ASS1

Summary

ASS1 (argininosuccinate synthase 1, HGNC:758) is a protein-coding gene on chromosome 9q34.11, encoding Argininosuccinate synthase (P00966). One of the enzymes of the urea cycle, the metabolic pathway transforming neurotoxic amonia produced by protein catabolism into inocuous urea in the liver of ureotelic animals. In precision oncology, ASS1 Loss confers sensitivity to Chloroquine + Pegargiminase in Sarcoma (CIViC Level D); 1 further curated variant–drug associations are listed below.

The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 445 — RefSeq curated summary.

At a glance

• Gene–disease (curated): citrullinemia type I (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 963 total — 87 pathogenic, 109 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• MANE Select transcript: NM_054012

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:758
Approved symbol	ASS1
Name	argininosuccinate synthase 1
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	CTLN1
Ensembl gene	ENSG00000130707
Ensembl biotype	protein_coding
OMIM	603470
Entrez	445

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 46 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000352480, ENST00000372386, ENST00000372393, ENST00000372394, ENST00000422569, ENST00000443588, ENST00000467695, ENST00000470849, ENST00000492400, ENST00000493984, ENST00000852176, ENST00000852177, ENST00000852178, ENST00000852179, ENST00000852180, ENST00000852181, ENST00000852183, ENST00000852185, ENST00000852187, ENST00000852189, ENST00000852191, ENST00000852193, ENST00000852194, ENST00000852196, ENST00000852197, ENST00000852198, ENST00000852199, ENST00000852200, ENST00000852201, ENST00000852202, ENST00000852203, ENST00000852204, ENST00000852205, ENST00000852206, ENST00000852207, ENST00000852208, ENST00000852209, ENST00000852210, ENST00000852211, ENST00000852212, ENST00000852213, ENST00000852214, ENST00000852215, ENST00000852216, ENST00000852217, ENST00000852218, ENST00000852219, ENST00000950032, ENST00000950033, ENST00000950034, ENST00000950035

RefSeq mRNA: 2 — MANE Select: NM_054012 NM_000050, NM_054012

CCDS: CCDS6933

Canonical transcript exons

ENST00000352480 — 15 exons

Exon	Start	End
ENSE00000896026	130458401	130458589
ENSE00001226401	130454305	130454373
ENSE00001457680	130500976	130501274
ENSE00001846144	130444961	130444995
ENSE00002397383	130452224	130452333
ENSE00003463692	130464111	130464167
ENSE00003477583	130479716	130479800
ENSE00003533016	130470834	130470904
ENSE00003538084	130466725	130466799
ENSE00003547320	130480385	130480449
ENSE00003587505	130471485	130471515
ENSE00003669751	130476871	130476961
ENSE00003755846	130489333	130489464
ENSE00003756254	130499505	130499570
ENSE00003756701	130494867	130495023

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.5842 / max 1314.6413, expressed in 1482 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99012	54.0136	1441
99011	5.1729	1239
99015	0.2364	130
99020	0.1613	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.75	gold quality
palpebral conjunctiva	UBERON:0001812	99.64	gold quality
liver	UBERON:0002107	99.64	gold quality
nephron tubule	UBERON:0001231	99.42	gold quality
adult organism	UBERON:0007023	99.42	gold quality
adult mammalian kidney	UBERON:0000082	99.27	gold quality
renal glomerulus	UBERON:0000074	99.25	gold quality
metanephric glomerulus	UBERON:0004736	99.16	gold quality
kidney epithelium	UBERON:0004819	98.84	gold quality
corpus epididymis	UBERON:0004359	98.75	gold quality
adipose tissue	UBERON:0001013	98.45	gold quality
rectum	UBERON:0001052	98.43	gold quality
mucosa of transverse colon	UBERON:0004991	98.40	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.39	gold quality
peritoneum	UBERON:0002358	98.34	gold quality
omental fat pad	UBERON:0010414	98.34	gold quality
left adrenal gland cortex	UBERON:0035825	98.28	gold quality
right adrenal gland	UBERON:0001233	98.25	gold quality
cartilage tissue	UBERON:0002418	98.25	gold quality
left adrenal gland	UBERON:0001234	98.21	gold quality
right adrenal gland cortex	UBERON:0035827	98.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.18	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.16	gold quality
adrenal cortex	UBERON:0001235	98.03	gold quality
connective tissue	UBERON:0002384	98.03	gold quality
urethra	UBERON:0000057	97.83	gold quality
seminal vesicle	UBERON:0000998	97.80	gold quality
colonic mucosa	UBERON:0000317	97.76	gold quality
kidney	UBERON:0002113	97.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.68	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-110499	yes	1402.35
E-CURD-119	yes	1208.87
E-MTAB-10137	yes	698.69
E-HCAD-56	yes	642.86
E-MTAB-9388	yes	583.38
E-HCAD-10	yes	35.70
E-MTAB-10553	yes	33.86
E-MTAB-6678	yes	26.44
E-HCAD-1	yes	13.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, KLF4, MYC, NR1I2, PPARG, SP4

miRNA regulators (miRDB)

21 targeting ASS1, 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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-6511B-5P	97.98	65.64	823
HSA-MIR-6811-5P	97.98	64.96	848
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-616-3P	96.82	66.99	784
HSA-MIR-4268	94.45	64.09	819
HSA-MIR-6750-5P	93.94	66.68	797
HSA-MIR-6822-5P	93.94	66.34	812
HSA-MIR-6720-3P	91.34	60.49	67

Literature-anchored findings (GeneRIF, showing 40)

• Mutational analysis revealed three alleles with a common mutation and five new mutations. (PMID:11708871)
• structure and use in diagnosing citrullinemia (PMID:11941481)
• Sixteen novel mutations have been identified in the argininosuccinate synthetase gene in citrullinemia patients. (PMID:12815590)
• argininosuccinate synthetase gene expression is stimulated by glutamine through cytosolic O-glycosylation of Sp1 in tumor cells (PMID:14570901)
• Argininosuccinate synthetase has a role in preventing autotoxicity from nitric oxide overproduction (PMID:15192091)
• Extensive mutation study by direct genomic sequencing of ASS demonstrated a homozygous G117S mutation in one patient and homozygous R363W mutations in the other two families (PMID:16124451)
• IL-1beta induces nitric oxide which has antagonistic effects on argininosuccinate synthetase gene and on the activity of argininosuccinate synthetase (PMID:16380201)
• ASS, the c-myc-regulated gene is involved in genotype-C-HBV-related HCC, suggesting that c-myc is related to the hepatocarcinogenic activity of genotype-C HBV. (PMID:16703398)
• Low argininosuccinate synthetase is associated with renal cell carcinoma (PMID:17096330)
• high levels of AS expression, which may be required for several arginine-dependent processes in cancer, including the production of nitric oxide, proline, pyrimidines and polyamines, is regulated by TNF-alpha (PMID:17354225)
• HSCARG regulation of argininosuccinate synthetase activity is crucial for maintaining the intracellular balance between redox state and nitric oxide levels (PMID:18263583)
• These results show that liver-specific enhancement of ASS gene expression is mediated in part by the cAMP signaling pathway through a distal CRE site. (PMID:18840401)
• argininosuccinate synthetase behaves as a typical suckling enzyme because its expression all but disappears in the putative weaning period of human infants. (PMID:19000307)
• a survey of the correlation between mutations in the ASS1 gene and the respective clinical courses of citrullinemia type I as described so far (Review) (PMID:19006241)
• The studied families showed the same mutation: ASS~p.G390R, associated with the early-onset/severe phenotype. (PMID:19358837)
• changes in gene expression are induced by laminar shear stress as well as by cellular senescence (PMID:19409979)
• Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer. (PMID:19533750)
• Studies indicate that the proximal region of the AS promoter contains an E-box that is recognized by c-Myc and HIF-1alpha and a GC-box by Sp4. (PMID:19934275)
• In patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. (PMID:20159990)
• Analysis of five SNPs of the ASS1 gene revealed that the G allele of rs7860909 is associated with increased CL/P risk. (PMID:20739017)
• the expression of ASS1 harmonized with that of NOS3 may be important for the optimized endothelial NO production and the prevention of the inflammatory monocyte adhesion to endothelial cells. (PMID:21106532)
• The ASS release represents a potential counteracting liver reaction to LPS. (PMID:21481813)
• The present study demonstrated a key regulatory role of KLF4 in the endothelial ASS1 expression and NO production in response to laminar shear stress. (PMID:22430140)
• Mutations are identified only in exons of ASS1 gene from the Korean patients with citrullinemia type I. (PMID:23099195)
• ASS expression is decreased significantly in hepatocellular carcinoma tissues. (PMID:23339388)
• Our findings highlight ASS1 as a novel tumor suppressor in myxofibrosarcomas, with loss of expression linked to promoter methylation, clinical aggressiveness, and sensitivity to ADI-PEG20. (PMID:23549872)
• Aberrant loss of ASS1 strongly links to DNA methylation in neck nodal metastases of NPC and significantly correlates with advanced T classification, and independently predicts worse DSS and DMFS in independent NPC tissue specimens. (PMID:23897555)
• Argininosuccinate synthetase gene is silenced by CpG methylation in children with phenylketonuria.The promoter of argininosuccinate synthetase was methylated which silence the transcription of argininosuccinate synthetase. (PMID:24192130)
• Together with the observation that AS1 protein and mRNA levels decrease during wild-type infection, this work suggests that reduced AS1 activity is partially responsible for the metabolic program induced by infection. (PMID:24297925)
• we reviewed the English literature on mutations in the ASS and SLC25A13 genes, and their genotype-phenotype correlations to provide valuable insights into the molecular genetic background of citrullinemia–{REVIEW} (PMID:24508627)
• Data indicate that argininosuccinate synthetase 1 (ASS1) abundance is a prognostic factor for overall breast cancer survival. (PMID:24692592)
• Point mutation of ASS1, ASL and SLC25A13 is associated with citrullinemia. (PMID:24927999)
• Three novel splicing and missense mutations have been identified in the ASS1 gene in classical citrullinemia patients. (PMID:25179242)
• ASS expression in gastric cancer was associated with a poor prognosis. (PMID:25333458)
• More than 50 % of the high-grade pulmonary neuroendocrine carcinomas tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. (PMID:25548129)
• results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis (PMID:26560030)
• ASS1 genomic variants (rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/beta-thalassemia compound heterozygous patients. (PMID:26895070)
• combining hypoxia and ADI-PEG20 synergistically inhibited ASS1. (PMID:26972697)
• results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1 (PMID:26982031)
• Of 21 ASS potential kinetic mutations, 13 were totally inactive while 8 exhibited decreased affinity for aspartate and citrulline. (PMID:27287393)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000103044
mus_musculus	Ass1	ENSMUSG00000076441
rattus_norvegicus	Ass1	ENSRNOG00000008837
drosophila_melanogaster	Ass	FBGN0026565

Protein

Protein identifiers

Argininosuccinate synthase — P00966 (reviewed: P00966)

Alternative names: Citrulline–aspartate ligase

All UniProt accessions (4): P00966, Q5T6L4, Q5T6L5, Q5T6L6

UniProt curated annotations — full annotation on UniProt →

Function. One of the enzymes of the urea cycle, the metabolic pathway transforming neurotoxic amonia produced by protein catabolism into inocuous urea in the liver of ureotelic animals. Catalyzes the formation of arginosuccinate from aspartate, citrulline and ATP and together with ASL it is responsible for the biosynthesis of arginine in most body tissues.

Subunit / interactions. Homotetramer. Interacts with NMRAL1. Interacts with CLOCK; in a circadian manner. Forms tissue-specific complexes with ASL, SLC7A1, HSP90AA1 and nitric oxide synthase NOS1, NOS2 or NOS3; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in adult liver.

Post-translational modifications. Acetylated by CLOCK in a circadian manner which negatively regulates its enzyme activity. Deacetylated by histone deacetylases.

Disease relevance. Citrullinemia 1 (CTLN1) [MIM:215700] The classic form of citrullinemia, an autosomal recessive disease characterized primarily by elevated serum and urine citrulline levels. Ammonia intoxication is another manifestation. It is a disorder of the urea cycle, usually manifesting in the first few days of life. Affected infants appear normal at birth, but as ammonia builds up in the body they present symptoms such as lethargy, poor feeding, vomiting, seizures and loss of consciousness. Less commonly, a milder form can develop later in childhood or adulthood. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid biosynthesis; L-arginine biosynthesis; L-arginine from L-ornithine and carbamoyl phosphate: step 2/3. Nitrogen metabolism; urea cycle; (N(omega)-L-arginino)succinate from L-aspartate and L-citrulline: step 1/1.

Similarity. Belongs to the argininosuccinate synthase family. Type 1 subfamily.

RefSeq proteins (2): NP_000041, NP_446464* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001518	Arginosuc_synth	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR018223	Arginosuc_synth_CS	Conserved_site
IPR023434	Arginosuc_synth_type_1_subfam	Family
IPR024074	AS_cat/multimer_dom_body	Homologous_superfamily
IPR048267	Arginosuc_syn_N	Domain
IPR048268	Arginosuc_syn_C	Domain

Pfam: PF00764, PF20979

Enzyme classification (BRENDA):

• EC 6.3.4.5 — argininosuccinate synthase (BRENDA: 22 organisms, 61 substrates, 51 inhibitors, 54 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
CITRULLINE	0.02–190	15
ATP	0.041–0.66	13
ASP	0.017–4.3	7
L-ASP	0.025–0.038	5
ASPARTATE	0.12–0.18	3
AMP	0.022	2
DIPHOSPHATE	0.016	2
L-CITRULLINE	0.026–0.03	2
ARGININOSUCCINATE	0.12	1
THREO-BETA-HYDROXY-L-ASP	4.5	1
THREO-BETA-METHYL-L-ASP	0.88	1

Catalyzed reactions (Rhea), 1 shown:

• L-citrulline + L-aspartate + ATP = 2-(N(omega)-L-arginino)succinate + AMP + diphosphate + H(+) (RHEA:10932)

UniProt features (159 total): sequence variant 98, helix 17, binding site 14, strand 14, modified residue 7, turn 5, mutagenesis site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2NZ2	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00966-F1	95.64	0.91

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 (14): 10–18; 127; 180; 189; 270; 282; 36; 87; 92; 115–123; 119; 123 …

Post-translational modifications (7): 87, 112, 113, 165, 176, 180, 219

Mutagenesis-validated functional residues (2):

Position	Phenotype
165	significant loss of acetylation but no decrease in enzyme activity; when associated with q-176 or r-176.
176	significant loss of acetylation but no decrease in enzyme activity; when associated with q-165 or r-165.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-70635	Urea cycle
R-HSA-9956520	ASS1 variants cause citrullinemia
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 454 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_CIRCADIAN_RHYTHM, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_ZINC_ION, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, JAEGER_METASTASIS_DN

GO Biological Process (39): urea cycle (GO:0000050), obsolete citrulline metabolic process (GO:0000052), obsolete argininosuccinate metabolic process (GO:0000053), kidney development (GO:0001822), liver development (GO:0001889), L-arginine biosynthetic process (GO:0006526), aspartate metabolic process (GO:0006531), acute-phase response (GO:0006953), midgut development (GO:0007494), response to nutrient (GO:0007584), circadian rhythm (GO:0007623), response to xenobiotic stimulus (GO:0009410), response to zinc ion (GO:0010043), response to mycotoxin (GO:0010046), response to estradiol (GO:0032355), positive regulation of nitric oxide biosynthetic process (GO:0045429), response to growth hormone (GO:0060416), diaphragm development (GO:0060539), cellular response to lipopolysaccharide (GO:0071222), cellular response to amino acid stimulus (GO:0071230), cellular response to ammonium ion (GO:0071242), cellular response to cAMP (GO:0071320), cellular response to type II interferon (GO:0071346), cellular response to tumor necrosis factor (GO:0071356), cellular response to glucagon stimulus (GO:0071377), cellular response to oleic acid (GO:0071400), cellular response to amine stimulus (GO:0071418), cellular response to laminar fluid shear stress (GO:0071499), cellular response to dexamethasone stimulus (GO:0071549), negative regulation of leukocyte cell-cell adhesion (GO:1903038), amino acid biosynthetic process (GO:0008652), response to toxic substance (GO:0009636), response to amine (GO:0014075), response to lipopolysaccharide (GO:0032496), response to amino acid (GO:0043200), response to peptide hormone (GO:0043434), response to steroid hormone (GO:0048545), response to glucocorticoid (GO:0051384), response to fatty acid (GO:0070542)

GO Molecular Function (9): RNA binding (GO:0003723), argininosuccinate synthase activity (GO:0004055), ATP binding (GO:0005524), toxic substance binding (GO:0015643), amino acid binding (GO:0016597), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), perikaryon (GO:0043204), extracellular exosome (GO:0070062), cell body fiber (GO:0070852), mitochondrion (GO:0005739), neuronal cell body (GO:0043025)

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
cellular anatomical structure	4
binding	3
response to chemical	2
cytoplasm	2
biosynthetic process	1
urea metabolic process	1
animal organ development	1
renal system development	1
gland development	1
hepaticobiliary system development	1
arginine metabolic process	1
glutamate family amino acid biosynthetic process	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
acute inflammatory response	1
digestive tract development	1
response to nutrient levels	1
rhythmic process	1
response to metal ion	1
response to toxic substance	1
response to lipid	1
response to oxygen-containing compound	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
response to peptide hormone	1
skeletal muscle organ development	1
respiratory system development	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to amino acid	1
cellular response to acid chemical	1
nucleic acid binding	1
ligase activity, forming carbon-nitrogen bonds	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASS1	SLC25A13	Q9UJS0	946
ASS1	ASL	P04424	933
ASS1	CPS1	P31327	926
ASS1	ADSS2	P30520	923
ASS1	OTC	P00480	875
ASS1	ARG2	P78540	874
ASS1	NAGS	Q8N159	816
ASS1	ARG1	P05089	807
ASS1	AK1	P00568	787
ASS1	ZNF169	Q14929	750
ASS1	OAT	P04181	725
ASS1	ASNS	P08184	716
ASS1	AASS	Q9UDR5	704
ASS1	ALDH18A1	P54886	703
ASS1	ODC1	P11926	693

IntAct

89 interactions, top by confidence:

A	B	Type	Score
MPC1	MPC2	psi-mi:“MI:0914”(association)	0.860
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ASS1	ASS1	psi-mi:“MI:0915”(physical association)	0.670
CA10	WDHD1	psi-mi:“MI:0914”(association)	0.640
PRMT7	ASS1	psi-mi:“MI:0915”(physical association)	0.640
PRMT7	ASS1	psi-mi:“MI:0407”(direct interaction)	0.640
PRMT7	ASS1	psi-mi:“MI:0403”(colocalization)	0.640
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
ZNF354C	IPO8	psi-mi:“MI:0914”(association)	0.530
ASS1	PC	psi-mi:“MI:0914”(association)	0.530
FAM117B	GAPDHS	psi-mi:“MI:0914”(association)	0.530
ZNF354C	LRP4	psi-mi:“MI:0914”(association)	0.530
ATP6V0A4	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
NMRAL1	ASS1	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (228): ASS1 (Two-hybrid), ASS1 (Affinity Capture-MS), ASS1 (Affinity Capture-MS), ASS1 (Two-hybrid), ADK (Co-fractionation), ALDOA (Co-fractionation), ARHGDIA (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation), ASS1 (Co-fractionation)

ESM2 similar proteins: A2BJL6, A4J173, A4YI75, A5D510, A6Q3P9, A8AA65, B0K4D8, B0KBW5, B2RIF9, B5YAL9, B8E0N9, B9K8S7, C0QPI1, C3MJX9, C3MRT0, C3N0R9, C3N905, C3NMG4, O26806, O27322, O28032, O28990, O29807, O58677, O67213, P00966, P09034, P13256, P16460, P59846, P61526, Q0W468, Q1AS35, Q3A9W5, Q46D96, Q4J8F1, Q60174, Q7MWL9, Q8PXK0, Q8R7C2

Diamond homologs: A0LE34, A0LEB2, A0Q1Z2, A0RP84, A1ATU4, A1VEQ0, A3DBU1, A4J173, A4XKG4, A5D510, A5FWI5, A5GDA4, A5ILL1, A5N6U2, A5V0J9, A5VN19, A6Q3P9, A6TL10, A6UE09, A6WV13, A7GYN4, A7HSW4, A7I281, A7NPB0, A8F446, A9HIQ4, A9M6S7, B0CII7, B0K4D8, B0KBW5, B0S9J6, B0SJR2, B1LAP4, B2S7X3, B5ED13, B6IVD0, B8DN64, B8ESL2, B8FH30, B8FWX2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
SARS-CoV-1-host interactions	5	12.9×	8e-03
SARS-CoV-1 Infection	5	10.5×	8e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	87
Likely pathogenic	109
Uncertain significance	215
Likely benign	370
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071055	NM_054012.4(ASS1):c.489C>A (p.Tyr163Ter)	Pathogenic
1071056	NM_054012.4(ASS1):c.490G>C (p.Ala164Pro)	Pathogenic
1071097	NM_054012.4(ASS1):c.1048C>T (p.Gln350Ter)	Pathogenic
1071462	NC_000009.12:g.130479718dup	Pathogenic
1071505	NC_000009.11:g.(?133333768)(133333996_?)del	Pathogenic
1072613	NM_054012.4(ASS1):c.1107_1108del (p.Tyr370fs)	Pathogenic
1339499	NM_054012.4(ASS1):c.364-2A>G	Pathogenic
1352022	NM_054012.4(ASS1):c.1010_1011delinsAA (p.Cys337Ter)	Pathogenic
1355373	NM_054012.4(ASS1):c.944T>A (p.Leu315Ter)	Pathogenic
1400634	NM_054012.4(ASS1):c.611del (p.Pro204fs)	Pathogenic
1425929	NM_054012.4(ASS1):c.536G>A (p.Trp179Ter)	Pathogenic
1434677	NM_054012.4(ASS1):c.621C>A (p.Tyr207Ter)	Pathogenic
1454396	NC_000009.11:g.(?133352248)(133352358_?)del	Pathogenic
1456047	NC_000009.11:g.(?133352248)(133355846_?)del	Pathogenic
1457339	NM_054012.4(ASS1):c.489C>G (p.Tyr163Ter)	Pathogenic
1458486	NC_000009.11:g.(?133355093)(133355236_?)del	Pathogenic
1460356	NM_054012.4(ASS1):c.373C>T (p.Gln125Ter)	Pathogenic
188776	NM_054012.4(ASS1):c.1138C>T (p.Gln380Ter)	Pathogenic
188832	NM_054012.4(ASS1):c.892del (p.Glu298fs)	Pathogenic
188885	NM_054012.4(ASS1):c.1030C>T (p.Arg344Ter)	Pathogenic
198386	NM_054012.4(ASS1):c.421-2A>G	Pathogenic
2003009	NM_054012.4(ASS1):c.188_189del (p.Asp63fs)	Pathogenic
2006582	NM_054012.4(ASS1):c.983_984insGGTGAATTTG (p.Ser328fs)	Pathogenic
2016666	NM_054012.4(ASS1):c.827_838+25del	Pathogenic
2034705	NM_054012.4(ASS1):c.687dup (p.Gly230fs)	Pathogenic
2061871	NM_054012.4(ASS1):c.463A>T (p.Lys155Ter)	Pathogenic
2087609	NM_054012.4(ASS1):c.1060del (p.Leu354fs)	Pathogenic
2136821	NM_054012.4(ASS1):c.271A>C (p.Thr91Pro)	Pathogenic
2136822	NM_054012.4(ASS1):c.285_286delinsTT (p.Arg95_Pro96delinsSerSer)	Pathogenic
2139638	NM_054012.4(ASS1):c.138_139del (p.Glu46fs)	Pathogenic

SpliceAI

3118 predictions. Top by Δscore:

Variant	Effect	Δscore
9:130454343:G:GT	donor_gain	1.0000
9:130454370:AAAGG:A	donor_loss	1.0000
9:130454373:GGTAC:G	donor_loss	1.0000
9:130454374:G:GA	donor_loss	1.0000
9:130454375:T:A	donor_loss	1.0000
9:130458587:AAGGT:A	donor_loss	1.0000
9:130458588:AG:A	donor_loss	1.0000
9:130458589:GG:G	donor_loss	1.0000
9:130458591:T:A	donor_loss	1.0000
9:130466795:CAAAG:C	donor_loss	1.0000
9:130466798:AGGTA:A	donor_loss	1.0000
9:130466799:GGT:G	donor_loss	1.0000
9:130466800:GT:G	donor_loss	1.0000
9:130466801:T:G	donor_loss	1.0000
9:130469192:A:T	donor_gain	1.0000
9:130470829:TGCA:T	acceptor_loss	1.0000
9:130470832:A:AG	acceptor_gain	1.0000
9:130470832:A:T	acceptor_loss	1.0000
9:130470833:G:GA	acceptor_gain	1.0000
9:130470833:GC:G	acceptor_gain	1.0000
9:130470833:GCA:G	acceptor_gain	1.0000
9:130470833:GCAA:G	acceptor_gain	1.0000
9:130470833:GCAAC:G	acceptor_gain	1.0000
9:130470901:TCAGG:T	donor_loss	1.0000
9:130470902:CAGGT:C	donor_loss	1.0000
9:130470903:AGGT:A	donor_loss	1.0000
9:130470904:GGTAA:G	donor_loss	1.0000
9:130470905:G:C	donor_loss	1.0000
9:130470906:T:A	donor_loss	1.0000
9:130471481:GCAGC:G	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000040724 (9:130470080 G>A), RS1000070242 (9:130479587 G>A), RS1000101488 (9:130475947 T>C), RS1000110967 (9:130448620 G>A), RS1000143993 (9:130496227 C>T), RS1000197423 (9:130488007 G>A), RS1000231523 (9:130461379 G>C), RS1000381338 (9:130493882 G>A), RS1000386602 (9:130466125 C>G,T), RS1000414152 (9:130493658 G>A,T), RS1000417842 (9:130466326 G>A), RS1000467121 (9:130458676 G>A,T), RS1000487129 (9:130497468 C>A), RS1000631251 (9:130487769 T>A,C,G), RS1000654029 (9:130488210 G>T)

Disease associations

OMIM: gene MIM:603470 | disease phenotypes: MIM:215700, MIM:603471, MIM:232200

GenCC curated gene-disease

Disease	Classification	Inheritance
citrullinemia type I	Definitive	Autosomal recessive
acute neonatal citrullinemia type I	Supportive	Autosomal recessive
adult-onset citrullinemia type I	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
citrullinemia type I	Definitive	AR

Mondo (7): citrullinemia (MONDO:0015991), citrullinemia type I (MONDO:0008988), citrullinemia, type II, adult-onset (MONDO:0011326), cardiac rhythm disease (MONDO:0007263), glycogen storage disease due to glucose-6-phosphatase deficiency type IA (MONDO:0009287), acute neonatal citrullinemia type I (MONDO:0016600), adult-onset citrullinemia type I (MONDO:0016601)

Orphanet (5): Citrullinemia (Orphanet:187), Citrullinemia type I (Orphanet:247525), Citrullinemia type II (Orphanet:247585), Glycogen storage disease due to glucose-6-phosphatase deficiency (Orphanet:364), Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia (Orphanet:79258)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001297	Stroke
HP:0001394	Cirrhosis
HP:0001508	Failure to thrive
HP:0001950	Respiratory alkalosis
HP:0001951	Episodic ammonia intoxication
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002038	Protein avoidance
HP:0002181	Cerebral edema
HP:0002240	Hepatomegaly
HP:0003217	Hyperglutaminemia
HP:0003218	Oroticaciduria
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0005961	Hypoargininemia
HP:0011966	Elevated plasma citrulline
HP:6000353	Reduced tissue argininosuccinate synthetase activity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012490_475	Femur bone mineral density x serum urate levels interaction	9.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020159	Citrullinemia	C10.228.140.163.100.937.374; C16.320.565.100.940.374; C16.320.565.189.937.374; C18.452.132.100.937.374; C18.452.648.100.940.374; C18.452.648.189.937.374
C538655	Hepatorenal form of glycogen storage disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066297 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ASS1 Loss	Chloroquine + Pegargiminase	Sarcoma	Sensitivity/Response	CIViC D	EID5988
ASS1 Loss	Taxol + Carboplatin + Cisplatin	Ovarian Cancer	Resistance	CIViC D	EID5989

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10793902	ASS1		0.00	0
rs10901080	ASS1		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	57.88	nM	CHEMBL5653589
7.24	ED50	57.88	nM	CHEMBL5653589
5.30	Kd	5022	nM	CHEMBL3752910
5.30	ED50	5022	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147899: Binding affinity to human ASS1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0579	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147899: Binding affinity to human ASS1 incubated for 45 mins by Kinobead based pull down assay	kd	5.0219	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, decreases expression	5
Tretinoin	affects cotreatment, decreases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
Arsenic Trioxide	increases expression, affects cotreatment, decreases expression	4
Benzo(a)pyrene	affects cotreatment, decreases expression, increases methylation	4
Cisplatin	affects cotreatment, increases expression, decreases response to substance, affects response to substance, affects expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases expression, decreases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
T-2 Toxin	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Valproic Acid	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
tert-Butylhydroperoxide	decreases expression	2
Particulate Matter	increases expression, affects cotreatment, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
testosterone enanthate	affects expression	1
propionaldehyde	increases expression	1
benzo(b)fluoranthene	affects cotreatment, decreases expression	1
deoxynivalenol	decreases expression	1
lead acetate	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	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
CHEMBL5650941	Binding	Binding affinity to human ASS1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

12 cell lines: 6 transformed cell line, 5 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_5M25	GM23851	Transformed cell line	Male
CVCL_5M27	GM23653	Transformed cell line	Female
CVCL_5M34	GM23705	Transformed cell line	Female
CVCL_5M36	GM23809	Transformed cell line	Male
CVCL_5M38	GM23879	Transformed cell line	Male
CVCL_A5PB	GM25134	Transformed cell line	Male
CVCL_B1K6	Abcam HeLa ASS1 KO	Cancer cell line	Female
CVCL_D1RN	Abcam U-87MG ASS1 KO	Cancer cell line	Male
CVCL_D8HJ	Ubigene HCT 116 ASS1 KO	Cancer cell line	Male
CVCL_RL77	WAe001-A-13	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	PHASE3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	PHASE3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
NCT00000561	PHASE3	COMPLETED	Mode Selection Trial in Sinus Node Dysfunction (MOST)
NCT00000609	PHASE3	COMPLETED	Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
NCT00004559	PHASE3	COMPLETED	Fatty Acid Antiarrhythmia Trial (FAAT)
NCT00004560	PHASE3	COMPLETED	Public Access Defibrillation (PAD) Community Trial
NCT00035490	PHASE3	COMPLETED	Efficacy and Safety Evaluation of Azimilide Dihydrochloride in Patients With Implantable Cardioverter Defibrillators