AMDHD1

Summary

AMDHD1 (amidohydrolase domain containing 1, HGNC:28577) is a protein-coding gene on chromosome 12q23.1, encoding Probable imidazolonepropionase (Q96NU7).

Predicted to enable imidazolonepropionase activity. Predicted to be involved in L-histidine catabolic process. Predicted to be located in cytosol.

Source: NCBI Gene 144193 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 69 total
• MANE Select transcript: NM_152435

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28577
Approved symbol	AMDHD1
Name	amidohydrolase domain containing 1
Location	12q23.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC35366
Ensembl gene	ENSG00000139344
Ensembl biotype	protein_coding
OMIM	620863
Entrez	144193

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000266736, ENST00000548310, ENST00000549171, ENST00000553023, ENST00000869918, ENST00000869919, ENST00000869920

RefSeq mRNA: 1 — MANE Select: NM_152435 NM_152435

CCDS: CCDS9057

Canonical transcript exons

ENST00000266736 — 9 exons

Exon	Start	End
ENSE00001280254	95943331	95943535
ENSE00002393164	95967756	95968720
ENSE00003481490	95966348	95966508
ENSE00003488380	95962355	95962479
ENSE00003493938	95960398	95960623
ENSE00003547502	95965686	95965779
ENSE00003612578	95956685	95956962
ENSE00003618100	95952717	95952823
ENSE00003651062	95954911	95954975

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 97.43.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3747 / max 347.4431, expressed in 359 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127448	0.8697	172
127446	0.2913	124
127447	0.2137	82

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.43	gold quality
liver	UBERON:0002107	97.29	gold quality
bone marrow cell	CL:0002092	94.66	gold quality
adrenal tissue	UBERON:0018303	93.04	gold quality
sural nerve	UBERON:0015488	91.16	gold quality
right adrenal gland cortex	UBERON:0035827	86.29	gold quality
adrenal gland	UBERON:0002369	84.90	gold quality
right adrenal gland	UBERON:0001233	84.68	gold quality
left adrenal gland	UBERON:0001234	84.22	gold quality
adrenal cortex	UBERON:0001235	84.06	gold quality
left adrenal gland cortex	UBERON:0035825	83.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.10	gold quality
kidney epithelium	UBERON:0004819	82.19	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.01	gold quality
adult mammalian kidney	UBERON:0000082	73.87	gold quality
colonic epithelium	UBERON:0000397	73.73	gold quality
spleen	UBERON:0002106	72.24	gold quality
gastrocnemius	UBERON:0001388	72.08	gold quality
kidney	UBERON:0002113	71.97	gold quality
apex of heart	UBERON:0002098	71.96	gold quality
granulocyte	CL:0000094	71.80	gold quality
muscle of leg	UBERON:0001383	71.34	gold quality
tonsil	UBERON:0002372	69.85	gold quality
right testis	UBERON:0004534	68.75	gold quality
cerebellar hemisphere	UBERON:0002245	67.94	gold quality
cerebellar cortex	UBERON:0002129	67.86	gold quality
cerebellum	UBERON:0002037	67.08	gold quality
metanephros	UBERON:0000081	66.84	gold quality
body of pancreas	UBERON:0001150	66.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting AMDHD1, 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-3646	100.00	73.56	5283
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-4464	98.95	67.73	820

Literature-anchored findings (GeneRIF, showing 1)

• This larger GWAS yields two loci harboring genome-wide significant variants affecting serum 25-hydroxyvitamin D levels (P = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-14) at rs10745742 in AMDHD1). (PMID:29343764)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	amdhd1	ENSDARG00000007366
mus_musculus	Amdhd1	ENSMUSG00000015890
rattus_norvegicus	Amdhd1	ENSRNOG00000005266
caenorhabditis_elegans		WBGENE00020436

Protein

Protein identifiers

Probable imidazolonepropionase — Q96NU7 (reviewed: Q96NU7)

Alternative names: Amidohydrolase domain-containing protein 1

All UniProt accessions (2): Q96NU7, H0YI62

UniProt curated annotations — full annotation on UniProt →

Cofactor. Binds 1 zinc or iron ion per subunit.

Pathway. Amino-acid degradation; L-histidine degradation into L-glutamate; N-formimidoyl-L-glutamate from L-histidine: step 3/3.

Similarity. Belongs to the metallo-dependent hydrolases superfamily. HutI family.

RefSeq proteins (1): NP_689648* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005920	HutI	Family
IPR006680	Amidohydro-rel	Domain
IPR011059	Metal-dep_hydrolase_composite	Homologous_superfamily
IPR032466	Metal_Hydrolase	Homologous_superfamily

Pfam: PF01979

Catalyzed reactions (Rhea), 1 shown:

• 4-imidazolone-5-propanoate + H2O = N-formimidoyl-L-glutamate (RHEA:23660)

UniProt features (12 total): binding site 9, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NU7-F1	96.23	0.92

Functional residue map

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

Ligand- & substrate-binding residues (9): 159; 159; 192; 260; 260; 263; 334; 334; 336

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70921	Histidine catabolism

MSigDB gene sets: 82 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_HISTIDINE_METABOLISM, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, TATA_C, GOBP_AMINO_ACID_CATABOLIC_PROCESS, GOBP_AROMATIC_AMINO_ACID_FAMILY_CATABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_UP

GO Biological Process (4): L-histidine catabolic process (GO:0006548), obsolete L-histidine catabolic process to glutamate and formamide (GO:0019556), obsolete L-histidine catabolic process to glutamate and formate (GO:0019557), obsolete L-histidine metabolic process (GO:0006547)

GO Molecular Function (7): hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides (GO:0016812), metal ion binding (GO:0046872), imidazolonepropionase activity (GO:0050480), molecular_function (GO:0003674), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
aromatic amino acid catabolic process	1
imidazole-containing compound catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cation binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides	1
binding	1
catalytic activity	1
hydrolase activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1110 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMDHD1	CYP2R1	Q6VVX0	736
AMDHD1	SEC23A	Q15436	716
AMDHD1	HAL	P42357	709
AMDHD1	UROC1	Q96N76	694
AMDHD1	CYP24A1	Q07973	684
AMDHD1	NADSYN1	Q6IA69	660
AMDHD1	FTCD	O95954	644
AMDHD1	DHCR7	Q9UBM7	584
AMDHD1	ADSS2	P30520	436
AMDHD1	ADSL	P30566	429
AMDHD1	GMPS	P49915	396
AMDHD1	TPI1	P00938	390
AMDHD1	NOXRED1	Q6NXP6	387
AMDHD1	KLHDC9	Q8NEP7	386
AMDHD1	ADSS1	Q8N142	382

IntAct

5 interactions, top by confidence:

A	B	Type	Score
AMDHD1	KLHL23	psi-mi:“MI:0915”(physical association)	0.590
SYT11	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): KLHL23 (Affinity Capture-MS), EIF1AX (Affinity Capture-MS), AMDHD1 (Co-fractionation), KLHL23 (Affinity Capture-MS), KLHL23 (Affinity Capture-MS), AMDHD1 (Affinity Capture-MS), AMDHD1 (Affinity Capture-MS)

ESM2 similar proteins: A0KF84, A1JS25, A1S1N6, A4SSN5, A4TJT7, A4XZQ4, A5F1X8, A5WA64, A6T6K7, A7FIK8, A9MJF3, A9MTJ5, A9QZ55, B4TC41, B4TQT2, B5BC37, B5ETN4, B5F065, B5FP54, B5QX58, B5R754, B5XZ83, C0PWX5, C1CWB5, C3LLQ1, Q0BZK3, Q1C8A1, Q1CJP8, Q1I3R1, Q2SEP8, Q3KJE5, Q48CD3, Q4KJN0, Q57RH0, Q5E0C3, Q5PG58, Q64NP4, Q66B14, Q6AKP5, Q7N291

Diamond homologs: A0KRC4, A0LKV6, A0RH37, A1RQ59, A1S1N6, A2RGR8, A3CL31, A3DAF6, A3QJH7, A4IMP4, A4Y1I0, A5VFA5, A6KX92, A6LI30, A6TSW9, A6WHH8, A7GQZ8, A7RX26, A7ZAE6, A8AZ63, A8G1S8, A8MF65, A9AW17, A9KV78, A9VPT6, B0KCB7, B0KM55, B0R543, B0SYU7, B0TM54, B1KP58, B2RLA8, B3R6A3, B5XIX5, B7HCC8, B7HKI9, B7ISJ0, B7JI78, B8CGY2, B8E3L5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1373 predictions. Top by Δscore:

Variant	Effect	Δscore
12:95943532:GCAA:G	donor_gain	1.0000
12:95943536:G:GG	donor_gain	1.0000
12:95956957:GCC:G	donor_gain	1.0000
12:95956959:C:CG	donor_gain	1.0000
12:95956959:C:G	donor_gain	1.0000
12:95956963:G:GG	donor_gain	1.0000
12:95960396:A:AG	acceptor_gain	1.0000
12:95960397:G:GG	acceptor_gain	1.0000
12:95960397:GA:G	acceptor_gain	1.0000
12:95960397:GAGGA:G	acceptor_gain	1.0000
12:95960615:GCTGC:G	donor_gain	1.0000
12:95962353:A:AG	acceptor_gain	1.0000
12:95962353:AGCTT:A	acceptor_gain	1.0000
12:95962354:G:GA	acceptor_gain	1.0000
12:95962354:GC:G	acceptor_gain	1.0000
12:95962354:GCTT:G	acceptor_gain	1.0000
12:95962354:GCTTG:G	acceptor_gain	1.0000
12:95965684:A:AG	acceptor_gain	1.0000
12:95965685:G:GA	acceptor_gain	1.0000
12:95965685:GACT:G	acceptor_gain	1.0000
12:95965742:G:GT	donor_gain	1.0000
12:95965742:G:T	donor_gain	1.0000
12:95965776:AATGG:A	donor_loss	1.0000
12:95965779:GGTA:G	donor_loss	1.0000
12:95965780:G:GA	donor_loss	1.0000
12:95965781:T:A	donor_loss	1.0000
12:95966340:T:TA	acceptor_gain	1.0000
12:95966345:TA:T	acceptor_loss	1.0000
12:95966346:A:AG	acceptor_gain	1.0000
12:95966346:A:AT	acceptor_loss	1.0000

AlphaMissense

2790 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:95960504:T:C	F232L	0.997
12:95960506:T:A	F232L	0.997
12:95960506:T:G	F232L	0.997
12:95962385:A:C	S282R	0.997
12:95962387:C:A	S282R	0.997
12:95962387:C:G	S282R	0.997
12:95965744:A:C	S333R	0.997
12:95965746:T:A	S333R	0.997
12:95965746:T:G	S333R	0.997
12:95965748:A:T	D334V	0.997
12:95954931:C:G	H89D	0.996
12:95956843:G:C	K156N	0.996
12:95956843:G:T	K156N	0.996
12:95965749:T:A	D334E	0.996
12:95965749:T:G	D334E	0.996
12:95954933:T:A	H89Q	0.995
12:95954933:T:G	H89Q	0.995
12:95965755:C:A	N336K	0.995
12:95965755:C:G	N336K	0.995
12:95967757:T:A	W399R	0.995
12:95967757:T:C	W399R	0.995
12:95956842:A:T	K156M	0.994
12:95956844:A:C	S157R	0.994
12:95956846:T:A	S157R	0.994
12:95956846:T:G	S157R	0.994
12:95962388:C:G	H283D	0.994
12:95962390:C:A	H283Q	0.994
12:95962390:C:G	H283Q	0.994
12:95954919:G:C	D85H	0.993
12:95954940:T:A	W92R	0.993

dbSNP variants (sampled 300 via entrez): RS1000067318 (12:95964494 T>C), RS1000135586 (12:95963049 T>C), RS1000178905 (12:95958032 G>A), RS1000397522 (12:95958294 A>T), RS1000424561 (12:95968626 C>T), RS1000460880 (12:95959154 G>A), RS1000693188 (12:95964648 C>G,T), RS1000752906 (12:95968988 C>T), RS1000784142 (12:95951149 C>G), RS1000837195 (12:95942221 A>C), RS1000888926 (12:95943741 C>T), RS1000934210 (12:95950781 T>C,G), RS1000969436 (12:95957274 T>C), RS1001084763 (12:95952436 A>G), RS1001216993 (12:95945415 T>A)

Disease associations

OMIM: gene MIM:620863 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005366_5	Vitamin D levels (dietary vitamin D intake interaction)	1.000000e-07
GCST005367_1	Vitamin D levels	2.000000e-20
GCST010002_220	Refractive error	1.000000e-19

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008539	vitamin D dietary intake measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	6
Benzo(a)pyrene	increases methylation, decreases expression	3
Cyclosporine	decreases expression	3
trichostatin A	decreases expression	2
Diethylhexyl Phthalate	decreases methylation, increases abundance, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Temozolomide	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Glycochenodeoxycholic Acid	decreases expression, affects cotreatment	1
Glycocholic Acid	affects cotreatment, decreases expression	1
Glycodeoxycholic Acid	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Oxyquinoline	decreases expression	1
Aflatoxin B1	decreases expression, decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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