MMAB

Summary

MMAB (metabolism of cobalamin associated B, HGNC:19331) is a protein-coding gene on chromosome 12q24.11, encoding Corrinoid adenosyltransferase MMAB (Q96EY8). Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion.

This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found.

Source: NCBI Gene 326625 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylmalonic aciduria, cblB type (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 40
• Clinical variants (ClinVar): 769 total — 55 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_052845

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19331
Approved symbol	MMAB
Name	metabolism of cobalamin associated B
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	cblB, CFAP23
Ensembl gene	ENSG00000139428
Ensembl biotype	protein_coding
OMIM	607568
Entrez	326625

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 nonsense_mediated_decay, 5 protein_coding, 2 retained_intron

ENST00000420167, ENST00000503497, ENST00000536760, ENST00000537236, ENST00000537496, ENST00000540016, ENST00000541763, ENST00000542390, ENST00000544051, ENST00000545712, ENST00000878519, ENST00000878520

RefSeq mRNA: 1 — MANE Select: NM_052845 NM_052845

CCDS: CCDS9131

Canonical transcript exons

ENST00000545712 — 9 exons

Exon	Start	End
ENSE00002267773	109553715	109557136
ENSE00003481491	109561420	109561517
ENSE00003541962	109568770	109568863
ENSE00003546036	109561780	109561852
ENSE00003583295	109571649	109571710
ENSE00003587859	109573347	109573504
ENSE00003671438	109559096	109559155
ENSE00003672319	109561040	109561104
ENSE00003688708	109565119	109565176

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 97.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.4007 / max 250.7676, expressed in 1802 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133194	25.4007	1802

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.41	gold quality
right adrenal gland cortex	UBERON:0035827	97.11	gold quality
right adrenal gland	UBERON:0001233	96.82	gold quality
left adrenal gland	UBERON:0001234	96.06	gold quality
left adrenal gland cortex	UBERON:0035825	95.99	gold quality
adrenal tissue	UBERON:0018303	95.21	gold quality
adrenal gland	UBERON:0002369	95.05	gold quality
adrenal cortex	UBERON:0001235	94.83	gold quality
apex of heart	UBERON:0002098	94.71	gold quality
liver	UBERON:0002107	94.57	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.45	gold quality
pancreatic ductal cell	CL:0002079	94.26	silver quality
mucosa of transverse colon	UBERON:0004991	94.25	gold quality
lower esophagus mucosa	UBERON:0035834	93.04	gold quality
esophagus mucosa	UBERON:0002469	92.87	gold quality
right atrium auricular region	UBERON:0006631	92.56	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.25	gold quality
left lobe of thyroid gland	UBERON:0001120	92.22	gold quality
heart left ventricle	UBERON:0002084	92.18	gold quality
right lobe of thyroid gland	UBERON:0001119	92.13	gold quality
spinal cord	UBERON:0002240	92.10	gold quality
body of pancreas	UBERON:0001150	92.05	gold quality
cardiac atrium	UBERON:0002081	91.77	gold quality
cardiac ventricle	UBERON:0002082	91.71	gold quality
endothelial cell	CL:0000115	91.60	gold quality
adenohypophysis	UBERON:0002196	91.53	gold quality
adult mammalian kidney	UBERON:0000082	91.45	gold quality
ventricular zone	UBERON:0003053	91.45	gold quality
thyroid gland	UBERON:0002046	91.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

142 targeting MMAB, 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-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-605-3P	99.88	69.22	1833

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 17)

• report the identification of ATR cDNA as well as the corresponding gene; ATR expression is altered in cell lines derived from cblB methylmalonyl aciduria patients; propose that inborn errors in the ATR gene identified here result in methylmalonyl aciduria (PMID:12514191)
• Results describe two common polymorphic variants of ATP:cob(I)alamin adenosyltransferase that are found in normal individuals, and their interactions with methionine synthase reductase. (PMID:15347655)
• Mutations in methylmalonic aciduria type B protein is associated with methylmalonic acidemia (PMID:17410422)
• 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)
• Results functionally defined the hATR active site and tentatively implicated three amino acid residues in facilitating the reduction of cob(II)alamin to cob(I)alamin which is a prerequisite to adenosylation. (PMID:18251506)
• homozygotes for the major allele (G) at MMAB_3U3527G–>C had higher LDL-cholesterol concentrations than did carriers of the minor allele (P = 0.034). (PMID:19605566)
• Characterization of ligand-binding by MMAB provides insight into the mechanism of cobalamin adenosylation and the effect of patient mutations in the inherited disorder (PMID:19625202)
• These data suggest MMAB is the most likely gene influencing high-density lipoprotein-cholesterol levels at MMAB-MVK locus. (PMID:20159775)
• c.584G>A, c.349-1G>C, and c.290G>A mutations affect the splicing process of ATR. (PMID:20556797)
• Pathogenicity of the human truncation mutant results from its inability to sequester AdoCbl for direct transfer to methylmalonyl-CoA mutase, resulting in holoenzyme formation. (PMID:21604717)
• MMAB mutations, including one novel nonsense mutation (c.12 C>A [p.C4X]), were identified in all members of the cblB cohort. (PMID:23707710)
• These findings suggest that rs11066782 in KCTD10, rs11613718 in KCTD10 and rs11067233 in MMAB may contribute to the susceptibility of coronary heart disease by altering plasma HDL-C levels in Han Chinese. (PMID:27716295)
• MMAB might be a target and potential biomarker of hepatotoxicity in EFV-induced liver toxicity (PMID:29190729)
• analysis of how molecular chaperones interact with ATR in methylmalonic aciduria cblB type (PMID:29197662)
• A genetic epidemiological study in British adults and older adults shows a high heritability of the combined indicator of vitamin B12 status (cB12) and connects B12 status with utilization of mitochondrial substrates and energy metabolism. (PMID:31203192)
• MMAB promotes negative feedback control of cholesterol homeostasis. (PMID:34750386)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmab	ENSDARG00000068344
mus_musculus	Mmab	ENSMUSG00000029575
rattus_norvegicus	Mmab	ENSRNOG00000049426
caenorhabditis_elegans		WBGENE00016144

Protein

Protein identifiers

Corrinoid adenosyltransferase MMAB — Q96EY8 (reviewed: Q96EY8)

Alternative names: ATP:co(I)rrinoid adenosyltransferase MMAB, Methylmalonic aciduria type B protein

All UniProt accessions (7): Q96EY8, A0A087X114, F5H079, F5H0C1, F5H4Z7, S4R3P5, S4R3Z1

UniProt curated annotations — full annotation on UniProt →

Function. Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion. Generates adenosylcobalamin (AdoCbl) and directly delivers the cofactor to MUT in a transfer that is stimulated by ATP-binding to MMAB and gated by MMAA.

Subunit / interactions. Homotrimer.

Subcellular location. Mitochondrion.

Tissue specificity. Expressed in liver and skeletal muscle.

Disease relevance. Methylmalonic aciduria, cblB type (MACB) [MIM:251110] 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.

Similarity. Belongs to the Cob(I)alamin adenosyltransferase family.

RefSeq proteins (1): NP_443077* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016030	CblAdoTrfase-like	Domain
IPR029499	PduO-typ	Family
IPR036451	CblAdoTrfase-like_sf	Homologous_superfamily

Pfam: PF01923

Enzyme classification (BRENDA):

• EC 2.5.1.17 — corrinoid adenosyltransferase (BRENDA: 19 organisms, 110 substrates, 35 inhibitors, 133 Km, 193 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0003–1.3	59
COB(I)ALAMIN	0.0001–0.06	46
COB(II)ALAMIN	0.0078–0.134	7
CYANOCOB(I)ALAMIN	0.01	2
HYDROXOCOBALAMIN	0.003–0.004	2
2’-DEOXY-ATP	0.0016	1
COB(I)INAMIDE	0.0001	1
COB(II)INAMIDE	0.0163	1
CTP	22	1
DATP	0.14	1
GTP	1.16	1
ITP	29	1
UTP	40	1

