3-methylglutaconic aciduria

Summary

3-methylglutaconic aciduria (MONDO:0017359) is a disease (an umbrella term covering 10 Mondo subtypes) with 5 cohort genes.

At a glance

• Umbrella term: 10 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria
Mondo ID	MONDO:0017359
MeSH	C579867
OMIM	250950
Orphanet	289902
DOID	DOID:0060336
ICD-10-CM	E71.111
ICD-11	1008261602
NCIT	C98678
SNOMED CT	237950009
UMLS	C3696376
MedGen	777186
GARD	0012966
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants.

Disease family

An umbrella term covering 10 Mondo subtypes.

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 › classic organic aciduria › 3-methylglutaconic aciduria

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxyisobutyryl-CoA hydrolase deficiency, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, propionic acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency, isobutyryl-CoA dehydrogenase deficiency, combined malonic and methylmalonic acidemia, multiple carboxylase deficiency, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, 3-methylcrotonyl-CoA carboxylase deficiency

Subtypes (10): 3-methylglutaconic aciduria type 1, 3-methylglutaconic aciduria type 4, 3-methylglutaconic aciduria type 3, Barth syndrome, 3-methylglutaconic aciduria type 5, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 3-methylglutaconic aciduria, type VIIB, 3-methylglutaconic aciduria type 8, 3-methylglutaconic aciduria type 9, 3-methylglutaconic aciduria, type VIIA

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

5 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3359774	NM_001698.3(AUH):c.830_831del (p.Glu277fs)	AUH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676588	NM_001258392.3(CLPB):c.1588G>A (p.Gly530Arg)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
3362877	NM_014263.4(YME1L1):c.1999C>G (p.Leu667Val)	YME1L1	Likely pathogenic	criteria provided, single submitter
2683843	NM_025136.4(OPA3):c.439_440del (p.Gly147fs)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587633	NM_145261.4(DNAJC19):c.62A>T (p.Tyr21Phe)	DNAJC19	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YME1L1	Orphanet:98676	Autosomal recessive isolated optic atrophy
DNAJC19	Orphanet:66634	Dilated cardiomyopathy with ataxia
CLPB	Orphanet:445038	3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome
CLPB	Orphanet:486	Autosomal dominant severe congenital neutropenia
OPA3	Orphanet:67036	Autosomal dominant optic atrophy and cataract
OPA3	Orphanet:67047	3-methylglutaconic aciduria type 3
AUH	Orphanet:67046	3-methylglutaconic aciduria type 1

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
YME1L1	HGNC:12843	ENSG00000136758	Q96TA2	ATP-dependent zinc metalloprotease YME1L1	clinvar
DNAJC19	HGNC:30528	ENSG00000205981	Q96DA6	Mitochondrial import inner membrane translocase subunit TIM14	clinvar
CLPB	HGNC:30664	ENSG00000162129	Q9H078	Mitochondrial disaggregase	clinvar
OPA3	HGNC:8142	ENSG00000125741	Q9H6K4	Optic atrophy 3 protein	clinvar
AUH	HGNC:890	ENSG00000148090	Q13825	Methylglutaconyl-CoA hydratase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YME1L1	ATP-dependent zinc metalloprotease YME1L1	ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region.
DNAJC19	Mitochondrial import inner membrane translocase subunit TIM14	Mitochondrial co-chaperone which forms a complex with prohibitins to regulate cardiolipin remodeling.
CLPB	Mitochondrial disaggregase	Functions as a regulatory ATPase and participates in secretion/protein trafficking process.
OPA3	Optic atrophy 3 protein	May play some role in mitochondrial processes.
AUH	Methylglutaconyl-CoA hydratase, mitochondrial	Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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
Protease	1	7.3×	0.471
Scaffold/PPI	1	3.5×	0.471
Enzyme (other)	1	2.4×	0.471
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
YME1L1	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
DNAJC19	Other/Unknown	no		DnaJ_domain, J_dom_sf
CLPB	Scaffold/PPI	no		ClpA/B, Ankyrin_rpt, AAA+_ATPase
OPA3	Other/Unknown	no		OPA3-like
AUH	Enzyme (other)	yes	4.2.1.18	Enoyl-CoA_hydra/iso, Enoyl-CoA_hydra_C, Enoyl-CoA_hyd/isom_CS

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tendon of biceps brachii	2
germinal epithelium of ovary	1
parietal pleura	1
tibia	1
calcaneal tendon	1
tendon	1
left testis	1
right testis	1
sperm	1
apex of heart	1
hindlimb stylopod muscle	1
lateral nuclear group of thalamus	1
nephron tubule	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YME1L1	295	ubiquitous	marker	germinal epithelium of ovary, tibia, parietal pleura
DNAJC19	256	ubiquitous	marker	tendon of biceps brachii, tendon, calcaneal tendon
CLPB	205	ubiquitous	marker	sperm, left testis, right testis
OPA3	213	ubiquitous	yes	tendon of biceps brachii, hindlimb stylopod muscle, apex of heart
AUH	290	ubiquitous	marker	renal medulla, lateral nuclear group of thalamus, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPB	5,095
YME1L1	4,274
DNAJC19	2,167
AUH	2,102
OPA3	87

Intra-cohort edges

A	B	Sources
AUH	DNAJC19	string_interaction
CLPB	OPA3	biogrid_interaction
CLPB	YME1L1	string_interaction
OPA3	YME1L1	biogrid_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLPB	Q9H078	7
AUH	Q13825	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC19	Q96DA6	87.50
OPA3	Q9H6K4	83.13
YME1L1	Q96TA2	70.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 5 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
3-methylglutaconic aciduria	1	3806.7×	0.003	AUH
Diseases of branched-chain amino acid catabolism	1	634.4×	0.009	AUH
Cellular response to mitochondrial stress	1	380.7×	0.010	YME1L1
Processing of SMDT1	1	211.5×	0.013	YME1L1
Branched-chain amino acid catabolism	1	158.6×	0.014	AUH
Mitochondrial protein import	1	56.0×	0.033	DNAJC19
Mitochondrial protein degradation	1	38.1×	0.041	YME1L1
Diseases of metabolism	1	26.8×	0.051	AUH
Metabolism of amino acids and derivatives	1	22.5×	0.053	AUH
Disease	1	4.4×	0.233	AUH
Metabolism	1	3.9×	0.237	AUH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cardiolipin metabolic process	1	1685.2×	0.009	DNAJC19
positive regulation of mitochondrial fusion	1	674.1×	0.009	YME1L1
mitochondrial protein processing	1	561.7×	0.009	YME1L1
L-leucine catabolic process	1	481.5×	0.009	AUH
RIG-I signaling pathway	1	481.5×	0.009	CLPB
mitochondrion organization	2	60.7×	0.009	YME1L1, OPA3
visual perception	2	31.8×	0.009	DNAJC19, OPA3
genitalia development	1	337.0×	0.009	DNAJC19
mitochondrial protein catabolic process	1	306.4×	0.009	YME1L1
protein hexamerization	1	280.9×	0.009	YME1L1
regulation of stem cell division	1	280.9×	0.009	YME1L1
granulocyte differentiation	1	240.7×	0.010	CLPB
regulation of growth	1	187.2×	0.012	OPA3
protein quality control for misfolded or incompletely synthesized proteins	1	153.2×	0.013	YME1L1
protein import into mitochondrial matrix	1	140.4×	0.013	DNAJC19
neuronal stem cell population maintenance	1	134.8×	0.013	YME1L1
obsolete protein targeting to mitochondrion	1	116.2×	0.015	DNAJC19
neuromuscular process	1	105.3×	0.015	OPA3
regulation of lipid metabolic process	1	86.4×	0.018	OPA3
fatty acid beta-oxidation	1	74.9×	0.019	AUH
cellular response to heat	1	68.8×	0.020	CLPB
bone development	1	55.2×	0.024	OPA3
antiviral innate immune response	1	45.5×	0.027	CLPB
cellular response to starvation	1	38.7×	0.031	YME1L1
fat cell differentiation	1	36.2×	0.032	OPA3
protein folding	1	20.7×	0.051	DNAJC19
cell population proliferation	1	20.6×	0.051	YME1L1
intracellular protein transport	1	13.0×	0.077	DNAJC19
negative regulation of apoptotic process	1	7.0×	0.136	YME1L1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
YME1L1	0	0
DNAJC19	0	0
CLPB	0	0
OPA3	0	0
AUH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YME1L1	3.4.24.B18
AUH	4.2.1.18	methylglutaconyl-CoA hydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	AUH
D	Druggable family + AlphaFold only, no drug	1	YME1L1
E	Difficult family or no structure, no drug	3	DNAJC19, CLPB, OPA3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
YME1L1	0	—
DNAJC19	0	—
CLPB	0	—
OPA3	0	—
AUH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.