methylmalonic aciduria, cblB type

Summary

methylmalonic aciduria, cblB type (MONDO:0009614) is a disease caused by MMAB (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MMAB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 541

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria, cblB type
Mondo ID	MONDO:0009614
OMIM	251110
Orphanet	79311
DOID	DOID:0060743
NCIT	C142172
UMLS	C1855102
MedGen	344420
GARD	0009479
Is cancer (heuristic)	no

Also known as: methylmalonic acidemia cblB type · methylmalonic acidemia, cblB type · methylmalonic aciduria, cblB type · methylmalonic aciduria, vitamin B12-responsive, cblB type · vitamin B12-responsive methylmalonic acidemia type cblB · vitamin B12-responsive methylmalonic aciduria, type cblB

Data availability: 541 ClinVar variants · 5 GenCC gene-disease records · 10 cell lines.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › methylmalonic acidemia › vitamin B12-responsive methylmalonic acidemia › methylmalonic aciduria, cblB type

Related subtypes (2): methylmalonic aciduria, cblA type, vitamin B12-responsive methylmalonic acidemia, type cblDv2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

541 retrieved; paginated sample, class counts are floors:

208 likely benign, 152 uncertain significance, 51 pathogenic, 44 likely pathogenic, 34 benign, 27 conflicting classifications of pathogenicity, 18 pathogenic/likely pathogenic, 6 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1017834	NM_052845.4(MMAB):c.563_577del (p.Val188_Ala192del)	MMAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068489	NM_052845.4(MMAB):c.220G>T (p.Glu74Ter)	MMAB	Pathogenic	criteria provided, multiple submitters, no conflicts
1173988	NM_052845.4(MMAB):c.23del (p.Ser8fs)	MMAB	Pathogenic	no assertion criteria provided
1173989	NM_052845.4(MMAB):c.87T>A (p.Tyr29Ter)	MMAB	Pathogenic	no assertion criteria provided
1173990	NM_052845.4(MMAB):c.135-1G>A	MMAB	Pathogenic	criteria provided, single submitter
1173991	NM_052845.4(MMAB):c.291-1G>T	MMAB	Pathogenic	no assertion criteria provided
1173992	NM_052845.4(MMAB):c.348+2_348+3del	MMAB	Pathogenic	no assertion criteria provided
1173993	NM_052845.4(MMAB):c.367del (p.Asp123fs)	MMAB	Pathogenic	criteria provided, multiple submitters, no conflicts
1173996	NM_052845.4(MMAB):c.462G>T (p.Glu154Asp)	MMAB	Pathogenic	no assertion criteria provided
1173997	NM_052845.4(MMAB):c.487C>T (p.Gln163Ter)	MMAB	Pathogenic	no assertion criteria provided
1173998	NM_052845.4(MMAB):c.558_559delinsC (p.Ala187fs)	MMAB	Pathogenic	no assertion criteria provided
1173999	NM_052845.4(MMAB):c.560_561insGGCACGGGC (p.Ala187_Val188insAlaArgAla)	MMAB	Pathogenic	no assertion criteria provided
1174000	NM_052845.4(MMAB):c.581_582dup (p.Arg195fs)	MMAB	Pathogenic	no assertion criteria provided
1174001	NM_052845.4(MMAB):c.650G>T (p.Ser217Ile)	MMAB	Pathogenic	no assertion criteria provided
1174002	NM_052845.4(MMAB):c.656_659del (p.Tyr219fs)	MMAB	Pathogenic	criteria provided, multiple submitters, no conflicts
1332746	NM_052845.4(MMAB):c.580A>G (p.Arg194Gly)	MMAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399066	NM_052845.4(MMAB):c.330del (p.Phe110fs)	MMAB	Pathogenic	criteria provided, single submitter
1402961	NM_052845.4(MMAB):c.467G>A (p.Trp156Ter)	MMAB	Pathogenic	criteria provided, single submitter
1434079	NM_052845.4(MMAB):c.61dup (p.Cys21fs)	MMAB	Pathogenic	criteria provided, single submitter
1451421	NM_052845.4(MMAB):c.523G>T (p.Gly175Ter)	MMAB	Pathogenic	criteria provided, multiple submitters, no conflicts
1453900	NM_052845.4(MMAB):c.460G>T (p.Glu154Ter)	MMAB	Pathogenic	criteria provided, single submitter
1454399	NM_052845.4(MMAB):c.638T>G (p.Leu213Ter)	MMAB	Pathogenic	criteria provided, single submitter
1454464	NM_052845.4(MMAB):c.197-1G>A	MMAB	Pathogenic	criteria provided, single submitter
1979899	NM_052845.4(MMAB):c.649dup (p.Ser217fs)	MMAB	Pathogenic	criteria provided, single submitter
2020905	NM_052845.4(MMAB):c.546_555dup (p.Arg186fs)	MMAB	Pathogenic	criteria provided, single submitter
2025769	NM_052845.4(MMAB):c.545_570del (p.Leu182fs)	MMAB	Pathogenic	criteria provided, single submitter
203819	NM_052845.4(MMAB):c.569G>A (p.Arg190His)	MMAB	Pathogenic	criteria provided, multiple submitters, no conflicts
203820	NM_052845.4(MMAB):c.700C>T (p.Gln234Ter)	MMAB	Pathogenic	criteria provided, multiple submitters, no conflicts
203822	NM_052845.4(MMAB):c.563_577dup (p.Val188_Ala192dup)	MMAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121959	NM_052845.4(MMAB):c.266del (p.Thr89fs)	MMAB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MMAB	Definitive	Autosomal recessive	methylmalonic aciduria, cblB type	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMAB	Orphanet:79311	Vitamin B12-responsive methylmalonic acidemia type cblB
MMAA	Orphanet:79310	Vitamin B12-responsive methylmalonic acidemia type cblA
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MMAB	HGNC:19331	ENSG00000139428	Q96EY8	Corrinoid adenosyltransferase MMAB	gencc,clinvar
MMAA	HGNC:18871	ENSG00000151611	Q8IVH4	Methylmalonic aciduria type A protein, mitochondrial	clinvar
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMAB	Corrinoid adenosyltransferase MMAB	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.
MMAA	Methylmalonic aciduria type A protein, mitochondrial	GTPase, binds and hydrolyzes GTP.
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.313
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMAB	Enzyme (other)	yes	2.5.1.17	CblAdoTrfase-like, PduO-typ, CblAdoTrfase-like_sf
MMAA	Other/Unknown	no		GTPase_ArgK, P-loop_NTPase
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
right adrenal gland	1
right adrenal gland cortex	1
oocyte	1
secondary oocyte	1
tibialis anterior	1
lower esophagus mucosa	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMAB	235	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, right adrenal gland
MMAA	251	ubiquitous	yes	secondary oocyte, oocyte, tibialis anterior
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424
MMAB	1,121
MMAA	305

Intra-cohort edges

A	B	Sources
MMAA	MMAB	string_interaction
MMAB	MVK	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMAB	Q96EY8	6
MMAA	Q8IVH4	2
MVK	Q03426	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cobalamin (Cbl) metabolism	2	845.9×	4e-05	MMAB, MMAA
Defects in cobalamin (B12) metabolism	2	543.8×	5e-05	MMAB, MMAA
Cobalamin (Cbl, vitamin B12) transport and metabolism	2	423.0×	5e-05	MMAB, MMAA
Defects in vitamin and cofactor metabolism	2	400.7×	5e-05	MMAB, MMAA
Metabolism of water-soluble vitamins and cofactors	2	120.8×	4e-04	MMAB, MMAA
Metabolism of vitamins and cofactors	2	77.7×	8e-04	MMAB, MMAA
Defective MMAB causes MMA, cblB type	1	1903.3×	0.001	MMAB
Defective MMAA causes MMA, cblA type	1	1903.3×	0.001	MMAA
Defective MUT causes MMAM	1	1903.3×	0.001	MMAA
Diseases of mitochondrial beta oxidation	1	1903.3×	0.001	MMAA
Diseases of propionyl-CoA catabolism	1	1903.3×	0.001	MMAA
Diseases of metabolism	2	53.6×	0.001	MMAB, MMAA
Metabolism	3	11.6×	0.001	MMAB, MMAA, MVK
Propionyl-CoA catabolism	1	761.3×	0.002	MMAA
Cholesterol biosynthesis	1	380.7×	0.004	MVK
Metabolism of lipids	2	21.0×	0.004	MMAA, MVK
Lanosterol biosynthesis	1	253.8×	0.005	MVK
Mitochondrial Fatty Acid Beta-Oxidation	1	126.9×	0.010	MMAA
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	105.7×	0.011	MVK
Activation of gene expression by SREBF (SREBP)	1	86.5×	0.013	MVK
Disease	2	8.7×	0.018	MMAB, MMAA
Metabolism of steroids	1	45.9×	0.023	MVK
Fatty acid metabolism	1	43.8×	0.023	MMAA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cobalamin metabolic process	2	1021.3×	7e-06	MMAB, MMAA
succinyl-CoA biosynthetic process	1	2808.7×	0.001	MMAA
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.001	MVK
isoprenoid biosynthetic process	1	561.7×	0.003	MVK
cholesterol biosynthetic process	1	140.4×	0.009	MVK
negative regulation of inflammatory response	1	45.7×	0.022	MVK

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMAB	0	0
MMAA	0	0
MVK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MMAB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMAB	2.5.1.17	corrinoid adenosyltransferase
MVK	2.7.1.36	mevalonate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	MMAB, MVK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MMAA

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MMAB	1	—
MMAA	0	—
MVK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.