ASNS

Summary

ASNS (asparagine synthetase (glutamine-hydrolyzing), HGNC:753) is a protein-coding gene on chromosome 7q21.3, encoding Asparagine synthetase [glutamine-hydrolyzing] (P08243). In precision oncology, ASNS Amplification is associated with resistance to Asparaginase in Ovarian Cancer (CIViC Level D). It is a selective cancer dependency (DepMap: 17.3% of cell lines).

The protein encoded by this gene is involved in the synthesis of asparagine. This gene complements a mutation in the temperature-sensitive hamster mutant ts11, which blocks progression through the G1 phase of the cell cycle at nonpermissive temperature. Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 440 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 804 total — 67 pathogenic, 70 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 17.3% of screened cell lines
• MANE Select transcript: NM_001673

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:753
Approved symbol	ASNS
Name	asparagine synthetase (glutamine-hydrolyzing)
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000070669
Ensembl biotype	protein_coding
OMIM	108370
Entrez	440

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 27 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000175506, ENST00000394308, ENST00000394309, ENST00000414884, ENST00000422745, ENST00000437628, ENST00000437657, ENST00000442734, ENST00000444334, ENST00000448127, ENST00000451771, ENST00000453600, ENST00000454046, ENST00000455086, ENST00000462436, ENST00000487714, ENST00000495255, ENST00000884568, ENST00000884569, ENST00000884570, ENST00000931343, ENST00000931344, ENST00000931345, ENST00000931346, ENST00000931347, ENST00000931348, ENST00000931349, ENST00000931350, ENST00000968225, ENST00000968226, ENST00000968227

RefSeq mRNA: 7 — MANE Select: NM_001673 NM_001178075, NM_001178076, NM_001178077, NM_001352496, NM_001673, NM_133436, NM_183356

CCDS: CCDS55131, CCDS55132, CCDS5652

Canonical transcript exons

ENST00000394308 — 13 exons

Exon	Start	End
ENSE00000707046	97854580	97854680
ENSE00000707047	97855353	97855459
ENSE00000707049	97858278	97858405
ENSE00000707050	97858854	97858955
ENSE00001182967	97859213	97859398
ENSE00001212450	97868908	97869179
ENSE00001714806	97872351	97872408
ENSE00001779167	97869778	97869813
ENSE00003486906	97856690	97856816
ENSE00003620537	97853305	97853386
ENSE00003625116	97853060	97853215
ENSE00003785828	97864259	97864496
ENSE00003845364	97851677	97852468

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 97.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.1989 / max 1059.1805, expressed in 1771 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85035	48.0539	1647
85036	32.8751	1743
85033	0.6843	360
85030	0.1798	71
85034	0.1538	66
85032	0.1387	61
85037	0.1063	61
85031	0.0070	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	97.94	gold quality
cerebellar cortex	UBERON:0002129	97.91	gold quality
cerebellum	UBERON:0002037	97.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.76	gold quality
cortical plate	UBERON:0005343	97.61	gold quality
superior frontal gyrus	UBERON:0002661	97.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.23	gold quality
primary visual cortex	UBERON:0002436	97.14	gold quality
islet of Langerhans	UBERON:0000006	96.98	gold quality
right frontal lobe	UBERON:0002810	96.90	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.86	gold quality
anterior cingulate cortex	UBERON:0009835	96.46	gold quality
frontal cortex	UBERON:0001870	96.41	gold quality
frontal lobe	UBERON:0016525	96.40	gold quality
cerebral cortex	UBERON:0000956	96.39	gold quality
ganglionic eminence	UBERON:0004023	96.13	gold quality
embryo	UBERON:0000922	96.12	gold quality
prefrontal cortex	UBERON:0000451	96.06	gold quality
hypothalamus	UBERON:0001898	95.83	gold quality
Ammon’s horn	UBERON:0001954	95.82	gold quality
pituitary gland	UBERON:0000007	95.77	gold quality
pancreas	UBERON:0001264	95.77	gold quality
brain	UBERON:0000955	95.73	gold quality
body of pancreas	UBERON:0001150	95.53	gold quality
adenohypophysis	UBERON:0002196	95.32	gold quality
nucleus accumbens	UBERON:0001882	94.72	gold quality
amygdala	UBERON:0001876	94.18	gold quality
temporal lobe	UBERON:0001871	94.14	gold quality
caudate nucleus	UBERON:0001873	94.09	gold quality
stromal cell of endometrium	CL:0002255	93.90	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	769.41
E-ANND-3	yes	4.72
E-GEOD-86618	no	717.30
E-GEOD-124858	no	683.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, ATF4, ATF5, CEBPA, CEBPB, CEBPG, CTNNB1, DDIT3, FOXC1, SP1, SP3, WWTR1, YY1

miRNA regulators (miRDB)

10 targeting ASNS, 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-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-219A-1-3P	98.91	67.87	639
HSA-MIR-3117-3P	95.96	67.82	473
HSA-MIR-8083	95.93	67.55	694

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 17.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Role of Sp1 and Sp3 in the nutrient-regulated expression of the human asparagine synthetase gene (PMID:11867623)
• ATF4 is a mediator of the nutrient-sensing response pathway that activates asparagine synthetase gene (PMID:11960987)
• Genomic sequences necessary for transcriptional activation by amino acid deprivation of mammalian cells. activation of asparagine synthetase gene by endoplasmic reticulum stress. (PMID:12097650)
• documentation of the comparison between CHOP and AS transcriptional control elements used by the amino acid pathway (PMID:12351626)
• ATF3-FL and C/EBPbeta act as transcriptional suppressors for the ASNS gene to counterbalance the transcription rate activated by ATF4 following amino acid deprivation (PMID:15385533)
• The Asparagine Synthetase), which is a housekeeping gene, is repressed and the promoting region of the gene is highly methylated. (PMID:15674423)
• coorelation between methylation of ASNS and acute lymphoblastic leukemia (PMID:16598302)
• ASNS RNAi potentiates L-asparaginase chemotherapeutic activity in ovarian cancer cell lines from the NCI-60, and ASNS mRNA expression predicts L-asparaginase activity in the ovarian subpanel of the NCI-60. (PMID:17088436)
• results suggest that the presence of MELAS and NARP mtDNA mutations elicits upregulation of CHOP and ASNS genes through the elevation of ATF4 expression and its binding to the amino acid regulatory element and nutrient-sensing response element-1 (PMID:17276738)
• RNA interference decreases capacity of mesenchymal stem cells to protect acute lymphoblastic leukemia cells from asparaginase, whereas enforced ASNS expression conferred enhanced protection. (PMID:17380207)
• ASNS (asparagine synthetase) transcription activity was up-regulated in HepG2 cells treated with the UPR activators thapsigargin and tunicamycin (PMID:18840095)
• ASNS protein expression predicts L-asparaginase chemotherapeutic activity in a large, diverse set of ovarian cancer cell lines. (PMID:18852115)
• These findings provide rationale for evaluation of ASNS protein expression as a predictive biomarker of clinical L-ASP activity in ovarian cancer. (PMID:18852115)
• CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF4-containing genes, such as ASNS (PMID:18940792)
• High expression of asparagine synthetase is associated with a poor outcome in ALL children. (PMID:19035175)
• DNA polymorphism of a tandem repeated sequence is associated with the asparagine synthetase gene in acute lymphoblastic leukemia (PMID:19054556)
• Declined asparagine synthetase mRNA expression and enhanced sensitivity to asparaginase in HL-60 cells committed to monocytic differentiation. (PMID:19414379)
• AsnS mRNA expression level in tumor cells reflects the sensitivity of cells to L-asparaginase. (PMID:20561401)
• Subcellular translocation of asparagine synthetase may play an important role in L-asparaginase resistance in leukemia cells. (PMID:21505976)
• Activation of asparagine synthetase by amino acid limitation results in dynamic changes in genomic histone association. (PMID:22978410)
• Identifying the roles of ASNS in fetal development, tissue differentiation, and tumor growth may reveal that ASNS function extends beyond asparagine biosynthesis. (PMID:23403946)
• expression of ASNS was higher in hepatocellular carcinoma tissues; expression of ASNS is an independent factor affecting the survival of HCC patients, and low ASNS expression in HCC was correlated with worse surgical outcomes (PMID:23764751)
• ASNS and MMP19, along with eIF3a, are the sensitivity factors for cisplatin treatment and may serve as potential candidate molecular markers for predicting cisplatin sensitivity of advanced nasopharyngeal carcinoma. (PMID:23956056)
• study indicates that asparagine synthesis is essential for the development and function of the brain. (PMID:24139043)
• A conditional interaction between the ASNS polymorphism and an early response to chemotherapy among pediatric patients with acute lymphoblastic leukemia. (PMID:24268318)
• cell differentiation was enhanced when asparagine in the culture media was depleted by an addition of L-asparaginase, indicating that downregulation of asparagine synthetase gene expression (PMID:24398846)
• ASNS deficiency is correlated with poor therapeutic response and worse survivals in patients with rectal cancer receiving neoadjuvant CCRT (PMID:24729124)
• Polymorphisms of ASNS are associated with an increased risk of asparaginase-related complications in children with acute lymphoblastic leukemia. (PMID:24907114)
• Data shows that high ASNS expression in NK/T cell lymphoma is correlated with worse clinicopathological features. (PMID:24913732)
• role of ASNS in melanoma cells A375 and human epidermoid carcinoma cell line A431 (PMID:25858017)
• Transient knockdown of ASNS inhibited cell proliferation and colony formation in AGS and MKN-45 cells. Stable knockdown of ASNS conferred sensitivity to cisplatin in these cells. Depletion of ASNS and cisplatin treatment exerted synergistic effects on tumor growth in AGS xenografts. Moreover, ASNS was found to be up-regulated in human gastric cancer tissues compared with matched normal colon tissues. (PMID:27251594)
• our study demonstrated that ASNS had an important role in the growth of human lung cancer cells by inhibiting the proliferation and arresting cell cycle of lung cancer cells (PMID:27444726)
• The expression of ASNS was significantly elevated when ATF6 was over expressed. The expressions of these 2 genes were both decreased in hepatocellular carcinoma (HCC)patients, and it was more significantly with ASNS. The mRNA levels of ASNS and ATF6 were positively correlated with each other. rs34050735 was associated with HCC in the case-control study and also an independent predictor of overall survival of HCC patients. (PMID:28629319)
• review of ASNS function, structure, mutations and roles in genetic disease and asparaginase drug resistance (PMID:29084849)
• Study results in two siblings suggest that the Arg49Gln variant affects the enzymatic function of ASNS. The clinical, cellular, and molecular observations from these siblings expand the known phenotypic spectrum of asparagine synthetase deficiency. (PMID:29279279)
• Four novel ASNS variants causing asparagine synthetase deficiency in 14 families have been described. (PMID:29405484)
• basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer. (PMID:30061420)
• ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy. (PMID:30978478)
• Asparagine Synthetase Is Highly Expressed at Baseline in the Pancreas Through Heightened PERK Signaling. (PMID:31421261)
• A novel compound heterozygous missense mutation in ASNS broadens the spectrum of asparagine synthetase deficiency. (PMID:32255274)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	asns	ENSDARG00000016375
mus_musculus	Asns	ENSMUSG00000029752
rattus_norvegicus	Asns	ENSRNOG00000007546

Paralogs (1): ASNSD1 (ENSG00000138381)

Protein

Protein identifiers

Asparagine synthetase [glutamine-hydrolyzing] — P08243 (reviewed: P08243)

Alternative names: Cell cycle control protein TS11, Glutamine-dependent asparagine synthetase

All UniProt accessions (8): P08243, C9J057, C9J605, C9JLA3, C9JLN6, C9JM09, C9JT45, F8WEJ5

UniProt curated annotations — full annotation on UniProt →

Disease relevance. Asparagine synthetase deficiency (ASNSD) [MIM:615574] An inborn error of asparagine biosynthesis that results in a severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid biosynthesis; L-asparagine biosynthesis; L-asparagine from L-aspartate (L-Gln route): step 1/1.

Isoforms (3)

UniProt ID	Names	Canonical?
P08243-1	1	yes
P08243-2	2
P08243-3	3

RefSeq proteins (7): NP_001171546, NP_001171547, NP_001171548, NP_001339425, NP_001664, NP_597680, NP_899199 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001962	Asn_synthase	Domain
IPR006426	Asn_synth_AEB	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR017932	GATase_2_dom	Domain
IPR029055	Ntn_hydrolases_N	Homologous_superfamily
IPR033738	AsnB_N	Domain
IPR050795	Asn_Synthetase	Family

Pfam: PF00733, PF13537

Enzyme classification (BRENDA):

• EC 6.3.5.4 — asparagine synthase (glutamine-hydrolysing) (BRENDA: 55 organisms, 73 substrates, 150 inhibitors, 157 Km, 86 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.013–2.24	38
L-ASP	0.13–1.2	19
L-GLN	0.04–9	19
ASP	0.53–55.7	13
GLN	0.16–5.24	12
L-GLUTAMINE	0.09–10.3	12
NH4+	2.1–120	9
L-ASPARTATE	0.6–6.21	8
NH3	0.75–9.9	8
L-GLUTAMIC ACID GAMMA-MONOHYDROXAMATE	0.09–0.26	3
HYDROXYLAMINE	11.5–17.1	2
ASPARTIC ACID	0.38	1
L-ASPARTIC ACID	1.3	1
GLUTAMINE	—	0
L-ASPARAGINE	—	0

Catalyzed reactions (Rhea), 1 shown:

• L-aspartate + L-glutamine + ATP + H2O = L-asparagine + L-glutamate + AMP + diphosphate + H(+) (RHEA:12228)

UniProt features (75 total): helix 24, strand 18, turn 7, binding site 6, sequence variant 4, sequence conflict 4, modified residue 3, splice variant 2, domain 2, initiator methionine 1, chain 1, site 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6GQ3	X-RAY DIFFRACTION	1.85
9B6C	ELECTRON MICROSCOPY	3.35
8SUE	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08243-F1	94.36	0.89

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 (2): 365 (important for beta-aspartyl-amp intermediate formation); 2 (for gatase activity)

Ligand- & substrate-binding residues (6): 363–364; 49–53; 75–77; 97; 256; 288

Post-translational modifications (3): 385, 545, 557

Mutagenesis-validated functional residues (1):

Position	Phenotype
2	loss of the glutamine-dependent asparagine synthetase activity, while the ammonia-dependent activity remained unaffected

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress
R-HSA-8963693	Aspartate and asparagine metabolism
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency
R-HSA-1430728	Metabolism
R-HSA-2262752	Cellular responses to stress
R-HSA-381042	PERK regulates gene expression
R-HSA-381119	Unfolded Protein Response (UPR)
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711097	Cellular response to starvation

MSigDB gene sets: 460 (showing top): MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, TSENG_IRS1_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, BASSO_B_LYMPHOCYTE_NETWORK, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_DN, IVANOVA_HEMATOPOIESIS_MATURE_CELL, CAFFAREL_RESPONSE_TO_THC_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN

GO Biological Process (6): obsolete asparagine biosynthetic process (GO:0006529), cellular response to glucose starvation (GO:0042149), negative regulation of apoptotic process (GO:0043066), positive regulation of mitotic cell cycle (GO:0045931), L-asparagine biosynthetic process (GO:0070981), amino acid biosynthetic process (GO:0008652)

GO Molecular Function (5): asparagine synthase (glutamine-hydrolyzing) activity (GO:0004066), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cellular responses to stress	3
PERK regulates gene expression	1
Metabolism of amino acids and derivatives	1
Cellular response to starvation	1
Cellular responses to stimuli	1
Unfolded Protein Response (UPR)	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to starvation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
positive regulation of cell cycle	1
aspartate family amino acid biosynthetic process	1
amino acid metabolic process	1
biosynthetic process	1
carbon-nitrogen ligase activity, with glutamine as amido-N-donor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

73 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ASNS	TRIM69	psi-mi:“MI:0915”(physical association)	0.670
TRIM69	ASNS	psi-mi:“MI:0915”(physical association)	0.670
WDR27	ASNS	psi-mi:“MI:0915”(physical association)	0.560
ASNS	WDR27	psi-mi:“MI:0915”(physical association)	0.560
ASNS	TRIM69	psi-mi:“MI:0915”(physical association)	0.560
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
RABGGTA	YKT6	psi-mi:“MI:0914”(association)	0.530
ASNS	RPL7A	psi-mi:“MI:0915”(physical association)	0.400
ASNS	NELFCD	psi-mi:“MI:0915”(physical association)	0.400
ATXN1	ASNS	psi-mi:“MI:0915”(physical association)	0.370
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
RRP1B	ZNF785	psi-mi:“MI:0914”(association)	0.350
HSPA8	PPP6C	psi-mi:“MI:0914”(association)	0.350
SDHA	HMGB3	psi-mi:“MI:0914”(association)	0.350
SDHA	NME2P1	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
CD74		psi-mi:“MI:0914”(association)	0.350
IRF2	VWA8	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350

BioGRID (217): TRIM69 (Two-hybrid), WDR27 (Two-hybrid), ASNS (Affinity Capture-MS), ASNS (Affinity Capture-MS), ASNS (Affinity Capture-MS), AARS (Co-fractionation), AHNAK (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation), ASNS (Co-fractionation)

ESM2 similar proteins: A8XKG6, B6HLP8, I1S3K8, O24338, O24661, P08243, P17714, P19251, P19252, P19891, P22106, P31752, P40510, P49078, P49088, P49089, P49090, P49091, P49092, P49093, P49094, P54888, P56658, P78753, P97427, Q0E671, Q10MX3, Q14194, Q14195, Q16555, Q18164, Q1LZA3, Q27601, Q291H5, Q43011, Q54MB4, Q55FT1, Q5R6W9, Q5ZJU3, Q61024

Diamond homologs: B6HLP8, I1S3K8, O24338, O24661, P08243, P17169, P17714, P19251, P19252, P19891, P22106, P31752, P49078, P49088, P49089, P49090, P49091, P49092, P49093, P49094, P78753, Q10MX3, Q1LZA3, Q43011, Q54MB4, Q58456, Q58516, Q5PKV9, Q5R6W9, Q5UQE1, Q5ZJU3, Q61024, Q83IY4, Q8FBT4, Q8XEG2, Q8Z2Q2, Q8ZKX1, Q9LFU1, Q9LV77, P44708

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
ATF3	“up-regulates quantity by expression”	ASNS	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	ASNS	“transcriptional regulation”
DDIT3	“down-regulates quantity by repression”	ASNS	“transcriptional regulation”
ATF4	“down-regulates quantity by repression”	ASNS	“transcriptional regulation”
WWTR1	“down-regulates quantity by repression”	ASNS	“transcriptional regulation”
ASNS	“down-regulates quantity”	L-aspartate(1-)	“chemical modification”
ASNS	“down-regulates quantity”	“L-glutamine zwitterion”	“chemical modification”
ASNS	“up-regulates quantity”	“L-asparagine zwitterion”	“chemical modification”
ASNS	“up-regulates quantity”	AMP	“chemical modification”
ASNS	“up-regulates quantity”	L-glutamate(1-)	“chemical modification”
SP1	“up-regulates quantity by expression”	ASNS	“transcriptional regulation”
SP3	“up-regulates quantity by expression”	ASNS	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	70
Uncertain significance	226
Likely benign	356
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1349462	NM_001673.5(ASNS):c.1460_1461insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCCGGCTAAAACGGTGAAACNNNNNNNNNNAAAAAAAAAAAAGATTTTACAGGA (p.Glu487_Tyr488insAlaGlyArgGlyGlySerArgLeuTer)	Pathogenic
1369744	NM_001673.5(ASNS):c.717del (p.Phe239fs)	Pathogenic
1382912	NM_001673.5(ASNS):c.692_693del (p.Val231fs)	Pathogenic
1394432	NM_001673.5(ASNS):c.1281_1294del (p.Tyr428fs)	Pathogenic
1408196	NM_001673.5(ASNS):c.498dup (p.Leu167fs)	Pathogenic
1416825	NM_001673.5(ASNS):c.1534del (p.Thr512fs)	Pathogenic
1418727	NM_001673.5(ASNS):c.554del (p.Tyr185fs)	Pathogenic
1448756	NM_001673.5(ASNS):c.1374dup (p.Pro459fs)	Pathogenic
1455131	NM_001673.5(ASNS):c.209T>A (p.Leu70Ter)	Pathogenic
1455753	NM_001673.5(ASNS):c.1610G>A (p.Trp537Ter)	Pathogenic
1457008	NC_000007.13:g.(?97481561)(97498478_?)del	Pathogenic
1457009	NC_000007.13:g.(?97498200)(97498468_?)del	Pathogenic
1457924	NM_001673.5(ASNS):c.688dup (p.Thr230fs)	Pathogenic
1458611	NM_001673.5(ASNS):c.552dup (p.Tyr185fs)	Pathogenic
1700067	NM_001673.5(ASNS):c.182C>T (p.Pro61Leu)	Pathogenic
1709129	NM_001673.5(ASNS):c.213G>A (p.Trp71Ter)	Pathogenic
2008550	NM_001673.5(ASNS):c.1191_1192insGG (p.Tyr398fs)	Pathogenic
2012637	NM_001673.5(ASNS):c.669del (p.Pro224fs)	Pathogenic
2020483	NM_001673.5(ASNS):c.65del (p.Met22fs)	Pathogenic
2023201	NM_001673.5(ASNS):c.374_381del (p.Leu125fs)	Pathogenic
2035058	NM_001673.5(ASNS):c.470_471insCT (p.Cys158fs)	Pathogenic
2058880	NM_001673.5(ASNS):c.1481del (p.Asp494fs)	Pathogenic
2087641	NM_001673.5(ASNS):c.692_695dup (p.Lys232fs)	Pathogenic
2118105	NM_001673.5(ASNS):c.464del (p.Leu155fs)	Pathogenic
2120794	NM_001673.5(ASNS):c.394A>T (p.Lys132Ter)	Pathogenic
2134487	NM_001673.5(ASNS):c.449del (p.Thr150fs)	Pathogenic
2427214	NC_000007.13:g.(?97488515)(97493818_?)del	Pathogenic
2443601	NM_001673.5(ASNS):c.198_202del (p.Lys66fs)	Pathogenic
2577189	NM_001673.5(ASNS):c.1209_1211delinsGCA (p.Arg404His)	Pathogenic
2704077	NM_001673.5(ASNS):c.156dup (p.Val53fs)	Pathogenic

SpliceAI

1821 predictions. Top by Δscore:

Variant	Effect	Δscore
7:97852464:TCAAC:T	acceptor_gain	1.0000
7:97852465:CAAC:C	acceptor_gain	1.0000
7:97852465:CAACC:C	acceptor_gain	1.0000
7:97852469:C:A	acceptor_loss	1.0000
7:97852469:C:CC	acceptor_gain	1.0000
7:97852477:A:AC	acceptor_gain	1.0000
7:97853054:TTATA:T	donor_loss	1.0000
7:97853055:TATA:T	donor_loss	1.0000
7:97853056:ATACC:A	donor_loss	1.0000
7:97853057:TA:T	donor_loss	1.0000
7:97853058:A:T	donor_loss	1.0000
7:97853059:C:CA	donor_loss	1.0000
7:97853074:ATT:A	donor_gain	1.0000
7:97853076:T:TA	donor_gain	1.0000
7:97853089:TAA:T	donor_gain	1.0000
7:97853090:AAA:A	donor_gain	1.0000
7:97853106:A:C	donor_gain	1.0000
7:97853211:CCATT:C	acceptor_gain	1.0000
7:97853212:CATT:C	acceptor_gain	1.0000
7:97853212:CATTC:C	acceptor_gain	1.0000
7:97853213:ATT:A	acceptor_gain	1.0000
7:97853214:TT:T	acceptor_gain	1.0000
7:97853215:TC:T	acceptor_loss	1.0000
7:97853216:C:CC	acceptor_gain	1.0000
7:97853216:C:T	acceptor_loss	1.0000
7:97853220:C:CT	acceptor_gain	1.0000
7:97853221:G:C	acceptor_gain	1.0000
7:97853221:G:GC	acceptor_gain	1.0000
7:97853225:C:CT	acceptor_gain	1.0000
7:97853382:CAAGA:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000038000 (7:97922117 C>A), RS1000147862 (7:97879863 A>G), RS1000153565 (7:97919724 A>G), RS1000167448 (7:97908287 A>C), RS1000319248 (7:97865648 A>G), RS1000350272 (7:97865877 A>C,G,T), RS1000415774 (7:97866288 T>C), RS1000470597 (7:97916964 A>T), RS1000522544 (7:97910396 C>T), RS1000546100 (7:97928532 C>G,T), RS1000644027 (7:97867298 A>G), RS1000754041 (7:97918374 G>T), RS1000794373 (7:97894553 T>C), RS1001018779 (7:97903018 AG>A), RS1001035581 (7:97853825 C>T)

Disease associations

OMIM: gene MIM:108370 | disease phenotypes: MIM:615574, MIM:619389

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	Definitive	AR

Mondo (2): congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (MONDO:0014258), spinocerebellar ataxia, autosomal recessive 29 (MONDO:0030312)

Orphanet (1): Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome (Orphanet:391376)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000316	Hypertelorism
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000400	Macrotia
HP:0000609	Optic nerve hypoplasia
HP:0000618	Blindness
HP:0000737	Irritability
HP:0001176	Large hands
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001298	Encephalopathy
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001558	Decreased fetal movement
HP:0001833	Long foot
HP:0002020	Gastroesophageal reflux
HP:0002079	Hypoplasia of the corpus callosum
HP:0002093	Respiratory insufficiency
HP:0002119	Ventriculomegaly
HP:0002169	Clonus
HP:0002198	Dilated fourth ventricle

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006922_15	Regular attendance at a religious group	9.000000e-09
GCST007231_3	Tuberculosis	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3120 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ASNS Amplification	Asparaginase	Ovarian Cancer	Resistance	CIViC D	EID953

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3832526	ASNS		0.00	0
rs1049674	ASNS		0.00	0

ChEMBL bioactivities

15 potent at pChembl≥5 of 16 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.60	Ki	2.5	nM	CHEMBL1627258
8.10	Ki	8	nM	CHEMBL2153507
7.62	Ki	24	nM	CHEMBL1627258
7.48	Ki	33	nM	CHEMBL2153507
6.55	Ki	280	nM	CHEMBL1627258
6.51	Ki	310	nM	CHEMBL2153508
6.35	Ki	450	nM	CHEMBL2153507
6.31	Ki	490	nM	CHEMBL2153507
6.11	Kd	770.8	nM	CHEMBL5653589
6.11	ED50	770.8	nM	CHEMBL5653589
6.08	Ki	840	nM	CHEMBL2153508
6.00	Ki	1000	nM	CHEMBL1627258
5.52	Ki	3040	nM	CHEMBL2153508
5.35	Ki	4500	nM	CHEMBL2153508
5.00	Ki	1e+04	nM	CHEMBL1627258

PubChem BioAssay actives

14 with measured affinity, of 41 total; 4 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
(2R)-2-amino-3-[N-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]-S-methylsulfonimidoyl]propanoic acid	690583: Inhibition of human recombinant ASNS expressed in Sf9 cells assessed as assessed as overall inhibition constant for ammonia dependent production of inorganic pyrophosphate by spectrophotometry analysis	ki	0.0025	uM
N-(2-aminoethyl-methyl-oxo-lambda6-sulfanylidene)-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]phosphonamidic acid	690582: Inhibition of human recombinant ASNS expressed in Sf9 cells assessed as overall inhibition constant for glutamine dependent production of inorganic pyrophosphate by spectrophotometry analysis	ki	0.0080	uM
3-[N-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]-S-methylsulfonimidoyl]propanoic acid	690583: Inhibition of human recombinant ASNS expressed in Sf9 cells assessed as assessed as overall inhibition constant for ammonia dependent production of inorganic pyrophosphate by spectrophotometry analysis	ki	0.3100	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147898: Binding affinity to human ASNS incubated for 45 mins by Kinobead based pull down assay	kd	0.7708	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, decreases methylation, affects cotreatment, increases abundance, increases expression	11
Cyclosporine	affects expression, increases expression	10
bisphenol A	decreases expression, increases expression, affects expression	9
Tunicamycin	decreases reaction, increases expression	7
Benzo(a)pyrene	affects methylation, affects cotreatment, decreases expression	6
Valproic Acid	increases expression, affects expression, decreases expression	6
Acetaminophen	increases expression, affects expression, affects cotreatment	5
Estradiol	affects cotreatment, decreases expression, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
perfluorooctanoic acid	increases expression	4
Rotenone	decreases expression, increases expression	4
Genistein	increases reaction, increases expression	4
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment, affects expression	4
ochratoxin A	decreases expression, increases expression	3
perfluorooctane sulfonic acid	increases expression	3
Arsenic Trioxide	increases expression, decreases expression	3
Amiodarone	increases expression	3
Amitriptyline	increases expression	3
Clozapine	increases expression	3
Fluoxetine	increases expression	3
Aflatoxin B1	affects expression, decreases expression	3
beta-Naphthoflavone	increases expression	3
deoxynivalenol	decreases expression	2
trichostatin A	affects cotreatment, increases expression	2
nickel chloride	increases expression	2
didecyldimethylammonium	increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	decreases expression, increases expression, affects cotreatment	2
monomethylarsonous acid	increases expression	2

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1074551	Binding	Inhibition of human recombinant ASNS expressed in Sf9 insect cells assessed as inorganic phosphate production in glutamine-dependent asparagine synthesis using continuous assay	A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase. — Bioorg Med Chem

Cellosaurus cell lines

12 cell lines: 5 transformed cell line, 4 induced pluripotent stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1RM	Abcam U-87MG ASNS KO	Cancer cell line	Male
CVCL_D1VE	Abcam A-549 ASNS KO	Cancer cell line	Male
CVCL_D2A0	Abcam HCT 116 ASNS KO	Cancer cell line	Male
CVCL_E8E1	HEK293T ASNS-Flag-H205P	Transformed cell line	Female
CVCL_E8E2	HEK293T ASNS-Flag-Y398Lfs*4	Transformed cell line	Female
CVCL_E8E3	LCL ASNS H205P	Transformed cell line	Female
CVCL_E8E4	LCL ASNS H205P+Y398Lfs*4	Transformed cell line	Male
CVCL_E8E5	LCL ASNS Y398Lfs*4	Transformed cell line	Male
CVCL_YM90	GZWWTi001-A [2019]	Induced pluripotent stem cell	Female
CVCL_YM91	GZWTZi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03587155	Not specified	UNKNOWN	Study on the Mechanism of Neurodevelopment Dysplasia of Fetal Brain Caused by ASNS Gene Mutation
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families