AMDHD2

Summary

AMDHD2 (amidohydrolase domain containing 2, HGNC:24262) is a protein-coding gene on chromosome 16p13.3, encoding N-acetylglucosamine-6-phosphate deacetylase (Q9Y303). Hydrolyzes the N-glycolyl group from N-glycolylglucosamine 6-phosphate (GlcNGc-6-P) in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway.

Enables N-acetylglucosamine-6-phosphate deacetylase activity. Involved in negative regulation of UDP-N-acetylglucosamine biosynthetic process. Located in nucleus.

Source: NCBI Gene 51005 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 118 total — 1 pathogenic, 3 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001330449

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24262
Approved symbol	AMDHD2
Name	amidohydrolase domain containing 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	CGI-14
Ensembl gene	ENSG00000162066
Ensembl biotype	protein_coding
OMIM	620864
Entrez	51005

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 14 protein_coding, 9 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000293971, ENST00000302956, ENST00000413459, ENST00000561487, ENST00000563145, ENST00000563444, ENST00000563453, ENST00000563556, ENST00000563633, ENST00000565570, ENST00000565963, ENST00000566706, ENST00000566947, ENST00000567475, ENST00000568263, ENST00000569219, ENST00000569879, ENST00000570028, ENST00000648227, ENST00000872243, ENST00000872244, ENST00000872245, ENST00000872246, ENST00000872247, ENST00000915809

RefSeq mRNA: 4 — MANE Select: NM_001330449 NM_001145815, NM_001330449, NM_001410943, NM_015944

CCDS: CCDS10471, CCDS53984, CCDS81936, CCDS92088

Canonical transcript exons

ENST00000293971 — 11 exons

Exon	Start	End
ENSE00001234307	2529475	2531417
ENSE00003496199	2528452	2528559
ENSE00003505260	2528650	2528718
ENSE00003514246	2528994	2529095
ENSE00003527301	2520984	2521123
ENSE00003541132	2528060	2528148
ENSE00003563063	2520769	2520905
ENSE00003565655	2527561	2527615
ENSE00003590669	2528236	2528380
ENSE00003605028	2527773	2527985
ENSE00003905479	2520371	2520541

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 94.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6778 / max 148.7481, expressed in 1805 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152246	11.5811	1803
152247	0.9614	604
152248	0.1353	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	94.46	gold quality
right testis	UBERON:0004534	93.61	gold quality
testis	UBERON:0000473	91.28	gold quality
right adrenal gland cortex	UBERON:0035827	91.06	gold quality
right adrenal gland	UBERON:0001233	90.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.36	gold quality
spleen	UBERON:0002106	90.08	gold quality
left adrenal gland	UBERON:0001234	90.02	gold quality
right uterine tube	UBERON:0001302	90.02	gold quality
left adrenal gland cortex	UBERON:0035825	89.90	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.82	gold quality
cerebellar hemisphere	UBERON:0002245	89.49	gold quality
cerebellar cortex	UBERON:0002129	89.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.09	gold quality
adrenal cortex	UBERON:0001235	88.57	gold quality
granulocyte	CL:0000094	88.48	gold quality
right lobe of thyroid gland	UBERON:0001119	88.44	gold quality
right frontal lobe	UBERON:0002810	88.15	gold quality
stromal cell of endometrium	CL:0002255	88.12	gold quality
metanephros cortex	UBERON:0010533	87.83	gold quality
transverse colon	UBERON:0001157	87.59	gold quality
left lobe of thyroid gland	UBERON:0001120	87.46	gold quality
minor salivary gland	UBERON:0001830	87.40	gold quality
adrenal gland	UBERON:0002369	87.35	gold quality
small intestine	UBERON:0002108	87.21	gold quality
cerebellum	UBERON:0002037	87.12	gold quality
apex of heart	UBERON:0002098	86.78	gold quality
skin of leg	UBERON:0001511	86.57	gold quality
ectocervix	UBERON:0012249	86.57	gold quality
mucosa of transverse colon	UBERON:0004991	86.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

1 targeting AMDHD2, 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-4308	97.56	67.13	1385

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	amdhd2	ENSDARG00000100376
mus_musculus	Amdhd2	ENSMUSG00000036820
rattus_norvegicus	Amdhd2	ENSRNOG00000006460
drosophila_melanogaster	CG17065	FBGN0031099
caenorhabditis_elegans		WBGENE00010308

Protein

Protein identifiers

N-acetylglucosamine-6-phosphate deacetylase — Q9Y303 (reviewed: Q9Y303)

Alternative names: Amidohydrolase domain-containing protein 2

All UniProt accessions (7): A0A3B3IU33, Q9Y303, H3BSD5, H3BSV9, H3BT49, H3BTE3, H3BTZ6

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the N-glycolyl group from N-glycolylglucosamine 6-phosphate (GlcNGc-6-P) in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway. Although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded.

Cofactor. Binds 1 divalent metal cation per subunit.

Pathway. Amino-sugar metabolism; N-acetylneuraminate degradation.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y303-1	1	yes
Q9Y303-2	2
Q9Y303-3	3

RefSeq proteins (4): NP_001139287, NP_001317378, NP_001397872, NP_057028 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003764	GlcNAc_6-P_deAcase	Family
IPR006680	Amidohydro-rel	Domain
IPR011059	Metal-dep_hydrolase_composite	Homologous_superfamily
IPR032466	Metal_Hydrolase	Homologous_superfamily

Pfam: PF01979

Catalyzed reactions (Rhea), 1 shown:

• N-acetyl-D-glucosamine 6-phosphate + H2O = D-glucosamine 6-phosphate + acetate (RHEA:22936)

UniProt features (64 total): strand 26, helix 15, binding site 8, sequence conflict 5, turn 5, splice variant 2, chain 1, active site 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7NUU	X-RAY DIFFRACTION	1.84
7NUT	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y303-F1	94.49	0.87

Functional residue map

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

Catalytic / active sites (1): 294 (proton donor/acceptor)

Ligand- & substrate-binding residues (8): 143; 154–155; 211; 232; 235–236; 243; 269–272; 328–330

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-446210	Synthesis of UDP-N-acetyl-glucosamine
R-HSA-392499	Metabolism of proteins
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-446219	Synthesis of substrates in N-glycan biosythesis
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 134 (showing top): RNGTGGGC_UNKNOWN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_AMINO_SUGAR_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, CHANDRAN_METASTASIS_DN, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, USF_01, GOBP_NEGATIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_AMINO_SUGAR_CATABOLIC_PROCESS

GO Biological Process (5): N-acetylglucosamine catabolic process (GO:0006046), UDP-N-acetylglucosamine biosynthetic process (GO:0006048), N-acetylneuraminate catabolic process (GO:0019262), negative regulation of UDP-N-acetylglucosamine biosynthetic process (GO:0106279), N-acetylglucosamine metabolic process (GO:0006044)

GO Molecular Function (5): N-acetylglucosamine-6-phosphate deacetylase activity (GO:0008448), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810)

GO Cellular Component (2): nucleus (GO:0005634), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Synthesis of substrates in N-glycan biosythesis	1
Asparagine N-linked glycosylation	1
Post-translational protein modification	1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
N-acetylglucosamine metabolic process	1
glucosamine-containing compound catabolic process	1
UDP-N-acetylglucosamine metabolic process	1
nucleotide-sugar biosynthetic process	1
amino sugar biosynthetic process	1
N-acetylneuraminate metabolic process	1
amino sugar catabolic process	1
carboxylic acid catabolic process	1
UDP-N-acetylglucosamine biosynthetic process	1
negative regulation of biosynthetic process	1
negative regulation of phosphorus metabolic process	1
negative regulation of nucleobase-containing compound metabolic process	1
negative regulation of small molecule metabolic process	1
regulation of UDP-N-acetylglucosamine biosynthetic process	1
amino sugar metabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
deacetylase activity	1
cation binding	1
binding	1
catalytic activity	1
hydrolase activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1260 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMDHD2	GNPDA1	P46926	827
AMDHD2	GNPDA2	Q8TDQ7	788
AMDHD2	NAGK	Q9UJ70	605
AMDHD2	LITAFD	A0A1B0GVX0	550
AMDHD2	GFPT2	O94808	549
AMDHD2	GFPT1	Q06210	517
AMDHD2	PGM3	O95394	498
AMDHD2	OR6N1	Q8NGY5	493
AMDHD2	OR6N2	Q8NGY6	489
AMDHD2	GNE	Q9Y223	473
AMDHD2	TEX13B	Q9BXU2	470
AMDHD2	CDC42EP2	O14613	453
AMDHD2	NANS	Q9NR45	450
AMDHD2	TPI1	P00938	448
AMDHD2	NAGA	P17050	446

IntAct

18 interactions, top by confidence:

A	B	Type	Score
AMDHD2	GNPDA2	psi-mi:“MI:0915”(physical association)	0.800
GNPDA2	AMDHD2	psi-mi:“MI:0915”(physical association)	0.800
GNPDA2	GNPDA1	psi-mi:“MI:0914”(association)	0.640
AMDHD2	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
TRIP13	AMDHD2	psi-mi:“MI:0915”(physical association)	0.560
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
GNPDA1	SEC31A	psi-mi:“MI:0914”(association)	0.350
GNPDA2	MYH11	psi-mi:“MI:0914”(association)	0.350
GNPDA1	ABLIM3	psi-mi:“MI:0914”(association)	0.350
TGIF2	ZNF213	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
purL	AMDHD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): AMDHD2 (Two-hybrid), GNPDA2 (Two-hybrid), AMDHD2 (Affinity Capture-MS), AMDHD2 (Co-fractionation), GNPDA1 (Co-fractionation), GNPDA2 (Co-fractionation), AMDHD2 (Affinity Capture-MS), AMDHD2 (Two-hybrid), AMDHD2 (Two-hybrid), GNPDA2 (Two-hybrid), AMDHD2 (Affinity Capture-MS), AMDHD2 (Affinity Capture-MS), AMDHD2 (Co-fractionation), AMDHD2 (Affinity Capture-MS), AMDHD2 (Affinity Capture-MS)

ESM2 similar proteins: A1A4L8, A2BDX3, A4RPM5, A5GFZ6, A6NK58, B4FAT0, B4NXF7, B6TNK6, O19179, O43323, O95396, O95571, P19971, P55203, P85971, Q02846, Q05922, Q08DH8, Q0VFH3, Q14BV6, Q17CA7, Q1WNP0, Q3KQV9, Q3TW96, Q3UQ84, Q561R2, Q58E95, Q5PQQ1, Q5ZKI2, Q61488, Q66JK4, Q6PAT0, Q7PY41, Q86U10, Q8AWD2, Q8NFV4, Q8VBZ0, Q8VDG5, Q923K4, Q96EY9

Diamond homologs: A0KYQ5, A7MBC0, O32445, O34450, P0AF18, P0AF19, P34480, P42906, P44537, P96166, Q5BJY6, Q6P0U0, Q8JZV7, Q8XAC3, Q9VR81, Q9Y303, Q84F86, A0B6I9, A1SPZ7, A4YXM5, A5EGE2, Q11JE6, Q1M901, Q28MB2, Q6ANH2, Q89QG3, A0AJJ5, A0AJU2, A0RHR0, A5D1A4, A7GRL3, A9VTC8, B1HQB9, B2TNG1, B2UW91, B3E3I1, B7H6M4, B7HLM2, B7IUP8, B7JJX5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	102
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
59427	GRCh38/hg38 16p13.3(chr16:2494804-3246579)x1	Pathogenic
152712	GRCh38/hg38 16p13.3(chr16:2406643-2782411)x1	Likely pathogenic
2685540	GRCh37/hg19 16p13.3(chr16:2480793-2590012)x1	Likely pathogenic
3233449	NM_001694.4(ATP6V0C):c.283G>A (p.Ala95Thr)	Likely pathogenic

SpliceAI

1652 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2520542:G:A	donor_loss	1.0000
16:2520543:T:A	donor_loss	1.0000
16:2521121:AAG:A	donor_loss	1.0000
16:2521123:GGTGA:G	donor_loss	1.0000
16:2521125:T:G	donor_loss	1.0000
16:2527771:AGGG:A	acceptor_loss	1.0000
16:2527940:G:GT	donor_gain	1.0000
16:2528145:GCCT:G	donor_gain	1.0000
16:2528149:G:GG	donor_gain	1.0000
16:2528229:T:TA	acceptor_gain	1.0000
16:2528233:CA:C	acceptor_loss	1.0000
16:2528234:A:AG	acceptor_gain	1.0000
16:2528234:A:G	acceptor_loss	1.0000
16:2528235:G:GA	acceptor_gain	1.0000
16:2528377:CAGG:C	donor_loss	1.0000
16:2528379:GG:G	donor_gain	1.0000
16:2528380:GG:G	donor_gain	1.0000
16:2528380:GGT:G	donor_loss	1.0000
16:2528446:CCCCA:C	acceptor_loss	1.0000
16:2528447:CCCAG:C	acceptor_loss	1.0000
16:2528448:CCAGG:C	acceptor_loss	1.0000
16:2528449:CAGG:C	acceptor_loss	1.0000
16:2528450:A:AG	acceptor_gain	1.0000
16:2528450:AG:A	acceptor_gain	1.0000
16:2528450:AGG:A	acceptor_gain	1.0000
16:2528451:G:GA	acceptor_gain	1.0000
16:2528451:GG:G	acceptor_gain	1.0000
16:2528451:GGG:G	acceptor_gain	1.0000
16:2528451:GGGC:G	acceptor_gain	1.0000
16:2528451:GGGCT:G	acceptor_gain	1.0000

AlphaMissense

2627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2528470:A:T	D294V	0.998
16:2527785:A:T	E143V	0.996
16:2528467:C:T	T293I	0.996
16:2527786:G:C	E143D	0.995
16:2527786:G:T	E143D	0.995
16:2528064:C:A	H211Q	0.995
16:2528064:C:G	H211Q	0.995
16:2528127:C:A	H232Q	0.995
16:2528127:C:G	H232Q	0.995
16:2528471:T:A	D294E	0.995
16:2528471:T:G	D294E	0.995
16:2527778:C:G	H141D	0.994
16:2527787:G:C	G144R	0.994
16:2527820:C:G	H155D	0.994
16:2528131:T:A	F234I	0.994
16:2528131:T:C	F234L	0.994
16:2528133:C:A	F234L	0.994
16:2528133:C:G	F234L	0.994
16:2528469:G:C	D294H	0.994
16:2528125:C:G	H232D	0.993
16:2528360:C:A	A281D	0.993
16:2528470:A:C	D294A	0.993
16:2528062:C:G	H211D	0.992
16:2528136:C:A	N235K	0.992
16:2528136:C:G	N235K	0.992
16:2528470:A:G	D294G	0.992
16:2528472:G:C	A295P	0.992
16:2520904:C:A	N73K	0.991
16:2520904:C:G	N73K	0.991
16:2521076:T:C	S105P	0.991

dbSNP variants (sampled 300 via entrez): RS1000559638 (16:2529814 G>A), RS1000632820 (16:2528883 C>T), RS1001340209 (16:2521279 C>T), RS1001497812 (16:2524364 C>T), RS1001672285 (16:2520865 C>A,T), RS1001766817 (16:2520530 G>A,T), RS1001903669 (16:2525705 C>G,T), RS1002134066 (16:2529229 C>G,T), RS1002345857 (16:2521603 G>T), RS1002558552 (16:2522704 G>C), RS1002703786 (16:2526956 T>A), RS1002715013 (16:2526751 T>C), RS1002850708 (16:2521433 C>A,G,T), RS1002868224 (16:2531400 C>G), RS1002919739 (16:2522889 G>GCCTC)

Disease associations

OMIM: gene MIM:620864 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): childhood-onset epilepsy syndrome (MONDO:0020072)

Orphanet (1): Childhood-onset epilepsy syndrome (Orphanet:98259)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3217376 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.47	Ki	34	nM	CHEMBL3219353

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
sodium arsenite	increases expression	2
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
beta-lapachone	decreases expression, increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
pyrimidifen	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Benzo(a)pyrene	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3223708	Binding	Inhibition of NagA (unknown origin)	The use of phosphate bioisosteres in medicinal chemistry and chemical biology — Medchemcomm

Clinical trials (associated diseases)

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