AUH

Summary

AUH (AU RNA binding methylglutaconyl-CoA hydratase, HGNC:890) is a protein-coding gene on chromosome 9q22.31, encoding Methylglutaconyl-CoA hydratase, mitochondrial (Q13825). 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).

This gene encodes bifunctional mitochondrial protein that has both RNA-binding and hydratase activities. The encoded protein is a methylglutaconyl-CoA hydratase that catalyzes the hydration of 3-methylglutaconyl-CoA to 3-hydroxy-3-methyl-glutaryl-CoA, a critical step in the leucine degradation pathway. This protein also binds AU-rich elements (AREs) found in the 3’ UTRs of rapidly decaying mRNAs including c-fos, c-myc and granulocyte/ macrophage colony stimulating factor. ARE elements are involved in directing RNA to rapid degradation and deadenylation. This protein is localizes to the mitochondrial matrix and the inner mitochondrial membrane and may be involved in mitochondrial protein synthesis. Mutations in this gene are the cause of 3-methylglutaconic aciduria, type I. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 549 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylglutaconic aciduria type 1 (Definitive, ClinGen)
• GWAS associations: 13
• Clinical variants (ClinVar): 266 total — 19 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_001698

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:890
Approved symbol	AUH
Name	AU RNA binding methylglutaconyl-CoA hydratase
Location	9q22.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000148090
Ensembl biotype	protein_coding
OMIM	600529
Entrez	549

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000303617, ENST00000375731, ENST00000473695, ENST00000475023, ENST00000478465, ENST00000895919, ENST00000895920, ENST00000895921, ENST00000895922, ENST00000895923, ENST00000895924, ENST00000895925, ENST00000895926, ENST00000895927, ENST00000895928, ENST00000968995, ENST00000968996, ENST00000968997

RefSeq mRNA: 5 — MANE Select: NM_001698 NM_001306190, NM_001351431, NM_001351432, NM_001351433, NM_001698

CCDS: CCDS6689, CCDS78409

Canonical transcript exons

ENST00000375731 — 10 exons

Exon	Start	End
ENSE00000000004	91213823	91214425
ENSE00001031476	91216059	91216106
ENSE00001031477	91297984	91298076
ENSE00001031481	91296021	91296077
ENSE00001031485	91220805	91220992
ENSE00003475378	91325318	91325404
ENSE00003507536	91356088	91356155
ENSE00003530688	91355883	91355970
ENSE00003684829	91217277	91217327
ENSE00004472051	91361628	91361918

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 97.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9538 / max 449.1848, expressed in 1813 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101370	23.9538	1813

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	97.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.36	gold quality
nephron tubule	UBERON:0001231	96.34	gold quality
heart right ventricle	UBERON:0002080	95.74	gold quality
pons	UBERON:0000988	95.72	gold quality
adult mammalian kidney	UBERON:0000082	95.42	gold quality
parotid gland	UBERON:0001831	95.34	gold quality
kidney epithelium	UBERON:0004819	95.31	gold quality
left ventricle myocardium	UBERON:0006566	95.16	gold quality
right adrenal gland cortex	UBERON:0035827	95.14	gold quality
left adrenal gland cortex	UBERON:0035825	94.96	gold quality
adrenal cortex	UBERON:0001235	94.94	gold quality
right adrenal gland	UBERON:0001233	94.83	gold quality
left adrenal gland	UBERON:0001234	94.80	gold quality
substantia nigra pars compacta	UBERON:0001965	94.71	gold quality
kidney	UBERON:0002113	94.61	gold quality
endothelial cell	CL:0000115	94.22	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.20	gold quality
sural nerve	UBERON:0015488	94.02	gold quality
renal glomerulus	UBERON:0000074	93.96	gold quality
myocardium	UBERON:0002349	93.93	gold quality
adrenal gland	UBERON:0002369	93.93	gold quality
seminal vesicle	UBERON:0000998	93.86	gold quality
metanephros	UBERON:0000081	93.66	gold quality
choroid plexus epithelium	UBERON:0003911	93.62	gold quality
metanephric glomerulus	UBERON:0004736	93.62	gold quality
jejunal mucosa	UBERON:0000399	93.58	gold quality
dorsal root ganglion	UBERON:0000044	93.34	gold quality
superior vestibular nucleus	UBERON:0007227	93.18	gold quality
cortex of kidney	UBERON:0001225	93.08	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting AUH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-410-3P	99.27	69.98	2457

Literature-anchored findings (GeneRIF, showing 16)

• monomeric D14-3-3zeta is capable of modulating dSlo channel activity in this regulatory complex. (PMID:12529354)
• These observations provide the first direct evidence that a 14-3-3 protein functions as a stress-induced molecular chaperone that dissolves and renaturalizes thermal-aggregated proteins. (PMID:16943323)
• Results report a bona fide third functional isoform encoded by leo divergent from the other two in structurally and functionally significant areas. (PMID:19665025)
• Hpo signaling inhibited Yki nuclear localization and activity by phosphorylating Yki and both isoforms of 14-3-3, 14-3-3varepsilon and 14-3-3zeta, regulate Yki activity through modulating its subcellular localization. (PMID:19900439)
• in vivo 14-3-3zeta monomer properties and functionality (PMID:19920133)
• The Khc73 stalk/14-3-3/NudE pathway defines a physical connection that coordinates the activities of multiple motor proteins to precisely position the spindle. (PMID:23987511)
• Study suggests a novel mechanism of Tor regulation mediated by 14-3-3 interaction with Tctp and Rheb. (PMID:27151460)
• Our collective data demonstrate the complexity of 14-3-3/Tau interactions in vivo and suggest that 14-3-3 attenuation is not appropriate ameliorative treatment of Tauopathies. Finally, we suggest that ‘bystander’ 14-3-3s are recruited by accumulating Tau with the consequences depending on the composition of available dimers within particular neurons and the Tau variant. (PMID:29659825)
• The adaptor protein 14-3-3zeta modulates intestinal immunity and aging in Drosophila. (PMID:37918806)
• 3-Methylglutaconic aciduria type I is caused by mutations in AUH (PMID:12434311)
• Human 3-methylglutaconyl-CoA hydratase is identical with RNA-binding protein (AUH); molecular analyses of MGA1 patients show homozygosity or compound heterozygosity for mutations in AUH. (PMID:12655555)
• Mutation analysis in the AUH gene revealed homozygosity for a novel splice site mutation IVS9-2A>G. We conclude that MGA1 may be associated with fever-associated seizures even in children without delayed psychomotor development. (PMID:15033206)
• Mutations in the AUH gene are linked to metabolic disease 3-methylglutaconic aciduria type I (MGA1). (PMID:16640564)
• The AUH trimer dimerizes upon binding to one molecule of a long RNA containing 24 repeats of the AUUU motif, (AUUU)(24)A. (PMID:18831052)
• Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel deletion of exons 1-3 within the AUH gene. (PMID:21840233)
• AUH localizes to the inner mitochondrial membrane and matrix where it associates with mitochondrial ribosomes and regulates protein synthesis. (PMID:24598254)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	auh	ENSDARG00000042975
mus_musculus	Auh	ENSMUSG00000021460
rattus_norvegicus	Auh	ENSRNOG00000011684
drosophila_melanogaster	CG14787	FBGN0027793
drosophila_melanogaster	CG8778	FBGN0033761
drosophila_melanogaster	Dci	FBGN0035169
drosophila_melanogaster	HIPP1	FBGN0037027
caenorhabditis_elegans		WBGENE00001154
caenorhabditis_elegans		WBGENE00007130

Paralogs (13): ECHDC1 (ENSG00000093144), ECH1 (ENSG00000104823), ECHDC2 (ENSG00000121310), ECHS1 (ENSG00000127884), CDY2B (ENSG00000129873), ECHDC3 (ENSG00000134463), CDYL (ENSG00000153046), CDYL2 (ENSG00000166446), ECI1 (ENSG00000167969), CDY1 (ENSG00000172288), CDY1B (ENSG00000172352), CDY2A (ENSG00000182415), HIBCH (ENSG00000198130)

Protein

Protein identifiers

Methylglutaconyl-CoA hydratase, mitochondrial — Q13825 (reviewed: Q13825)

Alternative names: AU-specific RNA-binding enoyl-CoA hydratase, Itaconyl-CoA hydratase

All UniProt accessions (1): Q13825

UniProt curated annotations — full annotation on UniProt →

Function. 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). Can catalyze the reverse reaction but at a much lower rate in vitro. HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate. Uses other substrates such as (2E)-glutaconyl-CoA efficiently in vitro, and to a lesser extent 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA), crotonyl-CoA ((2E)-butenoyl-CoA) and 3-hydroxybutanoyl-CoA (the missing carboxylate reduces affinity to the active site). Originally it was identified as an RNA-binding protein as it binds to AU-rich elements (AREs) in vitro. AREs direct rapid RNA degradation and mRNA deadenylation. Might have itaconyl-CoA hydratase activity, converting itaconyl-CoA into citramalyl-CoA in the C5-dicarboxylate catabolism pathway. The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, an antimicrobial metabolite and immunomodulator produced by macrophages during certain infections, that can act as a vitamin B12-poisoning metabolite.

Subunit / interactions. Homohexamer.

Subcellular location. Mitochondrion.

Disease relevance. 3-methylglutaconic aciduria 1 (MGCA1) [MIM:250950] An inborn error of leucine metabolism. It leads to an autosomal recessive syndrome with variable clinical phenotype, ranging from delayed speech development to severe psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. MGCA1 can be distinguished from other forms of MGCA by the pattern of metabolite excretion: 3-methylglutaconic acid levels are higher than those detected in other forms, whereas methylglutaric acid levels are usually only slightly elevated and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other MGCA forms). The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-leucine degradation; (S)-3-hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 3/3.

Similarity. Belongs to the enoyl-CoA hydratase/isomerase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13825-1	1	yes
Q13825-2	2

RefSeq proteins (5): NP_001293119, NP_001338360, NP_001338361, NP_001338362, NP_001689* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001753	Enoyl-CoA_hydra/iso	Domain
IPR014748	Enoyl-CoA_hydra_C	Homologous_superfamily
IPR018376	Enoyl-CoA_hyd/isom_CS	Conserved_site
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily

Pfam: PF00378

Enzyme classification (BRENDA):

• EC 4.2.1.18 — methylglutaconyl-CoA hydratase (BRENDA: 10 organisms, 26 substrates, 4 inhibitors, 18 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRANS-3-METHYLGLUTACONYL-COA	0.0291–0.08	3
(E)-GLUTACONYL-COA	0.0024–0.04	2
(S)-3-HYDROXY-3-METHYLGLUTARYL-COA	0.03–0.0531	2
(S)-3-HYDROXYMETHYLGLUTARYL-COA	0.0069–0.0094	2
(E)-3-METHYLGLUTACONYL-COA	0.0083	1
(R,S)-3-HYDROXY-3-METHYLGLUTARYL-COA	2.25	1
(S)-3-HYDROXYGLUTARYL-COA	0.05	1
3-HYDROXYBUTYRYL-COA	55.2	1
3-METHYLCROTONYL-COA	0.347	1
3-METHYLGLUTACONYL-COA	0.01	1
CROTONYL-COA	12.1	1

Catalyzed reactions (Rhea), 4 shown:

• (3S)-citramalyl-CoA = itaconyl-CoA + H2O (RHEA:13785)
• (3S)-3-hydroxy-3-methylglutaryl-CoA = 3-methyl-(2E)-glutaconyl-CoA + H2O (RHEA:21536)
• 3-hydroxyisovaleryl-CoA = 3-methylbut-2-enoyl-CoA + H2O (RHEA:31079)
• (S)-3-hydroxyglutaryl-CoA = (2E)-glutaconyl-CoA + H2O (RHEA:68456)

UniProt features (48 total): modified residue 14, helix 14, strand 9, mutagenesis site 3, turn 3, transit peptide 1, chain 1, splice variant 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1HZD	X-RAY DIFFRACTION	2.2
2ZQQ	X-RAY DIFFRACTION	2.2
2ZQR	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13825-F1	86.63	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (14): 148, 160, 204, 204, 211, 211, 329, 100, 100, 109, 113, 113, 144, 144

Mutagenesis-validated functional residues (3):

Position	Phenotype
105	abolishes rna-binding; when associated with e-109 and q-113.
109	abolishes rna-binding; when associated with n-105 and q-113.
113	abolishes rna-binding; when associated with n-105 and e-109.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9914274	3-methylglutaconic aciduria
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-9865118	Diseases of branched-chain amino acid catabolism

MSigDB gene sets: 254 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, HOEGERKORP_CD44_TARGETS_TEMPORAL_DN, TGACCTY_ERR1_Q2, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, SCHUHMACHER_MYC_TARGETS_UP, ONKEN_UVEAL_MELANOMA_UP, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_DETOXIFICATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (3): L-leucine catabolic process (GO:0006552), fatty acid beta-oxidation (GO:0006635), branched-chain amino acid catabolic process (GO:0009083)

GO Molecular Function (7): mRNA 3’-UTR binding (GO:0003730), enoyl-CoA hydratase activity (GO:0004300), methylglutaconyl-CoA hydratase activity (GO:0004490), itaconyl-CoA hydratase activity (GO:0050011), RNA binding (GO:0003723), catalytic activity (GO:0003824), lyase activity (GO:0016829)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Diseases of branched-chain amino acid catabolism	1
Disease	1
Metabolism	1
Diseases of metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hydro-lyase activity	3
L-leucine metabolic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
mRNA binding	1
nucleic acid binding	1
molecular_function	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AUH	DNAJC19	Q96DA6	908
AUH	TAFAZZIN	Q16635	843
AUH	IVD	P26440	644
AUH	HMGCL	P35914	628
AUH	HMGCLL1	Q8TB92	559
AUH	CLYBL	Q8N0X4	519
AUH	HIBADH	P31937	418
AUH	ALDH4A1	P30038	418
AUH	AASDH	Q4L235	388
AUH	A0A0A6YYL1	A0A0A6YYL1	370
AUH	ACOD1	A6NK06	359
AUH	CS	O75390	356
AUH	CRAT	P43155	351
AUH	ALDH6A1	Q02252	347
AUH	MCEE	Q96PE7	346

IntAct

20 interactions, top by confidence:

A	B	Type	Score
FOSB	JUN	psi-mi:“MI:0914”(association)	0.690
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
ATP5F1D	NDUFB5	psi-mi:“MI:0914”(association)	0.530
ECHDC2	NDUFS6	psi-mi:“MI:0914”(association)	0.530
AUH	CPLANE1	psi-mi:“MI:0915”(physical association)	0.400
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
	GTPBP10	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
OXLD1	PRORP	psi-mi:“MI:0914”(association)	0.350
HINT2	CST4	psi-mi:“MI:0914”(association)	0.350
MRPL21	FDXR	psi-mi:“MI:0914”(association)	0.350
ECHDC2	DBT	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
UBR4	METTL15	psi-mi:“MI:0914”(association)	0.350

BioGRID (324): AUH (Affinity Capture-MS), AUH (Affinity Capture-MS), AUH (Affinity Capture-MS), AUH (Affinity Capture-MS), AUH (Affinity Capture-MS), AUH (Affinity Capture-MS), AUH (Affinity Capture-MS), AUH (Two-hybrid), C20orf24 (Co-fractionation), DNAJC11 (Co-fractionation), NIPSNAP1 (Co-fractionation), AUH (Co-fractionation), AUH (Co-fractionation), AUH (Co-fractionation), AUH (Co-fractionation)

ESM2 similar proteins: A0PJR5, A9JS71, F1LU71, F1Q575, F1R6N4, F4JML5, O75521, P41942, P52045, Q05871, Q05B89, Q0P4F7, Q0P5I5, Q0V9K2, Q13268, Q13825, Q28C91, Q2HJ73, Q2TAP9, Q3MIE0, Q499N5, Q54HG7, Q54SS0, Q5E9S4, Q5HZQ8, Q5M8W9, Q5XGL6, Q5XIC0, Q5XIE6, Q6AYG5, Q6DRD9, Q6JQN1, Q6NL24, Q6NVY1, Q6NY77, Q78JN3, Q7SY54, Q869N6, Q86XE5, Q8C7H1

Diamond homologs: A0A481WNM8, A0KEL1, A0KV76, A1ADI8, A1JK30, A1RI92, A1S7L6, A3D684, A3QFP3, A4TM82, A4WCW6, A4Y897, A4YI89, A5F2P2, A5WH99, A6WQ25, A7FGK1, A7ZPF8, A8A2L0, A8ADP2, A9N453, B0TL21, B1IXA5, B1LME7, B1X9L4, B2TWV4, B4SZR0, B4TCA8, B4TQC2, B5EZR9, B5FPN1, B5R3R9, B5RCL3, B5XVW2, B5YXY4, B6I6Q4, B7LBJ5, B7LLD0, B7M6M2, B7MGV7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Respiratory electron transport	5	23.8×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

266 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	14
Uncertain significance	120
Likely benign	63
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1321874	NG_008017.1:g.?_(11043_41520)del	Pathogenic
1333620	NM_001698.3(AUH):c.330+1G>A	Pathogenic
1444539	NC_000009.12:g.91220993dup	Pathogenic
1452715	NM_001698.3(AUH):c.721C>T (p.Arg241Ter)	Pathogenic
148528	GRCh38/hg38 9q21.33-22.31(chr9:86079851-91827221)x1	Pathogenic
1686747	NM_001698.3(AUH):c.285_287delinsTTCCA (p.Arg96fs)	Pathogenic
2802918	NM_001698.3(AUH):c.516dup (p.Val173fs)	Pathogenic
2812871	NM_001698.3(AUH):c.471del (p.Phe157fs)	Pathogenic
3004570	NM_001698.3(AUH):c.419-2A>G	Pathogenic
30079	NM_001698.3(AUH):c.559G>A (p.Gly187Ser)	Pathogenic
30080	NM_001698.3(AUH):c.650G>A (p.Gly217Asp)	Pathogenic
619968	NC_000009.12:g.(?91355882)(91361889_?)del	Pathogenic
685654	GRCh37/hg19 9q22.31(chr9:94117511-94122902)x1	Pathogenic
831476	NC_000009.12:g.(?91220785)(91221012_?)del	Pathogenic
850052	NM_001698.3(AUH):c.197del (p.Gly66fs)	Pathogenic
9056	NM_001698.3(AUH):c.589C>T (p.Arg197Ter)	Pathogenic
9057	NM_001698.3(AUH):c.895-1G>A	Pathogenic
9058	NM_001698.3(AUH):c.80del (p.Ser27fs)	Pathogenic
9059	NM_001698.3(AUH):c.263-2A>G	Pathogenic
1067674	NM_001698.3(AUH):c.656-2_656-1del	Likely pathogenic
1332813	NM_001698.3(AUH):c.556G>T (p.Gly186Cys)	Likely pathogenic
214150	NM_001698.3(AUH):c.866C>A (p.Ala289Glu)	Likely pathogenic
2424217	NC_000009.11:g.(?94118145)(94118457_?)del	Likely pathogenic
2664514	NM_001698.3(AUH):c.491T>A (p.Val164Glu)	Likely pathogenic
3382011	NM_001698.3(AUH):c.612_613insC (p.Met205fs)	Likely pathogenic
3892997	NM_001698.3(AUH):c.262+1G>C	Likely pathogenic
422014	NM_001698.3(AUH):c.562dup (p.Leu188fs)	Likely pathogenic
529797	NM_001698.3(AUH):c.719C>T (p.Ala240Val)	Likely pathogenic
642421	NM_001698.3(AUH):c.599-2A>G	Likely pathogenic
810388	NM_001698.3(AUH):c.150G>A (p.Trp50Ter)	Likely pathogenic

SpliceAI

3334 predictions. Top by Δscore:

Variant	Effect	Δscore
9:91214422:TGGT:T	acceptor_gain	1.0000
9:91214426:C:CC	acceptor_gain	1.0000
9:91218863:T:TA	donor_gain	1.0000
9:91220800:AATAC:A	donor_loss	1.0000
9:91220801:ATACC:A	donor_loss	1.0000
9:91220802:TA:T	donor_loss	1.0000
9:91220804:CC:C	donor_loss	1.0000
9:91220840:T:TA	donor_gain	1.0000
9:91220860:T:TA	donor_gain	1.0000
9:91220988:CCCCC:C	acceptor_gain	1.0000
9:91220989:CCCC:C	acceptor_gain	1.0000
9:91220989:CCCCC:C	acceptor_gain	1.0000
9:91220990:CCC:C	acceptor_gain	1.0000
9:91220990:CCCC:C	acceptor_gain	1.0000
9:91220991:CC:C	acceptor_gain	1.0000
9:91220991:CCC:C	acceptor_gain	1.0000
9:91220992:CC:C	acceptor_gain	1.0000
9:91220993:C:A	acceptor_loss	1.0000
9:91220993:C:CC	acceptor_gain	1.0000
9:91220993:C:T	acceptor_gain	1.0000
9:91220994:T:C	acceptor_loss	1.0000
9:91221000:G:C	acceptor_gain	1.0000
9:91221000:G:GC	acceptor_gain	1.0000
9:91296078:C:CC	acceptor_gain	1.0000
9:91297978:TCTTA:T	donor_loss	1.0000
9:91297979:CTTA:C	donor_loss	1.0000
9:91297980:TTACC:T	donor_loss	1.0000
9:91297981:TACCT:T	donor_loss	1.0000
9:91297982:ACC:A	donor_loss	1.0000
9:91297983:C:CG	donor_loss	1.0000

AlphaMissense

2160 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:91217297:C:G	A292P	0.999
9:91220938:A:T	I237K	0.999
9:91220980:C:G	R223P	0.999
9:91298052:G:T	A177E	0.999
9:91355889:A:G	C138R	0.999
9:91355908:A:C	S131R	0.999
9:91355908:A:T	S131R	0.999
9:91355910:T:G	S131R	0.999
9:91214410:C:G	D320H	0.998
9:91216091:C:A	G304W	0.998
9:91217285:C:A	G296W	0.998
9:91217296:G:T	A292E	0.998
9:91220837:C:G	A271P	0.998
9:91220938:A:C	I237R	0.998
9:91220941:A:G	L236P	0.998
9:91220990:C:A	G220W	0.998
9:91220992:C:T	G219E	0.998
9:91296029:G:T	P216H	0.998
9:91296049:T:A	E209D	0.998
9:91296049:T:G	E209D	0.998
9:91296050:T:A	E209V	0.998
9:91297998:T:A	D195V	0.998
9:91298019:A:G	L188P	0.998
9:91298034:G:T	A183D	0.998
9:91298055:A:T	I176N	0.998
9:91355909:C:A	S131I	0.998
9:91355918:A:T	I128K	0.998
9:91214384:A:C	F328L	0.997
9:91214384:A:T	F328L	0.997
9:91214386:A:G	F328L	0.997

dbSNP variants (sampled 300 via entrez): RS1000017311 (9:91344334 C>T), RS1000021162 (9:91241299 T>G), RS1000031912 (9:91336507 G>A,C), RS1000042390 (9:91306463 T>A), RS1000046141 (9:91302246 T>C), RS1000085961 (9:91256739 A>G), RS1000091314 (9:91213441 G>A,C), RS1000101596 (9:91260187 CCTT>C), RS1000127926 (9:91273986 T>A), RS1000130658 (9:91325289 T>C), RS1000177012 (9:91360993 T>C), RS1000177741 (9:91317463 T>C), RS1000210297 (9:91350300 T>G), RS1000211979 (9:91266843 T>C), RS1000228008 (9:91324289 G>A,C)

Disease associations

OMIM: gene MIM:600529 | disease phenotypes: MIM:250950

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
3-methylglutaconic aciduria type 1	Definitive	AR

Mondo (2): 3-methylglutaconic aciduria type 1 (MONDO:0009610), 3-methylglutaconic aciduria (MONDO:0017359)

Orphanet (2): 3-methylglutaconic aciduria type 1 (Orphanet:67046), 3-methylglutaconic aciduria (Orphanet:289902)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000648	Optic atrophy
HP:0000726	Dementia
HP:0000736	Short attention span
HP:0000742	Self-mutilation
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001285	Spastic tetraparesis
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002059	Cerebral atrophy
HP:0002073	Progressive cerebellar ataxia
HP:0002134	Abnormal basal ganglia morphology
HP:0002240	Hepatomegaly
HP:0002305	Athetosis
HP:0002352	Leukoencephalopathy
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002500	Abnormal cerebral white matter morphology
HP:0002510	Spastic tetraplegia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000909_1	Type 2 diabetes nephropathy	6.000000e-06
GCST002749_9	Response to Homoharringtonine (cytotoxicity)	7.000000e-06
GCST002815_1	Bipolar disorder (inflammation and infection response interaction)	8.000000e-06
GCST004131_125	Inflammatory bowel disease	4.000000e-06
GCST004606_10	Eosinophil count	1.000000e-14
GCST004617_169	Eosinophil percentage of granulocytes	4.000000e-11
GCST004624_134	Sum eosinophil basophil counts	5.000000e-13
GCST005980_18	Total bilirubin levels	2.000000e-12
GCST010242_63	HDL cholesterol levels	4.000000e-09
GCST012229_69	Hip index	2.000000e-08
GCST90002381_477	Eosinophil count	3.000000e-25
GCST90002382_295	Eosinophil percentage of white cells	3.000000e-23
GCST90002406_278	Reticulocyte fraction of red cells	4.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0007037	cytomegalovirus seropositivity
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0004570	bilirubin measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C579867	3-Methylglutaconic Aciduria (supp.)
C562801	3-Methylglutaconic Aciduria, Type I (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Air Pollutants	increases abundance, decreases expression, affects expression	2
Silicon Dioxide	decreases expression	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
lead acetate	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
periodate-oxidized adenosine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
candoxin	decreases expression	1
ICG 001	decreases expression	1
Sunitinib	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1
Quartz	increases expression	1
Quercetin	decreases expression	1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan