Malonic aciduria

Summary

Malonic aciduria (MONDO:0009556) is a disease caused by MLYCD (GenCC Definitive), with 1 cohort gene and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MLYCD (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 620
• Phenotypes (HPO): 19
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		34	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0012120	Methylmalonic aciduria	Very frequent (80-99%)
HP:0034657	Elevated urine malonic acid level	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0001942	Metabolic acidosis	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:6000355	Reduced malonyl-CoA decarboxylase activity in cultured fibroblasts	Frequent (30-79%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001946	Ketosis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	malonic aciduria
Mondo ID	MONDO:0009556
MeSH	C535702
OMIM	248360
Orphanet	943
ICD-11	1373430210
SNOMED CT	361203007
UMLS	C0342793
MedGen	91001
GARD	0003371
Is cancer (heuristic)	no

Also known as: malonic acidemia · malonic aciduria · Malonicaciduria · malonyl-CoA decarboxylase deficiency · MCD deficiency

Data availability: 620 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › 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 › malonic aciduria

Related subtypes (6): methylmalonic acidemia, glutaryl-CoA dehydrogenase deficiency, glutaric acidemia type 3, maple syrup urine disease, methylmalonate semialdehyde dehydrogenase deficiency, classic organic aciduria

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

600 retrieved; paginated sample, class counts are floors:

328 likely benign, 162 uncertain significance, 49 pathogenic, 21 conflicting classifications of pathogenicity, 15 benign, 10 likely pathogenic, 9 benign/likely benign, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324724	NM_012213.3(MLYCD):c.928C>T (p.Arg310Ter)	LOC126862422	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2750438	NM_012213.3(MLYCD):c.910G>T (p.Gly304Ter)	LOC126862422	Pathogenic	criteria provided, single submitter
2872639	NM_012213.3(MLYCD):c.875del (p.Ser292fs)	LOC126862422	Pathogenic	criteria provided, single submitter
2634044	NM_012213.3(MLYCD):c.1A>C (p.Met1Leu)	LOC130059554	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2772013	NM_012213.3(MLYCD):c.162C>A (p.Tyr54Ter)	LOC130059554	Pathogenic	criteria provided, single submitter
4060	NM_012213.3(MLYCD):c.119T>C (p.Met40Thr)	LOC130059554	Pathogenic	no assertion criteria provided
4061	NM_012213.3(MLYCD):c.92_116del (p.Gln31fs)	LOC130059554	Pathogenic	no assertion criteria provided
847051	NM_012213.3(MLYCD):c.1A>T (p.Met1Leu)	LOC130059554	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1962527	NM_012213.3(MLYCD):c.512del (p.Glu171fs)	LOC130059555	Pathogenic	criteria provided, single submitter
2822247	NM_012213.3(MLYCD):c.172_493del (p.Glu58fs)	LOC130059555	Pathogenic	criteria provided, single submitter
3017380	NM_012213.3(MLYCD):c.493C>T (p.Gln165Ter)	LOC130059555	Pathogenic	criteria provided, multiple submitters, no conflicts
1070667	NM_012213.3(MLYCD):c.642-2A>C	MLYCD	Pathogenic	criteria provided, single submitter
1323278	NM_012213.3(MLYCD):c.368dup (p.Gln124fs)	MLYCD	Pathogenic	criteria provided, single submitter
1323279	NM_012213.3(MLYCD):c.758del (p.Leu253fs)	MLYCD	Pathogenic	criteria provided, single submitter
1390007	NM_012213.3(MLYCD):c.478_479insGGGCG (p.Asp160fs)	MLYCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1400055	NM_012213.3(MLYCD):c.22_34dup (p.Arg12fs)	MLYCD	Pathogenic	criteria provided, single submitter
1424276	NM_012213.3(MLYCD):c.60del (p.Arg21fs)	MLYCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458761	NC_000016.9:g.(?83932750)(84056514_?)del	MLYCD	Pathogenic	criteria provided, single submitter
1806239	NM_012213.3(MLYCD):c.175A>T (p.Lys59Ter)	MLYCD	Pathogenic	criteria provided, single submitter
2013700	NM_012213.3(MLYCD):c.583del (p.Phe194_Leu195insTer)	MLYCD	Pathogenic	criteria provided, single submitter
203813	NM_012213.3(MLYCD):c.475del (p.Ala159fs)	MLYCD	Pathogenic	criteria provided, multiple submitters, no conflicts
2137849	NM_012213.3(MLYCD):c.393_400del (p.Leu133fs)	MLYCD	Pathogenic	criteria provided, single submitter
2137851	NM_012213.3(MLYCD):c.953_954del	MLYCD	Pathogenic	criteria provided, single submitter
2174042	NM_012213.3(MLYCD):c.674del (p.Met225fs)	MLYCD	Pathogenic	criteria provided, single submitter
2695851	NM_012213.3(MLYCD):c.640G>T (p.Glu214Ter)	MLYCD	Pathogenic	criteria provided, single submitter
2705148	NM_012213.3(MLYCD):c.2T>C (p.Met1Thr)	MLYCD	Pathogenic	criteria provided, single submitter
2713597	NM_012213.3(MLYCD):c.199C>T (p.Gln67Ter)	MLYCD	Pathogenic	criteria provided, single submitter
2762272	NM_012213.3(MLYCD):c.248_252del (p.Gln83fs)	MLYCD	Pathogenic	criteria provided, single submitter
2762813	NM_012213.3(MLYCD):c.225C>G (p.Tyr75Ter)	MLYCD	Pathogenic	criteria provided, single submitter
2827180	NM_012213.3(MLYCD):c.682A>T (p.Lys228Ter)	MLYCD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
MLYCD	Definitive	Autosomal recessive	malonic aciduria	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MLYCD	Orphanet:943	Malonic aciduria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MLYCD	HGNC:7150	ENSG00000103150	O95822	Malonyl-CoA decarboxylase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MLYCD	Malonyl-CoA decarboxylase, mitochondrial	Catalyzes the conversion of malonyl-CoA to acetyl-CoA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MLYCD	Enzyme (other)	yes	4.1.1.9	Malonyl_CoA_deC_C, MCD_N, MCD_N_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
heart left ventricle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLYCD	248	ubiquitous	yes	skeletal muscle tissue of rectus abdominis, diaphragm, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MLYCD	1,314

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MLYCD	O95822	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Beta-oxidation of very long chain fatty acids	1	878.5×	0.002	MLYCD
Peroxisomal protein import	1	173.0×	0.006	MLYCD

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
malonyl-CoA catabolic process	1	3370.4×	0.001	MLYCD
regulation of fatty acid beta-oxidation	1	2808.7×	0.001	MLYCD
acetyl-CoA biosynthetic process	1	2407.4×	0.001	MLYCD
positive regulation of fatty acid oxidation	1	2407.4×	0.001	MLYCD
fatty acid oxidation	1	1053.2×	0.002	MLYCD
acyl-CoA metabolic process	1	702.2×	0.002	MLYCD
regulation of glucose metabolic process	1	561.7×	0.003	MLYCD
fatty acid biosynthetic process	1	351.1×	0.004	MLYCD
response to nutrient	1	295.6×	0.004	MLYCD
response to ischemia	1	251.5×	0.004	MLYCD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLYCD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MLYCD	11	Binding:8, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MLYCD	4.1.1.9	malonyl-CoA decarboxylase

Pharmacogenomics

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MLYCD	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01289158	Not specified	UNKNOWN	Combined Malonic and Methylmalonic Aciduria (CMAMMA): Gene Identification and Outcome Study
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan