ASL

Summary

ASL (argininosuccinate lyase, HGNC:746) is a protein-coding gene on chromosome 7q11.21, encoding Argininosuccinate lyase (P04424). Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine synthesis in nonhepatic tissues.

This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 435 — RefSeq curated summary.

At a glance

• Gene–disease (curated): argininosuccinic aciduria (Definitive, ClinGen)
• Clinical variants (ClinVar): 993 total — 79 pathogenic, 121 likely-pathogenic
• Phenotypes (HPO): 65
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000048

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:746
Approved symbol	ASL
Name	argininosuccinate lyase
Location	7q11.21
Locus type	gene with protein product
Status	Approved
Aliases	ASAL
Ensembl gene	ENSG00000126522
Ensembl biotype	protein_coding
OMIM	608310
Entrez	435

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 54 protein_coding, 8 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000304874, ENST00000362000, ENST00000380839, ENST00000395331, ENST00000395332, ENST00000464970, ENST00000487982, ENST00000488343, ENST00000493708, ENST00000496336, ENST00000671817, ENST00000672498, ENST00000672586, ENST00000672676, ENST00000673149, ENST00000673350, ENST00000673518, ENST00000673594, ENST00000906797, ENST00000906798, ENST00000906799, ENST00000906800, ENST00000906801, ENST00000906802, ENST00000906803, ENST00000906804, ENST00000906805, ENST00000906806, ENST00000906807, ENST00000906808, ENST00000906809, ENST00000906810, ENST00000906811, ENST00000906812, ENST00000906813, ENST00000906814, ENST00000906815, ENST00000906816, ENST00000906817, ENST00000906818, ENST00000906819, ENST00000906820, ENST00000906821, ENST00000906822, ENST00000906823, ENST00000906824, ENST00000906825, ENST00000906826, ENST00000906827, ENST00000906828, ENST00000906829, ENST00000906830, ENST00000906831, ENST00000930139, ENST00000930140, ENST00000930141, ENST00000952728, ENST00000952729, ENST00000952730, ENST00000952731, ENST00000952732, ENST00000952733, ENST00000952734, ENST00000952735

RefSeq mRNA: 4 — MANE Select: NM_000048 NM_000048, NM_001024943, NM_001024944, NM_001024946

CCDS: CCDS47597, CCDS47598, CCDS5531

Canonical transcript exons

ENST00000304874 — 17 exons

Exon	Start	End
ENSE00001167543	66087729	66087791
ENSE00001167550	66087334	66087386
ENSE00001167557	66086744	66086821
ENSE00001486497	66092768	66093576
ENSE00003461706	66088807	66088921
ENSE00003474820	66082368	66082451
ENSE00003483679	66082880	66082936
ENSE00003529046	66083077	66083174
ENSE00003531434	66092557	66092663
ENSE00003536992	66089276	66089335
ENSE00003552375	66089612	66089695
ENSE00003639784	66086585	66086662
ENSE00003644260	66076039	66076093
ENSE00003654446	66089091	66089175
ENSE00003666304	66092006	66092086
ENSE00003669988	66081803	66081997
ENSE00003896120	66075819	66075856

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9997 / max 405.4219, expressed in 1805 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78851	9.4163	1782
78853	2.5168	1277
78852	1.9165	1188
78850	1.1502	818

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.14	gold quality
liver	UBERON:0002107	98.80	gold quality
mucosa of transverse colon	UBERON:0004991	97.75	gold quality
duodenum	UBERON:0002114	96.50	gold quality
transverse colon	UBERON:0001157	95.15	gold quality
adult mammalian kidney	UBERON:0000082	94.56	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.19	gold quality
body of stomach	UBERON:0001161	94.03	gold quality
small intestine	UBERON:0002108	93.96	gold quality
rectum	UBERON:0001052	93.91	gold quality
bone marrow cell	CL:0002092	93.56	gold quality
metanephros cortex	UBERON:0010533	93.49	gold quality
stomach	UBERON:0000945	92.72	gold quality
body of pancreas	UBERON:0001150	92.48	gold quality
upper lobe of left lung	UBERON:0008952	92.38	gold quality
gall bladder	UBERON:0002110	92.30	gold quality
intestine	UBERON:0000160	92.04	gold quality
right lobe of thyroid gland	UBERON:0001119	92.01	gold quality
fundus of stomach	UBERON:0001160	91.91	gold quality
colon	UBERON:0001155	91.79	gold quality
apex of heart	UBERON:0002098	91.79	gold quality
spleen	UBERON:0002106	91.77	gold quality
kidney	UBERON:0002113	91.54	gold quality
right lung	UBERON:0002167	91.07	gold quality
left lobe of thyroid gland	UBERON:0001120	90.94	gold quality
tibial nerve	UBERON:0001323	90.94	gold quality
granulocyte	CL:0000094	90.89	gold quality
thyroid gland	UBERON:0002046	90.83	gold quality
esophagus mucosa	UBERON:0002469	90.83	gold quality
ascending aorta	UBERON:0001496	90.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	41.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting ASL, 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-1303	99.65	69.77	1662
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-6886-3P	96.96	66.36	844
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-4278	95.28	65.49	351
HSA-MIR-6732-5P	93.97	64.65	422
HSA-MIR-1292-3P	72.98	63.40	23

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• Structural studies of the ASL frequently complementing allele Q286R suggest that the mutation may hinder a conformational change in the 280’s loop (residues 270-290) and domain 3 that may be important for catalysis. (PMID:11747432)
• Complementation can occur at the ASL locus between thermolabile mutants and stable mutants by stabilization of the active oligomeric form of the hybrid enzyme, which may be sufficiently stable for catalysis to occur. (PMID:11747433)
• complete sequence of the human ASL gene and a complete ASL homologue on chromosome 22 (PMID:12384776)
• argininosuccinic aciduria patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical courses. (PMID:12408190)
• This unique mutation causes an elongation of fifty amino acids in the C-terminal region of the ASL protein, and is likely related to a milder phenotype compared with previously reported mutations. (PMID:12512996)
• a novel ASL pseudogene located in the centromeric region of chromosome 7, 14 novel mutations in the ASL gene, and a novel intronic polymorphism found in a cohort of Italian patients with argininosuccinic aciduria (PMID:17326097)
• analysis of human missense argininosuccinate lyase mutations in yeast (PMID:19703900)
• MDR analysis provided evidence of interaction between the genes for ASS1 and SLC25A13 on the risk of CL/P. (PMID:20739017)
• extent of protection of ASL and delta-crystallin at different ratios of alphaA-crystallin (PMID:20937351)
• analysis of mutant argininosuccinate lyase in argininosuccinic aciduria (PMID:21667091)
• Cox regression analysis showed that ASL is an independent prognostic marker for HCC. Therefore, reduced ASL expression may be a novel maker for poor prognosis in HCC patients (PMID:22531684)
• Our results suggest that ASL transcripts can contribute to the highly variable phenotype in ASA patients if expressed at high levels. (PMID:24136197)
• Data show that in patients with Argininosuccinate lyase deficiency, the ASl gene is subject to several mutations, the majority are missense; some more frequent then others. (PMID:24166829)
• Point mutation of ASS1, ASL and SLC25A13 is associated with citrullinemia. (PMID:24927999)
• The clinical and biochemical course in variant forms of ASL deficiency is associated with relevant residual levels of ASL activity as well as instability of mutant ASL proteins. (PMID:25778938)
• the mechanism induced by ASL shRNA which occurred in human breast cancer may be attributed to a decrease in cyclin A2 and NO. (PMID:26397737)
• ASL-targeting shRNA-induced growth inhibition is associated with decreased cyclin A2 expression and Nitric oxide content in colon cancer. (PMID:27840980)
• Overexpression of ASL may be a contributing factor in drug resistance for arginine deprivation therapy. (PMID:28035420)
• The remaining five patients were diagnosed with neonatal intrahepatic cholestasis due to citrin deficiency, and have respectively carried mutations of the SLC25A13 gene including [c.851-854delGTAT+c.851-854delGTAT], [c.851-854delGTAT+IVS6+5G>A], [c.851-854delGTAT+IVS16ins3kb], [c.851-854delGTAT+IVS6-11A>G] and [c.851-854delGTAT+c.1638-1660dup23] (PMID:28981931)
• Mechanistically, KLF7 transcriptionally activated argininosuccinate lyase (ASL), which was observed highly expressed in glioma tissues. KLF7 potentiates polyamine biosynthesis and glioma cell growth via transcriptionally activates ASL. (PMID:31018905)
• Compound heterozygous p.Lys69Arg and p.Arg213 * mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. (PMID:31183366)
• From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria. (PMID:31943503)
• Clinical and genetic analysis of five Chinese patients with urea cycle disorders. (PMID:32410394)
• Biomarkers for liver disease in urea cycle disorders. (PMID:33846069)
• Variants associated with urea cycle disorders in Japanese patients: Nationwide study and literature review. (PMID:33851512)
• Argininosuccinate lyase deficiency causes blood-brain barrier disruption via nitric oxide-mediated dysregulation of claudin expression. (PMID:37490345)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	asl	ENSDARG00000033361
mus_musculus	Asl	ENSMUSG00000025533
rattus_norvegicus	Asl	ENSRNOG00000000903
drosophila_melanogaster	Argl	FBGN0032076

Paralogs (2): FH (ENSG00000091483), ADSL (ENSG00000239900)

Protein

Protein identifiers

Argininosuccinate lyase — P04424 (reviewed: P04424)

Alternative names: Arginosuccinase

All UniProt accessions (8): P04424, A0A024RDL8, A0A0S2Z316, A0A0S2Z3B0, A0A5F9ZHC6, A0A5F9ZHM8, A0A5F9ZI35, F8W943

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine synthesis in nonhepatic tissues. Essential regulator of intracellular and extracellular L-arginine pools. As part of citrulline-nitric oxide cycle, forms tissue-specific multiprotein complexes with argininosuccinate synthase ASS1, transport protein SLC7A1 and nitric oxide synthase NOS1, NOS2 or NOS3, allowing for cell-autonomous L-arginine synthesis while channeling extracellular L-arginine to nitric oxide synthesis pathway.

Subunit / interactions. Homotetramer. Forms tissue-specific complexes with ASS1, SLC7A1, HSP90AA1 and nitric oxide synthase NOS1, NOS2 or NOS3; the complex maintenance is independent of ASL catalytic function.

Post-translational modifications. Acetylation modifies enzyme activity in response to alterations of extracellular nutrient availability. Acetylation increased with trichostin A (TSA) or with nicotinamide (NAM). Glucose increases acetylation by about a factor of 3 with decreasing enzyme activity. Acetylation on Lys-288 is decreased on the addition of extra amino acids resulting in activation of enzyme activity.

Disease relevance. Argininosuccinic aciduria (ARGINSA) [MIM:207900] An autosomal recessive disorder of the urea cycle. The disease is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness. The disease is caused by variants affecting the gene represented in this entry. The phenotype heterogeneity among patients is associated with interallelic complementation resulting in either complete loss of activity or partial regeneration of functional active sites in the heterotetrameric mutant protein.

Activity regulation. Enzyme activity is regulated by acetylation.

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

Similarity. Belongs to the lyase 1 family. Argininosuccinate lyase subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P04424-1	1	yes
P04424-2	2
P04424-3	3

RefSeq proteins (4): NP_000039, NP_001020114, NP_001020115, NP_001020117 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000362	Fumarate_lyase_fam	Family
IPR008948	L-Aspartase-like	Homologous_superfamily
IPR009049	Argininosuccinate_lyase	Family
IPR020557	Fumarate_lyase_CS	Conserved_site
IPR022761	Fumarate_lyase_N	Domain
IPR024083	Fumarase/histidase_N	Homologous_superfamily
IPR029419	Arg_succ_lyase_C	Domain

Pfam: PF00206, PF14698

Enzyme classification (BRENDA):

• EC 4.3.2.1 — argininosuccinate lyase (BRENDA: 29 organisms, 29 substrates, 33 inhibitors, 73 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ARGININOSUCCINATE	0.007–3.159	46
2-(NOMEGA-L-ARGININO)SUCCINATE	0.032–1.55	13
(NOMEGA-L-ARGININO)SUCCINATE	0.2–2.6	3
FUMARATE	0.067–5.3	3
N,N’-BIS(TERT-BUTOXYCARBONYL)-5-[(3-AMINOPROPYL)	0.12	2
ARG	3	1
ARGININE	3	1
DIFLUOROFUMARATE	0.046	1
MONOFLUOROFUMARATE	1.4	1

Catalyzed reactions (Rhea), 1 shown:

• 2-(N(omega)-L-arginino)succinate = fumarate + L-arginine (RHEA:24020)

UniProt features (120 total): sequence variant 65, helix 24, binding site 7, strand 5, modified residue 4, turn 3, mutagenesis site 3, splice variant 2, active site 2, sequence conflict 2, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1K62	X-RAY DIFFRACTION	2.65
1AOS	X-RAY DIFFRACTION	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04424-F1	96.51	0.95

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 (3): 294 (increases basicity of active site his); 160 (proton acceptor); 281 (proton donor)

Ligand- & substrate-binding residues (7): 329 (in chain a); 27 (in chain a); 114 (in chain a); 159 (in chain c); 289 (in chain b); 321 (in chain a); 326 (in chain a)

Post-translational modifications (4): 2, 7, 69, 288

Mutagenesis-validated functional residues (3):

Position	Phenotype
51	2-fold reduction in activity.
89	10-fold reduction in activity.
288	refractory to inhibition by tsa and nam and by addition of extra amino acids. no effect on protein structure.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-70635	Urea cycle
R-HSA-9956529	ASL variants cause argininosuccinate aciduria
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 308 (showing top): GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, GNF2_GSTM1, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GOBP_GLUTAMATE_METABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_GLUTAMINE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, UEDA_PERIFERAL_CLOCK

GO Biological Process (11): urea cycle (GO:0000050), arginine metabolic process (GO:0006525), L-arginine biosynthetic process (GO:0006526), locomotory behavior (GO:0007626), post-embryonic development (GO:0009791), ammonia assimilation cycle (GO:0019676), obsolete L-arginine biosynthetic process via ornithine (GO:0042450), positive regulation of nitric oxide biosynthetic process (GO:0045429), amino acid metabolic process (GO:0006520), amino acid biosynthetic process (GO:0008652), L-amino acid metabolic process (GO:0170033)

GO Molecular Function (5): argininosuccinate lyase activity (GO:0004056), identical protein binding (GO:0042802), catalytic activity (GO:0003824), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

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
amino acid metabolic process	3
biosynthetic process	2
carboxylic acid metabolic process	2
cellular anatomical structure	2
urea metabolic process	1
arginine metabolic process	1
glutamate family amino acid biosynthetic process	1
behavior	1
multicellular organism development	1
multicellular organismal process	1
glutamate metabolic process	1
L-glutamine metabolic process	1
nitrogen utilization	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
primary metabolic process	1
amidine-lyase activity	1
protein binding	1
molecular_function	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASL	ASS1	P00966	933
ASL	OTC	P00480	891
ASL	NAGS	Q8N159	847
ASL	HADH	Q16836	821
ASL	ARG2	P78540	797
ASL	ARG1	P05089	788
ASL	CPS1	P31327	749
ASL	OAT	P04181	745
ASL	AZIN2	Q96A70	657
ASL	ODC1	P11926	638
ASL	SRM	P19623	622
ASL	NOS3	P29474	617
ASL	ADSL	P30566	608
ASL	ALDH18A1	P54886	598
ASL	CRYGB	P07316	595

IntAct

31 interactions, top by confidence:

A	B	Type	Score
ASL	ASL	psi-mi:“MI:0915”(physical association)	0.850
ASL	NTAQ1	psi-mi:“MI:0915”(physical association)	0.780
NTAQ1	ASL	psi-mi:“MI:0915”(physical association)	0.780
MCMBP	ASL	psi-mi:“MI:0915”(physical association)	0.720
ASL	MCMBP	psi-mi:“MI:0915”(physical association)	0.720
TRIM3	ASL	psi-mi:“MI:0915”(physical association)	0.560
HMOX1	ASL	psi-mi:“MI:0915”(physical association)	0.370
ASL	CSNK2A2	psi-mi:“MI:0915”(physical association)	0.370
ASL	FBP1	psi-mi:“MI:0915”(physical association)	0.370
ASL	OVGP1	psi-mi:“MI:0915”(physical association)	0.370
ASL	QARS	psi-mi:“MI:0915”(physical association)	0.370
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
TRIM3	ASL	psi-mi:“MI:0915”(physical association)	0.000
ASL	ASL	psi-mi:“MI:0915”(physical association)	0.000
NTAQ1	ASL	psi-mi:“MI:0915”(physical association)	0.000
MCMBP	ASL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): ASL (Two-hybrid), WDYHV1 (Two-hybrid), QARS (Two-hybrid), ASL (Biochemical Activity), ASL (Biochemical Activity), ASL (Two-hybrid), ASL (Affinity Capture-RNA), ASL (Two-hybrid), ASL (Two-hybrid), WDYHV1 (Two-hybrid), MCMBP (Two-hybrid), ASL (Co-crystal Structure), ASL (Co-fractionation), ASL (Co-fractionation), ACOX1 (Co-fractionation)

ESM2 similar proteins: A0LEB1, A1ATU1, A1BG31, A1KSP4, A1UQY9, A3N1I1, A4IRS2, A5FQ74, A5GDA7, A5VJH2, A6SX31, A9IZG7, A9M2R4, B0BQC2, B2G6Y7, B3E9X6, B3ECP3, B3GY67, B4S7P9, B4S9T4, B7GGR5, B7K8U6, B8FH31, B8FWX3, B8IZS3, B9DVV8, B9M377, P04424, P0DXD4, P40369, Q0VM25, Q21EF4, Q24ZG7, Q2SQ67, Q30YB9, Q3A1V0, Q3ASM4, Q3MC57, Q3Z726, Q3ZYF9

Diamond homologs: A0AKJ8, A0LUB8, A0PP80, A0QHA7, A0QYS5, A1B3M0, A1KJ76, A1SJJ4, A1TAA5, A1UH95, A3Q0T2, A4FKC1, A4QDZ5, A4T9W3, A4WVB9, A5CSI8, A5FWI3, A5U316, A5UVX7, A6WCT0, A7HTI8, A7NF38, A7Z7L9, A8LL46, A9AWL1, A9WQ91, B0RHD6, B0T2T7, B0UJ26, B1I1D1, B1M509, B1MB03, B1W3B4, B1YJ36, B1ZKR9, B2HR33, B3DSY6, B7GTN9, B8DH27, B8EPF2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	79
Likely pathogenic	121
Uncertain significance	175
Likely benign	441
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028027	NM_000048.4(ASL):c.602+1G>T	Pathogenic
1075343	NM_000048.4(ASL):c.221G>A (p.Trp74Ter)	Pathogenic
1299524	NM_000048.4(ASL):c.1327del (p.Thr443fs)	Pathogenic
1420014	NM_000048.4(ASL):c.1219C>T (p.Gln407Ter)	Pathogenic
1454393	NC_000007.13:g.(?65546932)(65549932_?)del	Pathogenic
1458034	NM_000048.4(ASL):c.719-1G>A	Pathogenic
1458484	NC_000007.13:g.(?65557534)(65557909_?)del	Pathogenic
1458557	NM_000048.4(ASL):c.1290C>A (p.Tyr430Ter)	Pathogenic
1470472	NM_000048.4(ASL):c.377G>C (p.Arg126Pro)	Pathogenic
1914880	NM_000048.4(ASL):c.691G>C (p.Asp231His)	Pathogenic
2005777	NM_000048.4(ASL):c.58del (p.Ile20fs)	Pathogenic
203615	NM_000048.4(ASL):c.649C>T (p.Arg217Ter)	Pathogenic
203626	NM_000048.4(ASL):c.436C>T (p.Arg146Trp)	Pathogenic
203628	NM_000048.4(ASL):c.533_557dup (p.Arg186_Leu187insGlyThrAspProArgLeuTer)	Pathogenic
203629	NM_000048.4(ASL):c.1045_1057del (p.Val349fs)	Pathogenic
2085731	NM_000048.4(ASL):c.976C>T (p.Gln326Ter)	Pathogenic
2093251	NM_000048.4(ASL):c.231_243del (p.Phe79fs)	Pathogenic
2102465	NM_000048.4(ASL):c.406del (p.Leu136fs)	Pathogenic
2123808	NM_000048.4(ASL):c.280_281insTGAAG (p.Arg94fs)	Pathogenic
21253	NM_000048.4(ASL):c.1060C>T (p.Gln354Ter)	Pathogenic
2128322	NM_000048.4(ASL):c.446+1G>C	Pathogenic
2136547	NM_000048.4(ASL):c.1267G>C (p.Asp423His)	Pathogenic
2191291	NM_000048.4(ASL):c.425_426insAGCTCCCAGCT (p.Met143fs)	Pathogenic
224972	NM_000048.3(ASL):c.292delG	Pathogenic
224974	NM_000048.4(ASL):c.575_580dup (p.Lys192_Arg193dup)	Pathogenic
224978	NM_000048.4(ASL):c.1122dup (p.Tyr375fs)	Pathogenic
224981	NM_000048.4(ASL):c.524+2T>G	Pathogenic
226414	NM_000048.4(ASL):c.1079T>C (p.Met360Thr)	Pathogenic
2402	NM_000048.4(ASL):c.532G>A (p.Val178Met)	Pathogenic
2422197	NC_000007.13:g.(?65547857)(65548171_?)del	Pathogenic

SpliceAI

2288 predictions. Top by Δscore:

Variant	Effect	Δscore
7:66076092:AGGTG:A	donor_loss	1.0000
7:66076093:GGTG:G	donor_loss	1.0000
7:66076094:GTG:G	donor_loss	1.0000
7:66076095:T:G	donor_loss	1.0000
7:66081796:T:TA	acceptor_gain	1.0000
7:66081801:A:AG	acceptor_gain	1.0000
7:66081802:G:GG	acceptor_gain	1.0000
7:66081802:GA:G	acceptor_gain	1.0000
7:66081994:CAAGG:C	donor_loss	1.0000
7:66081998:G:GA	donor_loss	1.0000
7:66082363:TACAG:T	acceptor_loss	1.0000
7:66082451:GGT:G	donor_loss	1.0000
7:66082452:GT:G	donor_loss	1.0000
7:66082453:T:A	donor_loss	1.0000
7:66083170:GAGGC:G	donor_gain	1.0000
7:66083173:GC:G	donor_gain	1.0000
7:66086583:A:AG	acceptor_gain	1.0000
7:66086583:AG:A	acceptor_gain	1.0000
7:66086584:G:GG	acceptor_gain	1.0000
7:66086584:GG:G	acceptor_gain	1.0000
7:66086742:A:AG	acceptor_gain	1.0000
7:66086743:G:GA	acceptor_gain	1.0000
7:66086743:GC:G	acceptor_gain	1.0000
7:66086743:GCCAC:G	acceptor_gain	1.0000
7:66086820:AG:A	donor_loss	1.0000
7:66086821:GG:G	donor_loss	1.0000
7:66087332:A:AG	acceptor_gain	1.0000
7:66087332:AGTGG:A	acceptor_gain	1.0000
7:66087333:G:GG	acceptor_gain	1.0000
7:66087333:GTGGG:G	acceptor_gain	1.0000

AlphaMissense

3043 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:66089101:A:C	S282R	0.998
7:66089103:C:A	S282R	0.998
7:66089103:C:G	S282R	0.998
7:66082922:A:C	S112R	0.997
7:66082924:C:A	S112R	0.997
7:66082924:C:G	S112R	0.997
7:66086616:C:G	H160D	0.997
7:66089098:A:C	S281R	0.997
7:66089100:C:A	S281R	0.997
7:66089100:C:G	S281R	0.997
7:66089124:C:A	N289K	0.997
7:66089124:C:G	N289K	0.997
7:66092563:T:C	F384L	0.997
7:66092565:C:A	F384L	0.997
7:66092565:C:G	F384L	0.997
7:66086643:T:A	W169R	0.996
7:66086643:T:C	W169R	0.996
7:66088848:A:C	S254R	0.996
7:66088850:C:A	S254R	0.996
7:66088850:C:G	S254R	0.996
7:66089108:T:C	M284T	0.996
7:66089122:A:G	N289D	0.996
7:66082421:C:A	D87E	0.995
7:66082421:C:G	D87E	0.995
7:66082930:T:A	N114K	0.995
7:66082930:T:G	N114K	0.995
7:66086618:T:A	H160Q	0.995
7:66086618:T:G	H160Q	0.995
7:66089131:A:C	S292R	0.995
7:66089133:T:A	S292R	0.995

dbSNP variants (sampled 300 via entrez): RS1000172311 (7:66093093 G>A), RS1000391178 (7:66093390 A>G), RS1000485388 (7:66087194 G>A), RS1000606827 (7:66077337 A>G), RS1000711229 (7:66088689 T>A), RS1000975188 (7:66083049 C>T), RS1001225401 (7:66088451 A>G,T), RS1001438679 (7:66077299 C>A,G,T), RS1001527298 (7:66080432 A>C), RS1001642022 (7:66079972 C>T), RS1001864342 (7:66081943 G>T), RS1001975558 (7:66081599 C>G), RS1001994701 (7:66086407 C>A), RS1002023330 (7:66075845 G>A), RS1002406129 (7:66089549 G>A,T)

Disease associations

OMIM: gene MIM:608310 | disease phenotypes: MIM:207900, MIM:608931, MIM:209850, MIM:253220

GenCC curated gene-disease

Disease	Classification	Inheritance
argininosuccinic aciduria	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
argininosuccinic aciduria	Definitive	AR

Mondo (6): argininosuccinic aciduria (MONDO:0008815), neurodevelopmental disorder (MONDO:0700092), congenital myasthenic syndrome 4C (MONDO:0012157), autism (MONDO:0005260), congenital portosystemic shunt (MONDO:0018811), mucopolysaccharidosis type 7 (MONDO:0009662)

Orphanet (4): Argininosuccinic aciduria (Orphanet:23), Congenital myasthenic syndrome (Orphanet:590), Congenital portosystemic shunt (Orphanet:480531), Mucopolysaccharidosis type 7 (Orphanet:584)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000670	Carious teeth
HP:0000709	Psychosis
HP:0000737	Irritability
HP:0000742	Self-mutilation
HP:0000750	Delayed speech and language development
HP:0000822	Hypertension
HP:0000964	Eczematoid dermatitis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001328	Specific learning disability
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001399	Hepatic failure
HP:0001402	Hepatocellular carcinoma
HP:0001508	Failure to thrive
HP:0001894	Thrombocytosis
HP:0001950	Respiratory alkalosis
HP:0001951	Episodic ammonia intoxication
HP:0001987	Hyperammonemia
HP:0002013	Vomiting

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D056807	Argininosuccinic Aciduria	C10.228.140.163.100.937.124; C16.320.565.100.940.124; C16.320.565.189.937.124; C18.452.132.100.937.124; C18.452.648.100.940.124; C18.452.648.189.937.124
D001321	Autistic Disorder	F03.625.164.113.500
D016538	Mucopolysaccharidosis VII	C16.320.565.202.715.675; C16.320.565.595.600.675; C17.300.550.575.675; C18.452.648.202.715.675; C18.452.648.595.600.675
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
bisphenol A	increases expression, affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	2
Arsenic Trioxide	increases expression, decreases response to substance	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
beta-lapachone	decreases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
S 1 (combination)	increases response to substance	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Aspirin	decreases expression	1
Boron Compounds	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Diclofenac	affects expression	1

Cellosaurus cell lines

13 cell lines: 6 transformed cell line, 5 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2WA	GM26179	Transformed cell line	Female
CVCL_AE11	GM24028	Transformed cell line	Male
CVCL_AY70	GM23436	Transformed cell line	Female
CVCL_AY71	GM23437	Transformed cell line	Female
CVCL_AY78	GM23641	Transformed cell line	Male
CVCL_AY88	GM23823	Transformed cell line	Male
CVCL_D0N1	UCLi024-A	Induced pluripotent stem cell	Male
CVCL_D1LK	Abcam K-562 ASL KO	Cancer cell line	Female
CVCL_D2I6	Abcam Raji ASL KO	Cancer cell line	Male
CVCL_D7KL	Ubigene A-549 ASL KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism