methylmalonic aciduria, cblA type

Summary

methylmalonic aciduria, cblA type (MONDO:0009613) is a disease caused by MMAA (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MMAA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 590
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria, cblA type
Mondo ID	MONDO:0009613
OMIM	251100
Orphanet	79310
DOID	DOID:0060742
NCIT	C142171
SNOMED CT	73843004, 82245003
UMLS	C1855109
MedGen	344422
GARD	0005500
Is cancer (heuristic)	no

Also known as: cobalamin A disease · cobalamin B disease · methylmalonic acidemia cblA type · methylmalonic acidemia, cblA type · methylmalonic aciduria cblA type · methylmalonic aciduria, cblA type · methylmalonic aciduria, vitamin B12-responsive due to a defect in synthesis of adenosylcobalamin cblA type · Methylmalonic aciduria, vitamin B12-responsive, cblA type · methylmalonic aciduria, vitamin B12-responsive, due to defect in synthesis of adenosylcobalamin, cblA complementation type · MMA Cbl A type · vitamin B12-responsive methylmalonic acidemia type cblA · vitamin B12-responsive methylmalonic aciduria type cblA

Data availability: 590 ClinVar variants · 6 GenCC gene-disease records · 19 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, cblA type

Related subtypes (2): methylmalonic aciduria, cblB 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

590 retrieved; paginated sample, class counts are floors:

208 uncertain significance, 201 likely benign, 59 pathogenic, 58 likely pathogenic, 22 pathogenic/likely pathogenic, 21 conflicting classifications of pathogenicity, 18 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073197	NM_172250.3(MMAA):c.434G>A (p.Arg145Gln)	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350506	NM_172250.3(MMAA):c.898C>T (p.Arg300Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
1361666	NM_172250.3(MMAA):c.639del (p.Arg214fs)	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1374022	NM_172250.3(MMAA):c.127_134dup (p.Ser46fs)	MMAA	Pathogenic	criteria provided, single submitter
1414201	NM_172250.3(MMAA):c.756del (p.Val253fs)	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450413	NM_172250.3(MMAA):c.468dup (p.Ser157fs)	MMAA	Pathogenic	criteria provided, single submitter
1455101	NM_172250.3(MMAA):c.365T>C (p.Leu122Pro)	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455574	NM_172250.3(MMAA):c.795_796dup (p.Pro266fs)	MMAA	Pathogenic	criteria provided, single submitter
1459643	NC_000004.11:g.(?146575136)(146576596_?)del	MMAA	Pathogenic	criteria provided, single submitter
1950525	NM_172250.3(MMAA):c.443T>A (p.Leu148Ter)	MMAA	Pathogenic	criteria provided, single submitter
1954560	NM_172250.3(MMAA):c.1117G>T (p.Glu373Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
1975237	NM_172250.3(MMAA):c.1216_1229GCA[2]GACTTCTTTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGCAGCAGACTTCTT[1] (p.Leu410delinsPhePhePhePhePhePhePheXaaXaaXaaXaaIleArgProProArgProProLysValLeuGlyLeuGlnAlaTer)	MMAA	Pathogenic	criteria provided, single submitter
1999235	NM_172250.3(MMAA):c.170del (p.Leu57fs)	MMAA	Pathogenic	criteria provided, single submitter
2003201	NM_172250.3(MMAA):c.940del (p.Arg314fs)	MMAA	Pathogenic	criteria provided, single submitter
2025789	NM_172250.3(MMAA):c.817C>T (p.Gln273Ter)	MMAA	Pathogenic	criteria provided, single submitter
203814	NM_172250.3(MMAA):c.387C>A (p.Tyr129Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
203815	NM_172250.3(MMAA):c.593_596del (p.Thr198fs)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
203816	NM_172250.3(MMAA):c.988C>T (p.Arg330Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
2044227	NM_172250.3(MMAA):c.713_714del (p.Ile238fs)	MMAA	Pathogenic	criteria provided, single submitter
2057282	NM_172250.3(MMAA):c.184_185del (p.Lys62fs)	MMAA	Pathogenic	criteria provided, single submitter
218969	NM_172250.3(MMAA):c.64C>T (p.Arg22Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
218970	NM_172250.3(MMAA):c.161G>A (p.Trp54Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
218971	NM_172250.3(MMAA):c.266T>C (p.Leu89Pro)	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218972	NM_172250.3(MMAA):c.358C>T (p.Gln120Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
218973	NM_172250.3(MMAA):c.397C>T (p.Gln133Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
218974	NM_172250.3(MMAA):c.503del (p.Thr168fs)	MMAA	Pathogenic	criteria provided, single submitter
218976	NM_172250.3(MMAA):c.650T>A (p.Leu217Ter)	MMAA	Pathogenic	criteria provided, multiple submitters, no conflicts
218978	NM_172250.3(MMAA):c.733+1G>A	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218979	NM_172250.3(MMAA):c.1076G>A (p.Arg359Gln)	MMAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225189	NM_172250.3(MMAA):c.1025T>G (p.Met342Arg)	MMAA	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
MMAA	Definitive	Autosomal recessive	methylmalonic aciduria, cblA type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMAA	Orphanet:79310	Vitamin B12-responsive methylmalonic acidemia type cblA
TTC29	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MMAA	HGNC:18871	ENSG00000151611	Q8IVH4	Methylmalonic aciduria type A protein, mitochondrial	gencc,clinvar
TTC29	HGNC:29936	ENSG00000137473	Q8NA56	Tetratricopeptide repeat protein 29	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMAA	Methylmalonic aciduria type A protein, mitochondrial	GTPase, binds and hydrolyzes GTP.
TTC29	Tetratricopeptide repeat protein 29	Axonemal protein which is implicated in axonemal and/or peri-axonemal structure assembly and regulates flagellum assembly and beating and therefore sperm motility.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMAA	Other/Unknown	no		GTPase_ArgK, P-loop_NTPase
TTC29	Phosphatase	yes		TPR-like_helical_dom_sf, TPR_rpt, Bac_ResReg_Asp_Phosphatase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
tibialis anterior	1
bronchial epithelial cell	1
left testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMAA	251	ubiquitous	yes	secondary oocyte, oocyte, tibialis anterior
TTC29	105	broad	marker	sperm, bronchial epithelial cell, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTC29	771
MMAA	305

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMAA	Q8IVH4	2
TTC29	Q8NA56	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MMAA causes MMA, cblA type	1	5710.0×	7e-04	MMAA
Defective MUT causes MMAM	1	5710.0×	7e-04	MMAA
Diseases of mitochondrial beta oxidation	1	5710.0×	7e-04	MMAA
Diseases of propionyl-CoA catabolism	1	5710.0×	7e-04	MMAA
Propionyl-CoA catabolism	1	2284.0×	0.001	MMAA
Cobalamin (Cbl) metabolism	1	1268.9×	0.002	MMAA
Defects in cobalamin (B12) metabolism	1	815.7×	0.003	MMAA
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.003	MMAA
Defects in vitamin and cofactor metabolism	1	601.0×	0.003	MMAA
Mitochondrial Fatty Acid Beta-Oxidation	1	380.7×	0.004	MMAA
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	MMAA
Fatty acid metabolism	1	131.3×	0.011	MMAA
Metabolism of vitamins and cofactors	1	116.5×	0.011	MMAA
Diseases of metabolism	1	80.4×	0.015	MMAA
Metabolism of lipids	1	31.6×	0.036	MMAA
Disease	1	13.1×	0.081	MMAA
Metabolism	1	11.6×	0.086	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
succinyl-CoA biosynthetic process	1	4213.0×	9e-04	MMAA
cobalamin metabolic process	1	766.0×	0.003	MMAA
cilium organization	1	300.9×	0.004	TTC29
cilium movement	1	195.9×	0.005	TTC29

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMAA	0	0
TTC29	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	TTC29
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MMAA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MMAA	0	—
TTC29	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns