Arginase deficiency

Summary

Arginase deficiency (MONDO:0008814) is a disease caused by ARG1 (GenCC Definitive), with 2 cohort genes and 11 clinical trials. Top therapeutic interventions include pegzilarginase and arginine.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: ARG1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 545
• Phenotypes (HPO): 10
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Validated
Prevalence at birth	<1 / 1 000 000	0.04	Finland	Validated
Prevalence at birth	1-9 / 1 000 000	0.27	United States	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0008339	Diaminoaciduria	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002478	Progressive spastic quadriplegia	Frequent (30-79%)
HP:0004374	Hemiplegia/hemiparesis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	arginase deficiency
Mondo ID	MONDO:0008814
MeSH	D020162
OMIM	207800
Orphanet	90
DOID	DOID:9278
ICD-10-CM	E72.21
ICD-11	1619102598
NCIT	C84568
SNOMED CT	23501004
UMLS	C0268548
MedGen	78688
GARD	0005840
MedDRA	10062695
Is cancer (heuristic)	no

Also known as: arginase deficiency · argininemia · hyperargininemia

Data availability: 545 ClinVar variants · 6 GenCC gene-disease records · 9 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 › arginase deficiency

Related subtypes (9): argininosuccinic aciduria, 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

545 retrieved; paginated sample, class counts are floors:

240 likely benign, 143 uncertain significance, 67 pathogenic, 49 likely pathogenic, 22 pathogenic/likely pathogenic, 14 conflicting classifications of pathogenicity, 8 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030551	NM_000045.4(ARG1):c.370G>T (p.Asp124Tyr)	ARG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1044951	NM_000045.4(ARG1):c.23T>A (p.Ile8Lys)	ARG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064873	NM_000045.4(ARG1):c.839del (p.Pro280fs)	ARG1	Pathogenic	criteria provided, single submitter
1072006	NM_000045.4(ARG1):c.272del (p.Gly91fs)	ARG1	Pathogenic	criteria provided, single submitter
1074774	NM_000045.4(ARG1):c.50del (p.Lys17fs)	ARG1	Pathogenic	criteria provided, single submitter
1075842	NM_000045.4(ARG1):c.684del (p.His228_Leu229insTer)	ARG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332810	NM_000045.4(ARG1):c.547_549del (p.Asp183del)	ARG1	Pathogenic	criteria provided, single submitter
1343393	NM_000045.4(ARG1):c.305+1G>A	ARG1	Pathogenic	criteria provided, single submitter
1385981	NM_000045.4(ARG1):c.124G>T (p.Glu42Ter)	ARG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1386013	NM_000045.4(ARG1):c.603_604del (p.Glu202fs)	ARG1	Pathogenic	criteria provided, single submitter
1427598	NM_000045.4(ARG1):c.130+1G>A	ARG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1451696	NM_000045.4(ARG1):c.577_578del (p.Leu193fs)	ARG1	Pathogenic	criteria provided, single submitter
1453308	NM_000045.4(ARG1):c.766G>T (p.Glu256Ter)	ARG1	Pathogenic	criteria provided, single submitter
1453446	NM_000045.4(ARG1):c.807_811del (p.Leu270fs)	ARG1	Pathogenic	criteria provided, single submitter
1458205	NM_000045.4(ARG1):c.820_823dup (p.Ile275fs)	ARG1	Pathogenic	criteria provided, single submitter
1501863	NM_000045.4(ARG1):c.560+2T>C	ARG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1973646	NM_000045.4(ARG1):c.371A>G (p.Asp124Gly)	ARG1	Pathogenic	criteria provided, single submitter
1999814	NM_000045.4(ARG1):c.157del (p.Leu53fs)	ARG1	Pathogenic	criteria provided, single submitter
2018545	NM_000045.4(ARG1):c.124_125insT (p.Glu42fs)	ARG1	Pathogenic	criteria provided, single submitter
203606	NM_000045.4(ARG1):c.272dup (p.Arg92fs)	ARG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2041678	NC_000006.12:g.131583354GAAA[1]	ARG1	Pathogenic	criteria provided, single submitter
2058364	NM_000045.4(ARG1):c.802+1G>A	ARG1	Pathogenic	criteria provided, single submitter
2064930	NM_000045.4(ARG1):c.594_595dup (p.Ser199fs)	ARG1	Pathogenic	criteria provided, single submitter
2102477	NM_000045.4(ARG1):c.57+1G>T	ARG1	Pathogenic	criteria provided, single submitter
2124468	NM_000045.4(ARG1):c.640del (p.Glu214fs)	ARG1	Pathogenic	criteria provided, single submitter
2129477	NM_000045.4(ARG1):c.159_163del (p.Pro54fs)	ARG1	Pathogenic	criteria provided, single submitter
2133556	NM_000045.4(ARG1):c.666-2A>C	ARG1	Pathogenic	criteria provided, single submitter
2136470	NM_000045.4(ARG1):c.401C>T (p.Thr134Ile)	ARG1	Pathogenic	criteria provided, single submitter
2136471	NM_000045.4(ARG1):c.673del (p.Arg225fs)	ARG1	Pathogenic	criteria provided, single submitter
2386	NM_000045.4(ARG1):c.263_266del (p.Lys88fs)	ARG1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
ARG1	Definitive	Autosomal recessive	arginase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARG1	Orphanet:90	Argininemia
MED23	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARG1	HGNC:663	ENSG00000118520	P05089	Arginase-1	gencc,clinvar
MED23	HGNC:2372	ENSG00000112282	Q9ULK4	Mediator of RNA polymerase II transcription subunit 23	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARG1	Arginase-1	Key element of the urea cycle converting L-arginine to urea and L-ornithine, which is further metabolized into metabolites proline and polyamides that drive collagen synthesis and bioenergetic pathways critical for cell proliferation, resp…
MED23	Mediator of RNA polymerase II transcription subunit 23	Required for transcriptional activation subsequent to the assembly of the pre-initiation complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARG1	Enzyme (other)	yes	3.5.3.1	Ureohydrolase, Arginase, Ureohydrolase_Mn_BS
MED23	Other/Unknown	no		Mediator_Med23

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
penis	1
right lobe of liver	1
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARG1	194	tissue_specific	marker	right lobe of liver, liver, penis
MED23	283	ubiquitous	yes	right hemisphere of cerebellum, calcaneal tendon, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARG1	4,432
MED23	2,155

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARG1	P05089	60
MED23	Q9ULK4	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ARG1 variants cause hyperargininemia	1	5710.0×	0.005	ARG1
Urea cycle	1	439.2×	0.030	ARG1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.036	MED23
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.036	MED23
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.036	MED23
RSV-host interactions	1	78.2×	0.036	MED23
Adipogenesis	1	78.2×	0.036	MED23
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.036	MED23
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.036	MED23
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.036	MED23
Metabolism	2	11.6×	0.036	ARG1, MED23
PPARA activates gene expression	1	47.2×	0.046	MED23
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.048	MED23
Epigenetic regulation of gene expression	1	35.7×	0.051	MED23
Metabolism of amino acids and derivatives	1	33.8×	0.051	ARG1
Metabolism of lipids	1	15.8×	0.098	MED23
Viral Infection Pathways	1	15.4×	0.098	MED23
Innate Immune System	1	12.8×	0.107	ARG1
Infectious disease	1	12.4×	0.107	MED23
Neutrophil degranulation	1	11.5×	0.107	ARG1
RNA Polymerase II Transcription	1	11.3×	0.107	MED23
Gene expression (Transcription)	1	8.9×	0.129	MED23
Generic Transcription Pathway	1	7.5×	0.145	MED23
Developmental Biology	1	7.2×	0.145	MED23
Disease	1	6.5×	0.148	MED23
Immune System	1	6.5×	0.148	ARG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of neutrophil mediated killing of fungus	1	8426.0×	0.002	ARG1
positive regulation of T cell extravasation	1	4213.0×	0.002	MED23
negative regulation of T-helper 2 cell cytokine production	1	2106.5×	0.003	ARG1
L-arginine catabolic process	1	1404.3×	0.003	ARG1
negative regulation of type II interferon-mediated signaling pathway	1	1053.2×	0.003	ARG1
response to nematode	1	936.2×	0.003	ARG1
urea cycle	1	648.1×	0.004	ARG1
negative regulation of activated T cell proliferation	1	526.6×	0.005	ARG1
defense response to protozoan	1	300.9×	0.007	ARG1
transcription initiation at RNA polymerase II promoter	1	187.2×	0.010	MED23
negative regulation of T cell proliferation	1	165.2×	0.010	ARG1
positive regulation of transcription elongation by RNA polymerase II	1	150.5×	0.010	MED23
RNA polymerase II preinitiation complex assembly	1	135.9×	0.010	MED23
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.010	MED23
adaptive immune response	1	42.1×	0.030	ARG1
positive regulation of gene expression	1	19.4×	0.061	MED23
innate immune response	1	16.8×	0.066	ARG1
regulation of DNA-templated transcription	1	15.8×	0.066	MED23
regulation of transcription by RNA polymerase II	1	5.8×	0.164	MED23

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Pegzilarginase	Approved (phase 4)

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MED23	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARG1	2	2
MED23	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	MED23
NUMIDARGISTAT	2	ARG1
NOR-NOHA	1	ARG1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ARG1	90	Binding:86, Functional:4
MED23	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ARG1	3.5.3.1	arginase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
PALBOCICLIB	4	MED23
NUMIDARGISTAT	2	ARG1
NOR-NOHA	1	ARG1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MED23
B	Phased (≥1) drug, not yet approved	1	ARG1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE3	2
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03921541	PHASE3	COMPLETED	Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency
NCT05676853	PHASE3	TERMINATED	A Study of Safety of Weekly Subcutaneous Pegzilarginase in Subjects With Arginase 1 Deficiency
NCT02488044	PHASE1/PHASE2	COMPLETED	A Phase 1/2 Study of AEB1102 in Patients With Arginase I Deficiency
NCT03378531	PHASE2	COMPLETED	A Study of AEB1102 (Pegzilarginase) in Patients With Arginase I Deficiency
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
NCT05412160	Not specified	COMPLETED	Improving Quality of Life and Daily Life Activities With Bioarginine in Patients With COPD
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PEGZILARGINASE	4	4
ARGININE	3	1