3-methylglutaconic aciduria type 9

Summary

3-methylglutaconic aciduria type 9 (MONDO:0044724) is a disease caused by TIMM50 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TIMM50 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 25
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000718	Aggressive behavior	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001533	Slender build	Very frequent (80-99%)
HP:0002059	Cerebral atrophy	Very frequent (80-99%)
HP:0002133	Status epilepticus	Very frequent (80-99%)
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002169	Clonus	Very frequent (80-99%)
HP:0002194	Delayed gross motor development	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0003535	3-Methylglutaconic aciduria	Very frequent (80-99%)
HP:0007204	Diffuse white matter abnormalities	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011925	Decreased activity of mitochondrial ATP synthase complex	Very frequent (80-99%)
HP:0031936	Delayed ability to walk	Very frequent (80-99%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria type 9
Mondo ID	MONDO:0044724
OMIM	617698
Orphanet	505216
DOID	DOID:0070002
UMLS	C4540171
MedGen	1622927
GARD	0017940
Is cancer (heuristic)	no

Also known as: 3-methylglutaconic aciduria-epilepsy-spasticity-severe intellectual disability syndrome · MGA9 · MGCA9

Data availability: 25 ClinVar variants · 5 GenCC gene-disease records.

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 › classic organic aciduria › 3-methylglutaconic aciduria › 3-methylglutaconic aciduria type 9

Related subtypes (9): 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 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

25 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 4 conflicting classifications of pathogenicity, 4 benign, 4 pathogenic, 2 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208697	NM_001001563.5(TIMM50):c.805G>A (p.Gly269Ser)	TIMM50	Pathogenic	criteria provided, single submitter
488622	NM_001001563.5(TIMM50):c.664G>A (p.Ala222Thr)	TIMM50	Pathogenic	criteria provided, single submitter
559479	NM_001001563.5(TIMM50):c.260G>C (p.Gly87Ala)	TIMM50	Pathogenic	criteria provided, single submitter
559480	NM_001001563.5(TIMM50):c.26C>A (p.Ser9Ter)	TIMM50	Pathogenic	criteria provided, single submitter
1723218	NM_001001563.5(TIMM50):c.328C>T (p.Gln110Ter)	TIMM50	Likely pathogenic	criteria provided, single submitter
440792	NM_001001563.5(TIMM50):c.446C>T (p.Thr149Met)	TIMM50	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034334	NM_001001563.5(TIMM50):c.854-8G>C	TIMM50	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2093436	NM_001001563.5(TIMM50):c.884G>A (p.Arg295Gln)	TIMM50	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2869284	NM_001001563.5(TIMM50):c.337C>T (p.Arg113Cys)	TIMM50	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
488623	NM_001001563.5(TIMM50):c.715C>T (p.Arg239Trp)	TIMM50	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811457	NC_000019.10:g.39480831G>A		Uncertain significance	criteria provided, single submitter
1028411	NM_001001563.5(TIMM50):c.620G>T (p.Ser207Ile)	TIMM50	Uncertain significance	criteria provided, single submitter
1334174	NM_001001563.5(TIMM50):c.341G>A (p.Arg114Gln)	TIMM50	Uncertain significance	criteria provided, single submitter
1423336	NM_001001563.5(TIMM50):c.1033C>T (p.Arg345Cys)	TIMM50	Uncertain significance	criteria provided, multiple submitters, no conflicts
1488878	NM_001001563.5(TIMM50):c.658C>T (p.Arg220Trp)	TIMM50	Uncertain significance	criteria provided, multiple submitters, no conflicts
1940763	NM_001001563.5(TIMM50):c.44T>G (p.Leu15Arg)	TIMM50	Uncertain significance	criteria provided, multiple submitters, no conflicts
440793	NM_001001563.5(TIMM50):c.340C>T (p.Arg114Trp)	TIMM50	Uncertain significance	criteria provided, single submitter
4686084	NM_001001563.5(TIMM50):c.961-18A>G	TIMM50	Uncertain significance	criteria provided, single submitter
915392	NM_001001563.5(TIMM50):c.671G>T (p.Arg224Ile)	TIMM50	Uncertain significance	criteria provided, single submitter
1165754	NM_001001563.5(TIMM50):c.598-15C>T	TIMM50	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1168602	NM_001001563.5(TIMM50):c.108+21C>G	TIMM50	Benign	criteria provided, multiple submitters, no conflicts
1170144	NM_001001563.5(TIMM50):c.492+17C>G	TIMM50	Benign	criteria provided, multiple submitters, no conflicts
1288036	NM_001001563.5(TIMM50):c.597+38T>C	TIMM50	Benign	criteria provided, multiple submitters, no conflicts
1298014	NM_001001563.5(TIMM50):c.696+38G>A	TIMM50	Benign	criteria provided, multiple submitters, no conflicts
780558	NM_001001563.5(TIMM50):c.26C>G (p.Ser9Trp)	TIMM50	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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
TIMM50	Definitive	Autosomal recessive	3-methylglutaconic aciduria type 9	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TIMM50	Orphanet:505216	3-methylglutaconic aciduria type 9

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
TIMM50	HGNC:23656	ENSG00000105197	Q3ZCQ8	Mitochondrial import inner membrane translocase subunit TIM50	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TIMM50	Mitochondrial import inner membrane translocase subunit TIM50	Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.

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)
TIMM50	Other/Unknown	no		FCP1_dom, HAD_sf, HAD-like_sf

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
apex of heart	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TIMM50	259	ubiquitous	marker	left testis, right testis, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TIMM50	2,641

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TIMM50	Q3ZCQ8	80.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Mitochondrial protein import	1	167.9×	0.006	TIMM50

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
mitochondrial membrane organization	1	2407.4×	0.002	TIMM50
release of cytochrome c from mitochondria	1	702.2×	0.002	TIMM50
protein import into mitochondrial matrix	1	702.2×	0.002	TIMM50
protein dephosphorylation	1	221.7×	0.006	TIMM50
intracellular protein transport	1	64.8×	0.015	TIMM50

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
TIMM50	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
TIMM50	2	Binding:2

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	TIMM50

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)
TIMM50	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.