	Visual Outcome and Visual Quality After Bilateral Implantation of the AcrySof® IQ IOL Compared to MI60® and Tecnis® IOL
NCT00760487	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof® Toric Natural Intraocular Lens
NCT00761488	PHASE4	WITHDRAWN	Recommendations for Monitoring Clinical Experience Following Implantation of the AcrySof® Toric
NCT00763360	PHASE4	COMPLETED	To Compare the Ability of DiscoVisc® OVD to Protect the Corneal Endothelium and Maintain Anterior Chamber Space With Healon® and Amvisc® PLUS During Cataract Surgery.
NCT00786370	PHASE4	COMPLETED	Dexmedetomidine vs. Propofol for Cataract Surgery
NCT00786565	PHASE4	COMPLETED	Clinical Evaluation of a New Aspheric Intraocular Lens.