NAGS

Summary

NAGS (N-acetylglutamate synthase, HGNC:17996) is a protein-coding gene on chromosome 17q21.31, encoding N-acetylglutamate synthase, mitochondrial (Q8N159). Plays a role in the regulation of ureagenesis by producing the essential cofactor N-acetylglutamate (NAG), thus modulating carbamoylphosphate synthase I (CPS1) activity.

The N-acetylglutamate synthase gene encodes a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme-A. NAG is a cofactor of carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle in mammals. This gene may regulate ureagenesis by altering NAG availability and, thereby, CPSI activity. Deficiencies in N-acetylglutamate synthase have been associated with hyperammonemia.

Source: NCBI Gene 162417 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperammonemia due to N-acetylglutamate synthase deficiency (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 704 total — 37 pathogenic, 63 likely-pathogenic
• Phenotypes (HPO): 54
• MANE Select transcript: NM_153006

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17996
Approved symbol	NAGS
Name	N-acetylglutamate synthase
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	AGAS, ARGA, NAT7
Ensembl gene	ENSG00000161653
Ensembl biotype	protein_coding
OMIM	608300
Entrez	162417

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000293404, ENST00000589767, ENST00000592915, ENST00000906977, ENST00000906978

RefSeq mRNA: 1 — MANE Select: NM_153006 NM_153006

CCDS: CCDS11473

Canonical transcript exons

ENST00000293404 — 7 exons

Exon	Start	End
ENSE00001118574	44007323	44007494
ENSE00001118575	44006529	44006709
ENSE00001118578	44006024	44006237
ENSE00002394758	44005637	44005911
ENSE00002855826	44004622	44005089
ENSE00003577439	44007591	44007773
ENSE00003892665	44008448	44009068

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 95.61.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7839 / max 44.1708, expressed in 301 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161100	0.5786	219
161102	0.1408	66
161101	0.0644	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	95.61	gold quality
right lobe of liver	UBERON:0001114	93.48	gold quality
jejunal mucosa	UBERON:0000399	87.23	gold quality
liver	UBERON:0002107	87.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.47	gold quality
duodenum	UBERON:0002114	83.88	gold quality
mucosa of transverse colon	UBERON:0004991	80.73	gold quality
pancreatic ductal cell	CL:0002079	78.72	silver quality
kidney epithelium	UBERON:0004819	76.78	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.25	gold quality
small intestine	UBERON:0002108	76.06	gold quality
adult mammalian kidney	UBERON:0000082	75.86	gold quality
right lobe of thyroid gland	UBERON:0001119	74.69	gold quality
left lobe of thyroid gland	UBERON:0001120	73.49	gold quality
thyroid gland	UBERON:0002046	73.05	gold quality
granulocyte	CL:0000094	72.42	gold quality
metanephros cortex	UBERON:0010533	72.33	gold quality
cortex of kidney	UBERON:0001225	71.49	gold quality
lower esophagus mucosa	UBERON:0035834	71.44	gold quality
kidney	UBERON:0002113	70.83	gold quality
jejunum	UBERON:0002115	69.04	gold quality
transverse colon	UBERON:0001157	68.91	gold quality
upper lobe of left lung	UBERON:0008952	66.95	gold quality
leukocyte	CL:0000738	66.89	gold quality
monocyte	CL:0000576	66.36	gold quality
esophagus mucosa	UBERON:0002469	65.90	gold quality
right lung	UBERON:0002167	65.89	gold quality
metanephros	UBERON:0000081	65.12	gold quality
upper lobe of lung	UBERON:0008948	65.11	gold quality
epithelial cell of pancreas	CL:0000083	65.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, HNF1A, SP1

miRNA regulators (miRDB)

34 targeting NAGS, 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-3662	99.99	73.82	5684
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4650-3P	99.01	68.39	1062
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-6784-3P	98.39	64.88	662
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-6862-3P	97.92	64.86	531
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-15A-3P	97.47	65.08	527
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-3667-5P	97.16	64.87	591
HSA-MIR-4540	96.90	67.46	473
HSA-MIR-4433A-5P	96.79	65.01	599

Literature-anchored findings (GeneRIF, showing 20)

• The first mutation in NAGS has been reported in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. (PMID:12447942)
• Gene product expressed in E. coli shown to have NAGS enzyme activity. Gene name provisionally was assigned as NAT7. (PMID:12459178)
• identification and cloning of the human NAGS gene, determination of its genomic structure, verification of the catalytic activity of the purified recombinant enzyme, and the distribution of NAGS mRNA in human tissues (PMID:12459178)
• report two deleterious mutations within the NAGS gene found in two families with infants presenting with acute neonatal disease; finding confirms the genetic origin of NAGS deficiency (PMID:12594532)
• first report of mutation analysis in a series of families affected with deficiency of NAGS (PMID:12754705)
• 3 mutations in 2 families with NAGS deficiency revealed deleterious effects on NAGS affinity for substrates & the rate of catalysis. (PMID:15714518)
• Three novel mutations in the NAGS gene from the families affected by autosomal recessively inherited NAGS deficiency were described and characterized. (PMID:15878741)
• The biochemical properties of purified recombinant human and mouse NAGS-M and NAGS-C were determined in this study with the goal of better understanding the role of the variable domain in NAGS function. (PMID:16321554)
• This is the first comprehensive report of 21 mutations that cause NAGS deficiency and of commonly found polymorphisms in the NAGS gene. (PMID:17421020)
• case with genetically verified NAGS deficiency and neonatal onset of severe hyperammonaemia (PMID:17510757)
• Report patient with OCTN2 mutations/deficiency and N-acetylglutamate synthase deficiency. (PMID:17703373)
• After the human NAGS gene was identified, mutation analysis revealed that the older sibling on NCG therapy was homozygous for a 971G>A (W324X) mutation. (PMID:19533169)
• NAGS deficiency in humans leads to hyperammonemia and can be primary, due to mutations in the NAGS gene or secondary due to other mitochondrial aberrations that interfere with the normal function of the same enzyme. (PMID:20303810)
• Sp1, CREB, HNF-1, and NF-Y, known to be responsive to hormones and diet, regulate NAGS transcription (PMID:22383952)
• Data indicate the formation of alternative N-acylglutamates by N-acetylglutamate synthase (NAGS). (PMID:23643712)
• Results identified 36 NAGS mutations in NAGSD patients; 61% of which are missense mutations. Phenotypes associated with these mutations in the GNAT domain are more severe than phenotypes of that of amino acid kinase domain. Enzyme activity and stability assays with 12 mutations, together with in silico structural analysis, support the pathogenic role of most NAGSD-associated mutations found. (PMID:27037498)
• The specificity of the assay was validated by demonstrating a complete deficiency of NAGS in liver homogenates from Nags -/- mice. CONCLUSION: The novel NAGS enzyme assay reported herein can be used for the diagnosis of inherited NAGS deficiency and may also be of value in the study of secondary hyperammonemia present in various inborn errors of metabolism as well as drug treatment. (PMID:27771289)
• Variation in the N-acetylglutamate Synthase Enhancer Region is associated with N-Acetylglutamate Synthase Deficiency. (PMID:30337552)
• Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene. (PMID:34510628)
• NAGS, CPS1, and SLC25A13 (Citrin) at the Crossroads of Arginine and Pyrimidines Metabolism in Tumor Cells. (PMID:37047726)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nags	ENSDARG00000077193
mus_musculus	Nags	ENSMUSG00000048217
rattus_norvegicus	Nags	ENSRNOG00000020879

Protein

Protein identifiers

N-acetylglutamate synthase, mitochondrial — Q8N159 (reviewed: Q8N159)

Alternative names: Amino-acid acetyltransferase

All UniProt accessions (2): Q8N159, K7EK11

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the regulation of ureagenesis by producing the essential cofactor N-acetylglutamate (NAG), thus modulating carbamoylphosphate synthase I (CPS1) activity.

Subunit / interactions. Homodimer. Homotetramer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Highly expressed in the adult liver, kidney and small intestine. Weakly expressed in the fetal liver, lung, pancreas, placenta, heart and brain tissue.

Post-translational modifications. Probably processed by mitochondrial processing peptidase (MPP). The long form has not yet been isolated.

Disease relevance. N-acetylglutamate synthase deficiency (NAGSD) [MIM:237310] Rare autosomal recessively inherited metabolic disorder leading to severe neonatal or late-onset hyperammonemia without increased excretion of orotic acid. Clinical symptoms are somnolence, tachypnea, feeding difficulties, a severe neurologic presentation characterized by uncontrollable movements, developmental delay, visual impairment, failure to thrive and hyperammonemia precipitated by the introduction of high-protein diet or febrile illness. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Increased by L-arginine.

Domain organisation. The amino-acid kinase (AAK) domain mediates binding of the allosteric activator L-arginine.

Pathway. Amino-acid biosynthesis; L-arginine biosynthesis; N(2)-acetyl-L-ornithine from L-glutamate: step 1/4.

Similarity. Belongs to the acetyltransferase family.

RefSeq proteins (1): NP_694551* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000182	GNAT_dom	Domain
IPR001048	Asp/Glu/Uridylate_kinase	Domain
IPR006855	Vertebrate-like_GNAT_dom	Domain
IPR011243	GlcNAc_Synth_met	Family
IPR016181	Acyl_CoA_acyltransferase	Homologous_superfamily
IPR036393	AceGlu_kinase-like_sf	Homologous_superfamily

Pfam: PF00696, PF04768

Enzyme classification (BRENDA):

• EC 2.3.1.1 — amino-acid N-acetyltransferase (BRENDA: 34 organisms, 47 substrates, 96 inhibitors, 87 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.05–8.1	43
L-GLUTAMATE	1–557	38
GLUTAMATE	1.6–8.1	3
L-GLUTAMINE	280	1

Catalyzed reactions (Rhea), 1 shown:

• L-glutamate + acetyl-CoA = N-acetyl-L-glutamate + CoA + H(+) (RHEA:24292)

UniProt features (44 total): sequence variant 14, helix 8, strand 7, chain 3, binding site 3, mutagenesis site 3, region of interest 2, transit peptide 1, sequence conflict 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4K30	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N159-F1	80.38	0.56

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 (3): 474–479; 401; 444

Mutagenesis-validated functional residues (3):

Position	Phenotype
441	15% reduction in catalytic activity.
479	7-fold reduction in catalytic activity.
485	10-fold reduction in catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-70635	Urea cycle
R-HSA-9955693	NAGS variants cause NAGS deficiency
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 193 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, AAGCCAT_MIR135A_MIR135B, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_UP

GO Biological Process (3): urea cycle (GO:0000050), L-arginine biosynthetic process (GO:0006526), glutamate metabolic process (GO:0006536)

GO Molecular Function (4): L-glutamate N-acetyltransferase activity, acting on acetyl-CoA as donor (GO:0004042), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747)

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

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Diseases of the urea cycle	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
biosynthetic process	1
urea metabolic process	1
arginine metabolic process	1
glutamate family amino acid biosynthetic process	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
L-amino-acid N-acetyltransferase activity	1
catalytic activity	1
transferase activity	1
acyltransferase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NAGS	OTC	P00480	851
NAGS	ASL	P04424	847
NAGS	CPS1	P31327	830
NAGS	ASS1	P00966	816
NAGS	ARG1	P05089	702
NAGS	SLC25A15	Q9Y619	696
NAGS	SHMT2	P34897	695
NAGS	ARG2	P78540	682
NAGS	OAT	P04181	627
NAGS	SLC25A13	Q9UJS0	609
NAGS	NAGK	Q9UJ70	578
NAGS	ALDH18A1	P54886	574
NAGS	GLUL	P15104	532
NAGS	GLUD1	P00367	510
NAGS	PC	P11498	508

IntAct

3 interactions, top by confidence:

A	B	Type	Score
NAGS	TUSC2	psi-mi:“MI:0914”(association)	0.350
NAGS	TMEM39B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): NAGS (Synthetic Lethality), NAGS (Affinity Capture-RNA), TUBA1A (Affinity Capture-MS), CCT2 (Affinity Capture-MS), SAV1 (Affinity Capture-MS), TUSC2 (Affinity Capture-MS), NME7 (Affinity Capture-MS), TCP11L1 (Affinity Capture-MS), NAGS (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1D6K6U5, A0JJZ6, A2X4M8, A2XUN8, A2YQ58, A3ACF3, A5WVX1, A7X657, A7X665, B8BDK0, F1NW29, F4JZC2, O80568, O81893, P40935, Q06AU9, Q08DF7, Q0CF71, Q0D3F2, Q0DCM5, Q0J0B2, Q0J7N5, Q10B19, Q10PI9, Q14166, Q2QMG2, Q3UDE2, Q41771, Q4WD45, Q5VQG4, Q60EJ6, Q654M1, Q69NK8, Q6ET36, Q6K7B8, Q6Z398, Q7XBW0, Q7XK25, Q84J55, Q84Y01

Diamond homologs: A1C6J2, A1DH62, A2QGF0, A4RKF7, A6RBX7, A6SG85, A7F8R0, B0XSH8, B2B2C5, B2WME0, B6H6F3, B6JWC1, B6QS64, B8M3T8, B8NG97, O94330, P0CM18, P0CM19, Q0CY06, Q0U6Q5, Q1DNE1, Q1K8F6, Q2UES9, Q4X122, Q5B0R3, Q6CEE1, Q6FS75, Q75A07, Q87EL2, Q8N159, Q8P8J6, Q8PK29, Q8R4H7, Q9PEM7, A3GG03, A5DA88, A5DWN5, B9W7S3, Q595W7, Q59MB6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	63
Uncertain significance	173
Likely benign	370
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069451	NM_153006.3(NAGS):c.111_120del (p.Arg38fs)	Pathogenic
1070557	NM_153006.3(NAGS):c.777C>A (p.Cys259Ter)	Pathogenic
1370381	NM_153006.3(NAGS):c.138del (p.Arg47fs)	Pathogenic
1375065	NM_153006.3(NAGS):c.893del (p.Gly298fs)	Pathogenic
1378447	NM_153006.3(NAGS):c.1097-1G>C	Pathogenic
1385518	NM_153006.3(NAGS):c.1313dup (p.Thr439fs)	Pathogenic
1402826	NM_153006.3(NAGS):c.299C>A (p.Ser100Ter)	Pathogenic
1407326	NM_153006.3(NAGS):c.390C>A (p.Cys130Ter)	Pathogenic
1420832	NM_153006.3(NAGS):c.368G>A (p.Trp123Ter)	Pathogenic
1453310	NM_153006.3(NAGS):c.724G>T (p.Glu242Ter)	Pathogenic
1457560	NM_153006.3(NAGS):c.106_107del (p.Arg36fs)	Pathogenic
1933213	NM_153006.3(NAGS):c.1037_1070del (p.His346fs)	Pathogenic
2119764	NM_153006.3(NAGS):c.134del (p.Pro45fs)	Pathogenic
2131999	NM_153006.3(NAGS):c.116_122dup (p.Arg41fs)	Pathogenic
2427	NM_153006.3(NAGS):c.1025del (p.Arg342fs)	Pathogenic
2428	NM_153006.3(NAGS):c.971G>A (p.Trp324Ter)	Pathogenic
2431	NM_153006.3(NAGS):c.835G>A (p.Ala279Thr)	Pathogenic
2433	NM_153006.3(NAGS):c.1450T>C (p.Trp484Arg)	Pathogenic
2434	NM_153006.3(NAGS):c.1299G>C (p.Glu433Asp)	Pathogenic
2711343	NM_153006.3(NAGS):c.343del (p.Ala115fs)	Pathogenic
2712593	NM_153006.3(NAGS):c.1302del (p.Val435fs)	Pathogenic
2731701	NM_153006.3(NAGS):c.1272C>A (p.Tyr424Ter)	Pathogenic
2734569	NM_153006.3(NAGS):c.1328del (p.Asp443fs)	Pathogenic
2817617	NM_153006.3(NAGS):c.339C>A (p.Cys113Ter)	Pathogenic
2840352	NM_153006.3(NAGS):c.376C>T (p.Gln126Ter)	Pathogenic
2849686	NM_153006.3(NAGS):c.562dup (p.Ser188fs)	Pathogenic
2861616	NM_153006.3(NAGS):c.92_119del (p.Leu31fs)	Pathogenic
2863999	NM_153006.3(NAGS):c.998_1016del (p.Met333fs)	Pathogenic
2960648	NM_153006.3(NAGS):c.535dup (p.Ala179fs)	Pathogenic
3239821	NM_153006.3(NAGS):c.278del (p.Pro93fs)	Pathogenic

SpliceAI

1170 predictions. Top by Δscore:

Variant	Effect	Δscore
17:44006234:TAAGG:T	donor_loss	1.0000
17:44006235:AAGGT:A	donor_loss	1.0000
17:44006236:AGGTG:A	donor_loss	1.0000
17:44006238:G:C	donor_loss	1.0000
17:44006708:GG:G	donor_gain	1.0000
17:44006709:G:GT	donor_gain	1.0000
17:44006709:GGT:G	donor_loss	1.0000
17:44006710:GTG:G	donor_loss	1.0000
17:44006711:T:G	donor_loss	1.0000
17:44007318:TCCA:T	acceptor_loss	1.0000
17:44007320:CA:C	acceptor_loss	1.0000
17:44007321:A:AG	acceptor_gain	1.0000
17:44007321:AG:A	acceptor_gain	1.0000
17:44007321:AGG:A	acceptor_gain	1.0000
17:44007322:G:A	acceptor_gain	1.0000
17:44007322:G:GA	acceptor_gain	1.0000
17:44007322:GGG:G	acceptor_gain	1.0000
17:44007322:GGGT:G	acceptor_gain	1.0000
17:44007322:GGGTC:G	acceptor_gain	1.0000
17:44007490:GAGGG:G	donor_gain	1.0000
17:44007491:AGGG:A	donor_gain	1.0000
17:44007492:GGG:G	donor_gain	1.0000
17:44007492:GGGG:G	donor_gain	1.0000
17:44007493:GG:G	donor_gain	1.0000
17:44007493:GGG:G	donor_gain	1.0000
17:44007493:GGGT:G	donor_loss	1.0000
17:44007494:GG:G	donor_gain	1.0000
17:44007494:GGT:G	donor_loss	1.0000
17:44007495:G:GG	donor_gain	1.0000
17:44007495:GTAAG:G	donor_loss	1.0000

AlphaMissense

3438 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:44007739:T:A	W473R	0.999
17:44007739:T:C	W473R	0.999
17:44007605:C:A	A428D	0.998
17:44007654:A:C	K444N	0.998
17:44007654:A:T	K444N	0.998
17:44007746:C:T	S475F	0.998
17:44008500:T:A	W502R	0.998
17:44008500:T:C	W502R	0.998
17:44007652:A:G	K444E	0.997
17:44007742:C:A	R474S	0.997
17:44007745:T:C	S475P	0.997
17:44008488:T:A	W498R	0.997
17:44008488:T:C	W498R	0.997
17:44007421:T:C	F399L	0.996
17:44007423:C:A	F399L	0.996
17:44007423:C:G	F399L	0.996
17:44007647:T:C	L442P	0.996
17:44007653:A:T	K444I	0.996
17:44007759:C:A	N479K	0.996
17:44007759:C:G	N479K	0.996
17:44008473:T:C	F493L	0.996
17:44008475:C:A	F493L	0.996
17:44008475:C:G	F493L	0.996
17:44008497:T:C	F501L	0.996
17:44008499:C:A	F501L	0.996
17:44008499:C:G	F501L	0.996
17:44008549:C:A	A518D	0.996
17:44007604:G:C	A428P	0.995
17:44007643:T:G	Y441D	0.995
17:44007656:T:C	F445S	0.995

dbSNP variants (sampled 300 via entrez): RS1000045864 (17:44003885 G>A), RS1000242069 (17:44006847 T>A), RS1000293040 (17:44006498 G>A,T), RS1000481193 (17:44004210 C>G), RS1000653122 (17:44009325 G>C), RS1001085602 (17:44002699 G>A,C), RS1001833864 (17:44005584 G>A,C,T), RS1002761837 (17:44004638 T>C,G), RS1003388923 (17:44006852 C>A,G,T), RS1003762309 (17:44002639 T>C), RS1003770098 (17:44003061 AG>A), RS1004054278 (17:44004495 T>C,G), RS1004169773 (17:44003275 C>A), RS1004826424 (17:44005244 G>A), RS1005793667 (17:44007954 C>G)

Disease associations

OMIM: gene MIM:608300 | disease phenotypes: MIM:237310

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperammonemia due to N-acetylglutamate synthase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hyperammonemia due to N-acetylglutamate synthase deficiency	Definitive	AR

Mondo (3): hyperammonemia due to N-acetylglutamate synthase deficiency (MONDO:0009377), esophageal atresia (MONDO:0001044), pyloric stenosis (MONDO:0001561)

Orphanet (1): Hyperammonemia due to N-acetylglutamate synthase deficiency (Orphanet:927)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000725	Psychotic episodes
HP:0000733	Motor stereotypy
HP:0000739	Anxiety
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001271	Polyneuropathy
HP:0001276	Hypertonia
HP:0001289	Confusion
HP:0001297	Stroke
HP:0001298	Encephalopathy
HP:0001508	Failure to thrive
HP:0001948	Alkalosis
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002039	Anorexia
HP:0002045	Hypothermia
HP:0002098	Respiratory distress
HP:0002240	Hepatomegaly
HP:0002315	Headache

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010243_58	Apolipoprotein B levels	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004615	apolipoprotein B measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D017219	Gastric Outlet Obstruction	C06.405.748.340
D011707	Pyloric Stenosis	C06.405.748.340.690
C536109	N-acetyl glutamate synthetase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Cyclosporine	increases expression	4
Benzo(a)pyrene	increases expression, increases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
OTX015	decreases expression	1
mivebresib	decreases expression	1
bisphenol A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
monomethylarsonous acid	increases expression	1
K 7174	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Azathioprine	increases expression	1
Cisplatin	increases expression	1
Phthalic Acids	increases methylation	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_GZ52	GM23858	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00556283	PHASE4	COMPLETED	RCT: STARR vs Biofeedback
NCT00226044	PHASE3	COMPLETED	Rectal and Oral Omeprazole Treatment of Reflux Disease in Infants.
NCT03127345	PHASE2	WITHDRAWN	Omega 3 Fatty Acid Treatment for Pediatric Musculoskeletal Health
NCT01421888	Not specified	TERMINATED	The NIH UNI Study: Urea Cycle Disorders, Nutrition and Immunity
NCT03409003	Not specified	RECRUITING	Orphan Europe Carbaglu® Surveillance Protocol
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04908319	Not specified	RECRUITING	Hepatic Histopathology in Urea Cycle Disorders
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02466451	Not specified	COMPLETED	Study in Children With the Diagnosis of Congenital Diaphragmatic Hernia (CDH) and Oesophageal Atresia (EA)
NCT02525705	Not specified	COMPLETED	Dumping Syndrome After Operation of Esophageal Atresia Type III
NCT02883725	Not specified	COMPLETED	National Register of Oesophageal Atresia
NCT03023865	Not specified	UNKNOWN	Individualized Management for Long Gap Esophageal Atresia
NCT03415893	Not specified	COMPLETED	High-resolution Esophageal Manometry
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03615495	Not specified	COMPLETED	Flourish™ Pediatric Esophageal Atresia
NCT03619408	Not specified	UNKNOWN	Management of Esophagitis Following Repair of Esophageal Atresia
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair
NCT03767673	Not specified	UNKNOWN	Cardiorespiratory Performance and Pulmonary Microbiome in Patients After Repair of Esophageal Atresia
NCT03999008	Not specified	UNKNOWN	Oral Viscous Budesonide in Anastomotic Stricture After Esophageal Atresia Repair (OVB in EA)
NCT04072419	Not specified	UNKNOWN	Application of Enhanced Recovery After Surgery for Congenital Esophageal Atresia During Perioperative Period
NCT04136795	Not specified	UNKNOWN	Evaluation of the Respiratory Impact After Conventional or Minimally Invasive Esophageal Atresia Surgery
NCT04259528	Not specified	UNKNOWN	Endoscopic Ultrasound Findings in Esophageal Atresia Following Surgical Repair
NCT04522193	Not specified	RECRUITING	Dumping Syndrome and Esophageal Atresia
NCT04901546	Not specified	COMPLETED	Esophageal Atresia: a Natural Experiment of the Effects of Oral Inoculation on the Gut Microbiome
NCT04932746	Not specified	COMPLETED	The Effect of Dexmedetomidine on Oxygen During One Lung Ventilation in Pediatric Surgery.
NCT05129930	Not specified	COMPLETED	Fluid Overload and Pulmonary Function
NCT05527873	Not specified	COMPLETED	Respiratory Complications of Operated Esophageal Atresia in Children
NCT05995171	Not specified	RECRUITING	Long Term Outcome of Easophageal Atresia : Transmics Profiles in Adolescence
NCT06073158	Not specified	COMPLETED	Molecular Signatures of Esophageal Atresia
NCT06208449	Not specified	UNKNOWN	Robotic Versus Thoracoscopy Versus Thoracotomy Repair for Congenital Esophageal Atresia
NCT06335862	Not specified	ENROLLING_BY_INVITATION	Primary Posterior Tracheopexy Prevents Tracheal Collapse
NCT06731855	Not specified	RECRUITING	An Exploratory Physiological Study of Post-operative Recovery in Surgical Neonates and Dimethylarginine:Arginine Levels
NCT06860919	Not specified	RECRUITING	Prospective Evaluation of the Results of Multidisciplinary Follow-up After a Transitional Consultation for Esophageal Atresia
NCT06975982	Not specified	RECRUITING	Symptoms, Pulmonary Function, Muscle Strength, Exercise Capacity, and Frailty in Esophageal Atresia vs. Healthy Peers
NCT07100379	Not specified	RECRUITING	Balloon Inflation Time for Esophageal Strictures (BITES): A Randomized Multi-Center Study
NCT07210736	Not specified	NOT_YET_RECRUITING	Brazilian Multicenter Study on Esophageal Atresia
NCT03223480	PHASE2/PHASE3	COMPLETED	EUS - Guided Balloon-occluded Gastrojejunostomy Bypass