Combined malonic and methylmalonic acidemia

Summary

Combined malonic and methylmalonic acidemia (MONDO:0013661) is a disease caused by ACSF3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (United States) [Orphanet-validated]
• Causal gene: ACSF3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 939
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	3.3	United States	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0002912	Methylmalonic acidemia	Very frequent (80-99%)
HP:0003215	Dicarboxylic aciduria	Very frequent (80-99%)
HP:0012120	Methylmalonic aciduria	Very frequent (80-99%)
HP:0040145	Dicarboxylic acidemia	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001941	Acidosis	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001993	Ketoacidosis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002254	Intermittent diarrhea	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0011169	Generalized clonic seizure	Occasional (5-29%)
HP:0031064	Impaired continence	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined malonic and methylmalonic acidemia
Mondo ID	MONDO:0013661
MeSH	C580002
OMIM	614265
Orphanet	289504
DOID	DOID:0111263
SNOMED CT	702365002
UMLS	C3280314
MedGen	481944
GARD	0010818
Is cancer (heuristic)	no

Also known as: CMAMMA · combined malonic and methylmalonic acidemia · combined malonic and methylmalonic aciduria

Data availability: 939 ClinVar variants · 3 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 › methylmalonic acidemia › combined malonic and methylmalonic acidemia

Related subtypes (6): methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency, methylmalonic acidemia due to transcobalamin receptor defect, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, isolated methylmalonic aciduria cblD type

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:

341 likely benign, 87 uncertain significance, 57 likely pathogenic, 39 pathogenic, 38 pathogenic/likely pathogenic, 28 benign, 10 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029287	NM_001243279.3(ACSF3):c.1401G>A (p.Trp467Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029290	NM_001243279.3(ACSF3):c.1536G>A (p.Trp512Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068495	NM_001243279.3(ACSF3):c.891C>A (p.Tyr297Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068650	NM_001243279.3(ACSF3):c.1311G>A (p.Trp437Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069517	NM_001243279.3(ACSF3):c.1329dup (p.Lys444Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070125	NM_001243279.3(ACSF3):c.1296del (p.Arg434fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070367	NM_001243279.3(ACSF3):c.1328del (p.Thr443fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071065	NM_001243279.3(ACSF3):c.820C>T (p.Gln274Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071765	NM_001243279.3(ACSF3):c.576G>A (p.Trp192Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072051	NM_001243279.3(ACSF3):c.238C>T (p.Gln80Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072093	NC_000016.9:g.(?89199534)(89199680_?)del	ACSF3	Pathogenic	criteria provided, single submitter
1072094	NC_000016.9:g.(?89160207)(89212467_?)del	ACSF3	Pathogenic	criteria provided, single submitter
1072095	NC_000016.9:g.(?89167070)(89180915_?)del	ACSF3	Pathogenic	criteria provided, single submitter
1072096	NC_000016.9:g.(?89178490)(89207694_?)del	ACSF3	Pathogenic	criteria provided, single submitter
1072097	NC_000016.9:g.(?89187199)(89222264_?)del	ACSF3	Pathogenic	criteria provided, single submitter
1072354	NM_001243279.3(ACSF3):c.186_196dup (p.His66fs)	ACSF3	Pathogenic	criteria provided, single submitter
1074075	NC_000016.10:g.89112092del	ACSF3	Pathogenic	criteria provided, single submitter
1074603	NM_001243279.3(ACSF3):c.155_161del (p.Ala52fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075477	NM_001243279.3(ACSF3):c.757dup (p.Ala253fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075808	NM_001243279.3(ACSF3):c.643_647del (p.Thr215fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076675	NM_001243279.3(ACSF3):c.1270del (p.Glu424fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1187781	NM_001243279.3(ACSF3):c.1580C>G (p.Ser527Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322759	NM_001243279.3(ACSF3):c.666+1G>A	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373556	NM_001243279.3(ACSF3):c.1110del (p.Ala371fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1396014	NM_001243279.3(ACSF3):c.1643C>A (p.Ser548Ter)	ACSF3	Pathogenic	criteria provided, single submitter
1400260	NM_001243279.3(ACSF3):c.408T>A (p.Tyr136Ter)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404244	NM_001243279.3(ACSF3):c.1613+1G>A	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426657	NM_001243279.3(ACSF3):c.1003del (p.Leu335fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1429622	NM_001243279.3(ACSF3):c.1609del (p.Ala537fs)	ACSF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441215	NC_000016.9:g.(?89164989)(89222264_?)del	ACSF3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
ACSF3	Strong	Autosomal recessive	combined malonic and methylmalonic acidemia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACSF3	Orphanet:289504	Combined malonic and methylmalonic acidemia

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
ACSF3	HGNC:27288	ENSG00000176715	Q4G176	Malonate–CoA ligase ACSF3, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACSF3	Malonate–CoA ligase ACSF3, mitochondrial	Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACSF3	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
mucosa of transverse colon	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACSF3	173	ubiquitous	marker	mucosa of transverse colon, granulocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACSF3	2,854

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSF3	Q4G176	86.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Synthesis of very long-chain fatty acyl-CoAs	1	456.8×	0.006	ACSF3
Fatty acyl-CoA biosynthesis	1	439.2×	0.006	ACSF3
Fatty acid metabolism	1	131.3×	0.013	ACSF3
Metabolism of lipids	1	31.6×	0.040	ACSF3
Metabolism	1	11.6×	0.086	ACSF3

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
malonate catabolic process	1	16852.0×	2e-04	ACSF3
long-chain fatty-acyl-CoA biosynthetic process	1	842.6×	0.002	ACSF3
fatty acid biosynthetic process	1	351.1×	0.004	ACSF3
fatty acid metabolic process	1	193.7×	0.005	ACSF3

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
ACSF3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ACSF3	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACSF3

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)
ACSF3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.