Argininosuccinic aciduria

Summary

Argininosuccinic aciduria (MONDO:0008815) is a disease caused by ASL (GenCC Definitive), with 1 cohort gene and 8 clinical trials. Top therapeutic interventions include phenylbutanoic acid and arginine.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: ASL (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 879
• Phenotypes (HPO): 51
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.46	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.69	Finland	Validated
Prevalence at birth	1-9 / 100 000	1.05	Austria	Validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0003217	Hyperglutaminemia	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0005961	Hypoargininemia	Very frequent (80-99%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001950	Respiratory alkalosis	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002329	Drowsiness	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0011966	Elevated plasma citrulline	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0025630	Argininosuccinic aciduria	Frequent (30-79%)
HP:0032470	Monilethrix	Frequent (30-79%)
HP:0032491	Increased circulating argininosuccinic acid	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000742	Self-mutilation	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001395	Hepatic fibrosis	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0001894	Thrombocytosis	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002155	Hypertriglyceridemia	Occasional (5-29%)
HP:0002232	Patchy alopecia	Occasional (5-29%)
HP:0002283	Global brain atrophy	Occasional (5-29%)
HP:0002900	Hypokalemia	Occasional (5-29%)
HP:0003218	Oroticaciduria	Occasional (5-29%)
HP:0003777	Pili torti	Occasional (5-29%)
HP:0006280	Chronic pancreatitis	Occasional (5-29%)
HP:0006970	Periventricular leukomalacia	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007183	Focal T2 hyperintense basal ganglia lesion	Occasional (5-29%)
HP:0009886	Trichorrhexis nodosa	Occasional (5-29%)
HP:0011362	Abnormal hair quantity	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	argininosuccinic aciduria
Mondo ID	MONDO:0008815
MeSH	D056807
OMIM	207900
Orphanet	23
DOID	DOID:14755
ICD-11	439383288
NCIT	C84569
SNOMED CT	41013004
UMLS	C0268547
MedGen	78687
GARD	0005843
MedDRA	10058299
NORD	802
Is cancer (heuristic)	no

Also known as: arginino succinase deficiency · argininosuccinase deficiency · argininosuccinate acidemia · argininosuccinatelyase deficiency · argininosuccinic acid lyase deficiency · argininosuccinic aciduria · argininosuccinicaciduria · ASA deficiency · ASL deficiency · inborn error of urea synthesis, arginino succinic type · urea cycle disorder, arginino succinase type

Data availability: 879 ClinVar variants · 7 GenCC gene-disease records · 28 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › urea cycle disorder › urea cycle disorder or inherited hyperammonemia › argininosuccinic aciduria

Related subtypes (9): arginase deficiency, citrullinemia type I, carbamoyl phosphate synthetase I deficiency disease, hyperammonemia due to N-acetylglutamate synthase deficiency, ornithine translocase deficiency, ornithine carbamoyltransferase deficiency, hyperinsulinism-hyperammonemia syndrome, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, citrin deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

356 likely benign, 74 likely pathogenic, 62 uncertain significance, 38 pathogenic, 29 pathogenic/likely pathogenic, 22 conflicting classifications of pathogenicity, 15 benign, 3 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028027	NM_000048.4(ASL):c.602+1G>T	ASL	Pathogenic	criteria provided, multiple submitters, no conflicts
1050820	NM_000048.4(ASL):c.556C>T (p.Arg186Trp)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066380	NM_000048.4(ASL):c.349-1G>A	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075343	NM_000048.4(ASL):c.221G>A (p.Trp74Ter)	ASL	Pathogenic	criteria provided, single submitter
1383503	NM_000048.4(ASL):c.1193C>A (p.Ala398Asp)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420014	NM_000048.4(ASL):c.1219C>T (p.Gln407Ter)	ASL	Pathogenic	criteria provided, single submitter
1432406	NM_000048.4(ASL):c.1128C>A (p.Tyr376Ter)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454393	NC_000007.13:g.(?65546932)(65549932_?)del	ASL	Pathogenic	criteria provided, single submitter
1458034	NM_000048.4(ASL):c.719-1G>A	ASL	Pathogenic	criteria provided, single submitter
1458484	NC_000007.13:g.(?65557534)(65557909_?)del	ASL	Pathogenic	criteria provided, single submitter
1458557	NM_000048.4(ASL):c.1290C>A (p.Tyr430Ter)	ASL	Pathogenic	criteria provided, single submitter
1459454	NM_000048.4(ASL):c.509G>A (p.Ser170Asn)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1465183	NM_000048.4(ASL):c.688A>G (p.Met230Val)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1470472	NM_000048.4(ASL):c.377G>C (p.Arg126Pro)	ASL	Pathogenic	criteria provided, single submitter
1489478	NM_000048.4(ASL):c.331C>T (p.Arg111Trp)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1512721	NM_000048.4(ASL):c.437G>C (p.Arg146Pro)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1914880	NM_000048.4(ASL):c.691G>C (p.Asp231His)	ASL	Pathogenic	criteria provided, single submitter
2005777	NM_000048.4(ASL):c.58del (p.Ile20fs)	ASL	Pathogenic	criteria provided, single submitter
203613	NM_000048.4(ASL):c.545G>A (p.Arg182Gln)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203615	NM_000048.4(ASL):c.649C>T (p.Arg217Ter)	ASL	Pathogenic	criteria provided, multiple submitters, no conflicts
203621	NM_000048.4(ASL):c.1297A>C (p.Ser433Arg)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203626	NM_000048.4(ASL):c.436C>T (p.Arg146Trp)	ASL	Pathogenic	criteria provided, multiple submitters, no conflicts
203628	NM_000048.4(ASL):c.533_557dup (p.Arg186_Leu187insGlyThrAspProArgLeuTer)	ASL	Pathogenic	criteria provided, multiple submitters, no conflicts
203629	NM_000048.4(ASL):c.1045_1057del (p.Val349fs)	ASL	Pathogenic	criteria provided, multiple submitters, no conflicts
2066939	NM_000048.4(ASL):c.767T>C (p.Met256Thr)	ASL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2085731	NM_000048.4(ASL):c.976C>T (p.Gln326Ter)	ASL	Pathogenic	criteria provided, single submitter
2093251	NM_000048.4(ASL):c.231_243del (p.Phe79fs)	ASL	Pathogenic	criteria provided, single submitter
2102465	NM_000048.4(ASL):c.406del (p.Leu136fs)	ASL	Pathogenic	criteria provided, single submitter
2123808	NM_000048.4(ASL):c.280_281insTGAAG (p.Arg94fs)	ASL	Pathogenic	criteria provided, single submitter
21253	NM_000048.4(ASL):c.1060C>T (p.Gln354Ter)	ASL	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ASL	Definitive	Autosomal recessive	argininosuccinic aciduria	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASL	Orphanet:23	Argininosuccinic aciduria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ASL	HGNC:746	ENSG00000126522	P04424	Argininosuccinate lyase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASL	Argininosuccinate lyase	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 sy…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASL	Enzyme (other)	yes	4.3.2.1	Fumarate_lyase_fam, L-Aspartase-like, Argininosuccinate_lyase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASL	145	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASL	1,486

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASL	P04424	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ASL variants cause argininosuccinate aciduria	1	11420.0×	4e-04	ASL
Urea cycle	1	878.5×	0.002	ASL
Metabolism of amino acids and derivatives	1	67.6×	0.020	ASL
Metabolism	1	11.6×	0.086	ASL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ammonia assimilation cycle	1	16852.0×	5e-04	ASL
obsolete L-arginine biosynthetic process via ornithine	1	8426.0×	5e-04	ASL
L-arginine biosynthetic process	1	5617.3×	5e-04	ASL
arginine metabolic process	1	2407.4×	8e-04	ASL
urea cycle	1	1296.3×	0.001	ASL
positive regulation of nitric oxide biosynthetic process	1	455.5×	0.003	ASL
post-embryonic development	1	205.5×	0.006	ASL
locomotory behavior	1	179.3×	0.006	ASL

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

1 drug in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Arginine	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ASL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASL	4.3.2.1	argininosuccinate lyase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ASL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ASL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00345605	PHASE2	COMPLETED	Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04612764	Not specified	ACTIVE_NOT_RECRUITING	Liver Disease in Urea Cycle Disorders
NCT04908319	Not specified	RECRUITING	Hepatic Histopathology in Urea Cycle Disorders
NCT01421888	Not specified	TERMINATED	The NIH UNI Study: Urea Cycle Disorders, Nutrition and Immunity
NCT02252770	Not specified	COMPLETED	Nitric Oxide Supplementation in Argininosuccinic Aciduria
NCT03064048	Not specified	COMPLETED	Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYLBUTANOIC ACID	4	2
ARGININE	3	1