Catalyzed reactions (Rhea), 1 shown:

• cob(I)alamin-[corrinoid adenosyltransferase] + ATP = apo-[corrinoid adenosyltransferase] + adenosylcob(III)alamin + triphosphate (RHEA:56796)

UniProt features (30 total): sequence variant 8, helix 6, binding site 5, modified residue 4, turn 2, strand 2, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7RUT	X-RAY DIFFRACTION	1.5
7RUU	X-RAY DIFFRACTION	1.85
7RUV	X-RAY DIFFRACTION	2.1
6D5X	X-RAY DIFFRACTION	2.4
2IDX	X-RAY DIFFRACTION	2.5
6D5K	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EY8-F1	82.39	0.67

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 (5): 60–63; 68–69; 78; 190–194; 214

Post-translational modifications (4): 230, 230, 134, 211

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-3359471	Defective MMAB causes MMA, cblB type
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-5668914	Diseases of metabolism

MSigDB gene sets: 688 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, KOBAYASHI_EGFR_SIGNALING_24HR_UP, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT

GO Biological Process (1): cobalamin metabolic process (GO:0009235)

GO Molecular Function (7): ATP binding (GO:0005524), corrinoid adenosyltransferase activity (GO:0008817), transferase activity, transferring alkyl or aryl (other than methyl) groups (GO:0016765), cobalamin binding (GO:0031419), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Defects in cobalamin (B12) metabolism	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1
Defects in vitamin and cofactor metabolism	1
Diseases of metabolism	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heterocyclic compound binding	2
tetrapyrrole metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
transferase activity	1
vitamin binding	1
tetrapyrrole binding	1
nucleoside phosphate binding	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

904 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMAB	MMAA	Q8IVH4	990
MMAB	MMADHC	Q9H3L0	977
MMAB	MMUT	P22033	973
MMAB	LMBRD1	Q9NUN5	955
MMAB	MMACHC	Q9Y4U1	947
MMAB	MTRR	Q9UBK8	864
MMAB	CD320	Q9NPF0	845
MMAB	MTR	Q99707	831
MMAB	CBL	P22681	828
MMAB	MCEE	Q96PE7	794
MMAB	PCCB	P05166	691
MMAB	MVK	Q03426	675
MMAB	GALNT2	Q10471	643
MMAB	ACSF3	Q4G176	624
MMAB	ABCD4	O14678	622

IntAct

68 interactions, top by confidence:

A	B	Type	Score
PSMG2	PSMG1	psi-mi:“MI:0914”(association)	0.850
MRRF	DBT	psi-mi:“MI:0914”(association)	0.620
MMAB	DBT	psi-mi:“MI:0915”(physical association)	0.620
MMAB	DBT	psi-mi:“MI:0914”(association)	0.620
MMAB	CBY2	psi-mi:“MI:0915”(physical association)	0.560
CALR	MMAB	psi-mi:“MI:0915”(physical association)	0.560
DLST	MMAB	psi-mi:“MI:0915”(physical association)	0.560
OPTN	MMAB	psi-mi:“MI:0915”(physical association)	0.560
MMAB	NEK7	psi-mi:“MI:0915”(physical association)	0.560
NUDT6	DENR	psi-mi:“MI:0914”(association)	0.530
CDK5R1	DENR	psi-mi:“MI:0914”(association)	0.530
FDPS	ZMPSTE24	psi-mi:“MI:0914”(association)	0.530
MMAB	PMPCB	psi-mi:“MI:0914”(association)	0.530
NS1	PIK3R2	psi-mi:“MI:0914”(association)	0.530
NS1	SAC3D1	psi-mi:“MI:0914”(association)	0.350

BioGRID (149): MMAB (Two-hybrid), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Co-fractionation), MMAB (Affinity Capture-MS), SPERT (Two-hybrid), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS), MMAB (Affinity Capture-MS)

ESM2 similar proteins: A1BD33, A1KV07, A1US81, A1VDQ5, A4SF07, A4SGJ6, A4WEU0, A5EXU4, A7MYX3, A7RF00, A9IS21, A9IVY8, A9M186, B0VEG5, B1VB74, B2GKK6, B2UKT4, B2UKT9, B3LFA4, B3M098, B4K8A4, B8DKL0, O34899, P45515, P53523, P64370, P64371, P64804, P9WP98, P9WP99, Q1LJ80, Q2LPW5, Q30ZH8, Q39VQ6, Q3B1I7, Q3B6D2, Q469F5, Q58D49, Q5F7D6, Q5HZE4

Diamond homologs: B1VB74, O34899, P0DX96, P45515, P45517, P53523, P64804, P9WP98, P9WP99, Q1LJ80, Q58D49, Q8ZNR5, Q96EY8, Q9D273

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	44
Uncertain significance	268
Likely benign	225
Benign	69

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068489	NM_052845.4(MMAB):c.220G>T (p.Glu74Ter)	Pathogenic
1173988	NM_052845.4(MMAB):c.23del (p.Ser8fs)	Pathogenic
1173989	NM_052845.4(MMAB):c.87T>A (p.Tyr29Ter)	Pathogenic
1173990	NM_052845.4(MMAB):c.135-1G>A	Pathogenic
1173991	NM_052845.4(MMAB):c.291-1G>T	Pathogenic
1173992	NM_052845.4(MMAB):c.348+2_348+3del	Pathogenic
1173993	NM_052845.4(MMAB):c.367del (p.Asp123fs)	Pathogenic
1173996	NM_052845.4(MMAB):c.462G>T (p.Glu154Asp)	Pathogenic
1173997	NM_052845.4(MMAB):c.487C>T (p.Gln163Ter)	Pathogenic
1173998	NM_052845.4(MMAB):c.558_559delinsC (p.Ala187fs)	Pathogenic
1173999	NM_052845.4(MMAB):c.560_561insGGCACGGGC (p.Ala187_Val188insAlaArgAla)	Pathogenic
1174000	NM_052845.4(MMAB):c.581_582dup (p.Arg195fs)	Pathogenic
1174001	NM_052845.4(MMAB):c.650G>T (p.Ser217Ile)	Pathogenic
1174002	NM_052845.4(MMAB):c.656_659del (p.Tyr219fs)	Pathogenic
1399066	NM_052845.4(MMAB):c.330del (p.Phe110fs)	Pathogenic
1402961	NM_052845.4(MMAB):c.467G>A (p.Trp156Ter)	Pathogenic
1434079	NM_052845.4(MMAB):c.61dup (p.Cys21fs)	Pathogenic
1451421	NM_052845.4(MMAB):c.523G>T (p.Gly175Ter)	Pathogenic
1453900	NM_052845.4(MMAB):c.460G>T (p.Glu154Ter)	Pathogenic
1454399	NM_052845.4(MMAB):c.638T>G (p.Leu213Ter)	Pathogenic
1454464	NM_052845.4(MMAB):c.197-1G>A	Pathogenic
1979899	NM_052845.4(MMAB):c.649dup (p.Ser217fs)	Pathogenic
2020905	NM_052845.4(MMAB):c.546_555dup (p.Arg186fs)	Pathogenic
2025769	NM_052845.4(MMAB):c.545_570del (p.Leu182fs)	Pathogenic
203819	NM_052845.4(MMAB):c.569G>A (p.Arg190His)	Pathogenic
203820	NM_052845.4(MMAB):c.700C>T (p.Gln234Ter)	Pathogenic
2121959	NM_052845.4(MMAB):c.266del (p.Thr89fs)	Pathogenic
217750	NM_000431.2(MVK):c.-1880_527+533del	Pathogenic
218324	NM_052845.4(MMAB):c.571C>T (p.Arg191Trp)	Pathogenic
219004	NM_052845.4(MMAB):c.291-1G>A	Pathogenic

SpliceAI

1443 predictions. Top by Δscore:

Variant	Effect	Δscore
12:109559154:CA:C	acceptor_gain	1.0000
12:109559156:C:CC	acceptor_gain	1.0000
12:109561034:TCTTA:T	donor_loss	1.0000
12:109561035:CTTAC:C	donor_loss	1.0000
12:109561036:TTAC:T	donor_loss	1.0000
12:109561037:TA:T	donor_loss	1.0000
12:109561038:A:AC	donor_gain	1.0000
12:109561038:A:T	donor_loss	1.0000
12:109561039:C:CC	donor_gain	1.0000
12:109561039:CCGT:C	donor_gain	1.0000
12:109561100:CCCGA:C	acceptor_gain	1.0000
12:109561101:CCGA:C	acceptor_gain	1.0000
12:109561101:CCGAC:C	acceptor_gain	1.0000
12:109561102:CGA:C	acceptor_gain	1.0000
12:109561102:CGAC:C	acceptor_gain	1.0000
12:109561105:C:CC	acceptor_gain	1.0000
12:109561418:A:AC	donor_gain	1.0000
12:109561419:C:CC	donor_gain	1.0000
12:109561419:CAGG:C	donor_gain	1.0000
12:109561514:TACT:T	acceptor_gain	1.0000
12:109561518:C:CC	acceptor_gain	1.0000
12:109561527:C:CT	acceptor_gain	1.0000
12:109561527:C:T	acceptor_gain	1.0000
12:109561528:A:T	acceptor_gain	1.0000
12:109561778:A:AC	donor_gain	1.0000
12:109561779:C:CC	donor_gain	1.0000
12:109561782:A:AC	donor_gain	1.0000
12:109561783:A:C	donor_gain	1.0000
12:109559091:AGTAC:A	donor_loss	0.9900
12:109559092:GTA:G	donor_loss	0.9900

AlphaMissense

1610 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:109561429:G:C	F170L	0.992
12:109561429:G:T	F170L	0.992
12:109561431:A:G	F170L	0.992
12:109557118:G:C	F221L	0.987
12:109557118:G:T	F221L	0.987
12:109557120:A:G	F221L	0.987
12:109557130:A:C	S217R	0.985
12:109557130:A:T	S217R	0.985
12:109557132:T:G	S217R	0.985
12:109561057:G:C	C189W	0.985
12:109568827:T:A	K78I	0.981
12:109559096:C:G	R215T	0.979
12:109561050:C:G	A192P	0.979
12:109568781:A:C	S93R	0.979
12:109568781:A:T	S93R	0.979
12:109568783:T:G	S93R	0.979
12:109568826:T:A	K78N	0.979
12:109568826:T:G	K78N	0.979
12:109557136:T:A	R215S	0.978
12:109557136:T:G	R215S	0.978
12:109561087:G:C	S179R	0.978
12:109561087:G:T	S179R	0.978
12:109561089:T:G	S179R	0.978
12:109557131:C:A	S217I	0.977
12:109561055:C:G	R190P	0.977
12:109561056:G:T	R190S	0.976
12:109561059:A:G	C189R	0.976
12:109557106:T:A	R225S	0.975
12:109557106:T:G	R225S	0.975
12:109557107:C:G	R225T	0.974

dbSNP variants (sampled 300 via entrez): RS1000010737 (12:109567641 T>G), RS1000200580 (12:109573973 T>G), RS1000589004 (12:109573780 C>G), RS1000661842 (12:109567836 C>T), RS1000886588 (12:109562121 A>G), RS1000935242 (12:109573931 T>A,C), RS1000951261 (12:109557243 C>T), RS1001110548 (12:109556203 C>T), RS1001159649 (12:109557551 AGGGCT>A,AGGGCTGGGCT,AGGGCTGGGCTGGGCT), RS1001213714 (12:109557835 G>A), RS1001338588 (12:109561922 C>G,T), RS1001401183 (12:109563015 C>T), RS1001524899 (12:109568262 T>C), RS1001702767 (12:109572413 T>G), RS1002153446 (12:109572123 T>C)

Disease associations

OMIM: gene MIM:607568 | disease phenotypes: MIM:251110, MIM:251000, MIM:260920, MIM:610377, MIM:175900, MIM:620430, MIM:232200

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonic aciduria, cblB type	Definitive	Autosomal recessive
autoimmune disease, multisystem, infantile-onset, 3	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
methylmalonic aciduria, cblB type	Definitive	AR

Mondo (8): methylmalonic aciduria, cblB type (MONDO:0009614), methylmalonic acidemia (MONDO:0002012), hyperimmunoglobulinemia D with periodic fever (MONDO:0009849), mevalonic aciduria (MONDO:0012481), porokeratosis 3, disseminated superficial actinic type (MONDO:0008293), autoimmune disease, multisystem, infantile-onset, 3 (MONDO:0957388), autoinflammatory syndrome (MONDO:0019751), glycogen storage disease due to glucose-6-phosphatase deficiency type IA (MONDO:0009287)

Orphanet (7): Vitamin B12-responsive methylmalonic acidemia (Orphanet:28), Vitamin B12-responsive methylmalonic acidemia type cblB (Orphanet:79311), Mevalonic aciduria (Orphanet:29), Hyperimmunoglobulinemia D with periodic fever (Orphanet:343), Autoinflammatory syndrome (Orphanet:93665), Glycogen storage disease due to glucose-6-phosphatase deficiency (Orphanet:364), Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia (Orphanet:79258)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001644	Dilated cardiomyopathy
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001946	Ketosis
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002098	Respiratory distress
HP:0002154	Hyperglycinemia
HP:0002194	Delayed gross motor development
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:0003623	Neonatal onset
HP:0008872	Feeding difficulties in infancy
HP:0011463	Childhood onset
HP:0012120	Methylmalonic aciduria

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000135_3	HDL cholesterol	3.000000e-08
GCST000290_10	HDL cholesterol	1.000000e-10
GCST000680_1	Multiple sclerosis	2.000000e-10
GCST000755_40	HDL cholesterol	7.000000e-15
GCST000805_11	HDL cholesterol	3.000000e-06
GCST002498_12	Age-related nuclear cataracts	6.000000e-07
GCST002899_13	HDL cholesterol	9.000000e-10
GCST002934_18	Zinc levels	7.000000e-06
GCST004290_3	Multiple sclerosis	2.000000e-07
GCST004861_46	Itch intensity from mosquito bite	7.000000e-07
GCST004863_126	Mosquito bite size	3.000000e-07
GCST006052_4	Polymyositis	4.000000e-06
GCST008058_44	Estimated glomerular filtration rate	2.000000e-10
GCST008060_25	Estimated glomerular filtration rate	8.000000e-06
GCST009301_1	Antipsychotic drug-induced weight gain in schizophrenia or autism	6.000000e-06
GCST009367_46	HDL cholesterol levels x short total sleep time interaction (2df test)	4.000000e-13
GCST009367_47	HDL cholesterol levels x short total sleep time interaction (2df test)	2.000000e-16
GCST009367_48	HDL cholesterol levels x short total sleep time interaction (2df test)	4.000000e-13
GCST009367_49	HDL cholesterol levels x short total sleep time interaction (2df test)	2.000000e-16
GCST009367_50	HDL cholesterol levels x short total sleep time interaction (2df test)	3.000000e-11
GCST009367_51	HDL cholesterol levels x short total sleep time interaction (2df test)	2.000000e-20
GCST009367_52	HDL cholesterol levels x short total sleep time interaction (2df test)	5.000000e-14
GCST009368_5	HDL cholesterol levels x long total sleep time interaction (2df test)	2.000000e-13
GCST009441_17	Age-related cognitive decline (memory) (slope of z-scores)	7.000000e-06
GCST009504_1	Waist circumference	6.000000e-07
GCST009597_123	Multiple sclerosis	5.000000e-12
GCST010134_6	Non-oily fish consumption	6.000000e-11
GCST010135_11	Oily fish consumption	6.000000e-11
GCST010135_3	Oily fish consumption	7.000000e-17
GCST010140_3	Pork consumption	6.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004567	antipsychotic drug related weight gain
EFO:0007710	cognitive decline measurement
EFO:0008111	diet measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0009188	Red cell distribution width

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C538655	Hepatorenal form of glycogen storage disease (supp.)
C537358	Methylmalonic acidemia (supp.)
C536339	Porokeratosis, disseminated superficial actinic 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066327 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.42	Kd	376.2	nM	CHEMBL5653589
6.24	ED50	574.5	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148757: Binding affinity to human MMAB incubated for 45 mins by Kinobead based pull down assay	kd	0.3762	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	6
Benzo(a)pyrene	decreases expression, increases methylation	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
mercuric bromide	affects cotreatment, decreases expression	2
Leflunomide	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
afuresertib	increases expression	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
dodecyldimethylamine oxide	increases expression	1
arsenite	affects binding, increases reaction	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
monomethylarsonous acid	decreases 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
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651799	Binding	Binding affinity to human MMAB incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

6 cell lines: 4 finite cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3UH	WG2147	Finite cell line
CVCL_B3UI	WG3293	Finite cell line
CVCL_B3UJ	WG3332	Finite cell line
CVCL_B3UK	WG1641	Finite cell line
CVCL_VF02	UAMi002-A	Induced pluripotent stem cell	Female
CVCL_VF03	UAMi003-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

43 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)
NCT05139316	PHASE3	COMPLETED	A Study of Adeno-Associated Virus Serotype 8-Mediated Gene Transfer of Glucose-6-Phosphatase in Patients With Glycogen Storage Disease Type Ia (GSDIa)
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
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
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
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
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
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
NCT01568736	Not specified	WITHDRAWN	B7 Coreceptor Molecules in Hyper IgD Syndrome Form of Mevalonate Kinase Deficiency
NCT06838143	Not specified	RECRUITING	Ilaris NIS in Korea
NCT00260299	Not specified	TERMINATED	Dietary Cholesterol and Defects in Cholesterol Synthesis in Mevalonate Kinase Deficiency
NCT05292768	Not specified	NOT_YET_RECRUITING	Are Mast Cells Involved in Autoinflammatory Diseases
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
NCT03517085	PHASE1/PHASE2	COMPLETED	Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in Adults With Glycogen Storage Disease Type Ia (GSDIa)
NCT04311307	PHASE1/PHASE2	COMPLETED	Endogenous Glucose Production in Patients With Glycogen Storage Disease Type Ia
NCT06735755	PHASE1/PHASE2	RECRUITING	A Phase 1/2, Dose-Exploration Study to Evaluate the Safety and Efficacy of BEAM-301 in Patients With Glycogen Storage Disease Type Ia (GSDIa)
NCT01854242	Not specified	COMPLETED	Study of the Relationship Between Glycogen Storage Disease Type Ia and Inflammatory Bowel Disease
NCT02054832	Not specified	COMPLETED	Sleep and Quality of Life in Patients With Glycogen Storage Disease on Standard Versus Modified Uncooked Cornstarch
NCT03970278	Not specified	COMPLETED	Study of Long-Term Safety and Efficacy on Gene Therapy in Glycogen Storage Disease Type Ia
NCT04708015	Not specified	COMPLETED	Retrospective Study of Glucose Monitoring for Glycemic Control in Patients With GSDIa
NCT04909346	Not specified	TERMINATED	Adeno-Associated Virus (AAV) Antibody Study in Subjects OTC Deficiency, GSDIa, and Wilson Disease