Citrullinemia

Summary

Citrullinemia (MONDO:0015991) is a disease with 4 cohort genes and 6 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 4
• ClinVar variants: 810
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	citrullinemia
Mondo ID	MONDO:0015991
MeSH	D020159
OMIM	215700
Orphanet	187
DOID	DOID:9273
ICD-10-CM	E72.23
ICD-11	640937125
NCIT	C84639
SNOMED CT	124711003
UMLS	C0175683
MedGen	104491
GARD	0016522
Is cancer (heuristic)	no

Also known as: ass deficiency · deficiency of citrulline-aspartate ligase

Data availability: 810 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

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 › citrullinemia

Related subtypes (2): 3-methylcrotonyl-CoA carboxylase 1 deficiency, urea cycle disorder or inherited hyperammonemia

Subtypes (2): citrullinemia type I, 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:

306 likely benign, 109 uncertain significance, 69 pathogenic, 39 likely pathogenic, 37 pathogenic/likely pathogenic, 25 conflicting classifications of pathogenicity, 9 benign/likely benign, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034022	NM_054012.4(ASS1):c.812dup (p.Asn271fs)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071055	NM_054012.4(ASS1):c.489C>A (p.Tyr163Ter)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071056	NM_054012.4(ASS1):c.490G>C (p.Ala164Pro)	ASS1	Pathogenic	criteria provided, single submitter
1071097	NM_054012.4(ASS1):c.1048C>T (p.Gln350Ter)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071462	NC_000009.12:g.130479718dup	ASS1	Pathogenic	criteria provided, single submitter
1071505	NC_000009.11:g.(?133333768)(133333996_?)del	ASS1	Pathogenic	criteria provided, single submitter
1072613	NM_054012.4(ASS1):c.1107_1108del (p.Tyr370fs)	ASS1	Pathogenic	criteria provided, single submitter
1352022	NM_054012.4(ASS1):c.1010_1011delinsAA (p.Cys337Ter)	ASS1	Pathogenic	criteria provided, single submitter
1355373	NM_054012.4(ASS1):c.944T>A (p.Leu315Ter)	ASS1	Pathogenic	criteria provided, single submitter
1400634	NM_054012.4(ASS1):c.611del (p.Pro204fs)	ASS1	Pathogenic	criteria provided, single submitter
1424757	NM_054012.4(ASS1):c.1117G>T (p.Glu373Ter)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425929	NM_054012.4(ASS1):c.536G>A (p.Trp179Ter)	ASS1	Pathogenic	criteria provided, single submitter
1434677	NM_054012.4(ASS1):c.621C>A (p.Tyr207Ter)	ASS1	Pathogenic	criteria provided, single submitter
1454396	NC_000009.11:g.(?133352248)(133352358_?)del	ASS1	Pathogenic	criteria provided, single submitter
1456047	NC_000009.11:g.(?133352248)(133355846_?)del	ASS1	Pathogenic	criteria provided, single submitter
1457339	NM_054012.4(ASS1):c.489C>G (p.Tyr163Ter)	ASS1	Pathogenic	criteria provided, single submitter
1457481	NM_054012.4(ASS1):c.174+1G>A	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458486	NC_000009.11:g.(?133355093)(133355236_?)del	ASS1	Pathogenic	criteria provided, single submitter
1460356	NM_054012.4(ASS1):c.373C>T (p.Gln125Ter)	ASS1	Pathogenic	criteria provided, single submitter
1495594	NM_054012.4(ASS1):c.919C>A (p.Arg307Ser)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166704	NM_054012.4(ASS1):c.1194-1G>C	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188776	NM_054012.4(ASS1):c.1138C>T (p.Gln380Ter)	ASS1	Pathogenic	criteria provided, single submitter
188832	NM_054012.4(ASS1):c.892del (p.Glu298fs)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
188885	NM_054012.4(ASS1):c.1030C>T (p.Arg344Ter)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
189044	NM_054012.4(ASS1):c.450_451del (p.Phe150fs)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198386	NM_054012.4(ASS1):c.421-2A>G	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2003009	NM_054012.4(ASS1):c.188_189del (p.Asp63fs)	ASS1	Pathogenic	criteria provided, single submitter
2006582	NM_054012.4(ASS1):c.983_984insGGTGAATTTG (p.Ser328fs)	ASS1	Pathogenic	criteria provided, single submitter
2016666	NM_054012.4(ASS1):c.827_838+25del	ASS1	Pathogenic	criteria provided, single submitter
2034705	NM_054012.4(ASS1):c.687dup (p.Gly230fs)	ASS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A13	Orphanet:247585	Citrullinemia type II
SLC25A13	Orphanet:247598	Neonatal intrahepatic cholestasis due to citrin deficiency
ARSA	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
ARSA	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
ARSA	Orphanet:309271	Metachromatic leukodystrophy, adult form
ASS1	Orphanet:247546	Acute neonatal citrullinemia type I
ASS1	Orphanet:247573	Late-onset citrullinemia type I
ABL1	Orphanet:521	Chronic myeloid leukemia
ABL1	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
ABL1	Orphanet:643503	Marfanoid habitus-facial dysmorphism-skeletal abnormality-heart defect syndrome
ABL1	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A13	HGNC:10983	ENSG00000004864	Q9UJS0	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	clinvar
ARSA	HGNC:713	ENSG00000100299	P15289	Arylsulfatase A	clinvar
ASS1	HGNC:758	ENSG00000130707	P00966	Argininosuccinate synthase	clinvar
ABL1	HGNC:76	ENSG00000097007	P00519	Tyrosine-protein kinase ABL1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A13	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle.
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.
ASS1	Argininosuccinate synthase	One of the enzymes of the urea cycle, the metabolic pathway transforming neurotoxic amonia produced by protein catabolism into inocuous urea in the liver of ureotelic animals.
ABL1	Tyrosine-protein kinase ABL1	Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autopha…

Protein-family classification

Druggable: 4 · 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
Phosphatase	1	21.0×	0.101
Transporter	1	19.4×	0.101
Kinase	1	6.9×	0.182
Enzyme (other)	1	3.0×	0.294

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A13	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair
ARSA	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
ASS1	Enzyme (other)	yes	6.3.4.5	Arginosuc_synth, Rossmann-like_a/b/a_fold, Arginosuc_synth_CS
ABL1	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
secondary oocyte	1
granulocyte	1
right testis	1
right uterine tube	1
palpebral conjunctiva	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A13	283	ubiquitous	marker	right lobe of liver, liver, secondary oocyte
ARSA	177	ubiquitous	marker	right uterine tube, right testis, granulocyte
ASS1	292	ubiquitous	marker	right lobe of liver, palpebral conjunctiva, liver
ABL1	283	ubiquitous	marker	frontal pole, paraflocculus, middle frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABL1	6,937
ASS1	3,101
SLC25A13	1,895
ARSA	1,356

Intra-cohort edges

A	B	Sources
ASS1	SLC25A13	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABL1	P00519	85
ARSA	P15289	10
SLC25A13	Q9UJS0	1
ASS1	P00966	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ASS1 variants cause citrullinemia	1	1427.5×	0.039	ASS1
Role of ABL in ROBO-SLIT signaling	1	317.2×	0.039	ABL1
Malate-aspartate shuttle	1	317.2×	0.039	SLC25A13
Aspartate and asparagine metabolism	1	259.6×	0.039	SLC25A13
The activation of arylsulfatases	1	219.6×	0.039	ARSA
Urea cycle	1	219.6×	0.039	ASS1
RUNX2 regulates bone development	1	203.9×	0.039	ABL1
DNA Double Strand Break Response	1	119.0×	0.039	ABL1
RUNX2 regulates osteoblast differentiation	1	114.2×	0.039	ABL1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	105.7×	0.039	ARSA
G1 Phase	1	98.5×	0.039	ABL1
Myogenesis	1	95.2×	0.039	ABL1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	89.2×	0.039	ABL1
Parasite infection	1	86.5×	0.039	ABL1
Leishmania phagocytosis	1	86.5×	0.039	ABL1
RHO GTPases Activate WASPs and WAVEs	1	79.3×	0.039	ABL1
Homology Directed Repair	1	77.2×	0.039	ABL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.039	ABL1
Glycosphingolipid metabolism	1	75.1×	0.039	ARSA
Response of endothelial cells to shear stress	1	75.1×	0.039	ABL1
HDR through Single Strand Annealing (SSA)	1	73.2×	0.039	ABL1
Glycosphingolipid catabolism	1	73.2×	0.039	ARSA
Metabolism of amino acids and derivatives	2	33.8×	0.039	SLC25A13, ASS1
Innate Immune System	2	12.8×	0.039	ARSA, ABL1
Metabolism	3	8.7×	0.039	SLC25A13, ARSA, ASS1
Fcgamma receptor (FCGR) dependent phagocytosis	1	69.6×	0.040	ABL1
Cellular responses to mechanical stimuli	1	64.9×	0.040	ABL1
Transcriptional regulation by RUNX2	1	63.4×	0.040	ABL1
DNA Double-Strand Break Repair	1	62.1×	0.040	ABL1
Cyclin D associated events in G1	1	58.3×	0.041	ABL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete argininosuccinate metabolic process	1	4213.0×	0.006	ASS1
protein localization to cytoplasmic microtubule plus-end	1	4213.0×	0.006	ABL1
obsolete citrulline metabolic process	1	2106.5×	0.006	ASS1
transitional one stage B cell differentiation	1	2106.5×	0.006	ABL1
phospholipase C-inhibiting G protein-coupled receptor signaling pathway	1	2106.5×	0.006	ABL1
DNA conformation change	1	2106.5×	0.006	ABL1
podocyte apoptotic process	1	2106.5×	0.006	ABL1
DN4 thymocyte differentiation	1	2106.5×	0.006	ABL1
L-arginine biosynthetic process	1	1404.3×	0.006	ASS1
response to mycotoxin	1	1404.3×	0.006	ASS1
cerebellum morphogenesis	1	1404.3×	0.006	ABL1
neuropilin signaling pathway	1	1404.3×	0.006	ABL1
cellular response to oleic acid	1	1404.3×	0.006	ASS1
cellular response to amine stimulus	1	1404.3×	0.006	ASS1
response to epinephrine	1	1404.3×	0.006	ABL1
regulation of modification of synaptic structure	1	1404.3×	0.006	ABL1
B-1 B cell homeostasis	1	1053.2×	0.006	ABL1
microspike assembly	1	1053.2×	0.006	ABL1
negative regulation of ubiquitin-protein transferase activity	1	1053.2×	0.006	ABL1
regulation of postsynaptic specialization assembly	1	1053.2×	0.006	ABL1
positive regulation of extracellular matrix organization	1	1053.2×	0.006	ABL1
positive regulation of establishment of T cell polarity	1	1053.2×	0.006	ABL1
cellular response to lipopolysaccharide	2	49.0×	0.006	ASS1, ABL1
platelet-derived growth factor receptor-beta signaling pathway	1	842.6×	0.006	ABL1
cellular response to ammonium ion	1	842.6×	0.006	ASS1
vascular endothelial cell response to oscillatory fluid shear stress	1	842.6×	0.006	ABL1
positive regulation of phospholipase C/protein kinase C signal transduction	1	842.6×	0.006	ABL1
response to xenobiotic stimulus	2	34.5×	0.006	ASS1, ABL1
B cell proliferation involved in immune response	1	702.2×	0.007	ABL1
negative regulation of leukocyte cell-cell adhesion	1	702.2×	0.007	ASS1

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 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
ABL1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABL1	122	4
SLC25A13	0	0
ARSA	0	0
ASS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	ABL1
AFATINIB	4	ABL1
FEDRATINIB	4	ABL1
TIVOZANIB	4	ABL1
LENVATINIB	4	ABL1
AXITINIB	4	ABL1
SORAFENIB	4	ABL1
DASATINIB ANHYDROUS	4	ABL1
IMATINIB MESYLATE	4	ABL1
RUXOLITINIB	4	ABL1
NERATINIB	4	ABL1
INFIGRATINIB PHOSPHATE	4	ABL1
INFIGRATINIB	4	ABL1
IBRUTINIB	4	ABL1
REGORAFENIB	4	ABL1
ENTRECTINIB	4	ABL1
DABRAFENIB	4	ABL1
TOFACITINIB CITRATE	4	ABL1
AFATINIB DIMALEATE	4	ABL1
CABOZANTINIB	4	ABL1
TOFACITINIB	4	ABL1
CERITINIB	4	ABL1
VANDETANIB	4	ABL1
NILOTINIB	4	ABL1
BOSUTINIB	4	ABL1
FILGOTINIB	4	ABL1
TOVORAFENIB	4	ABL1
BRIGATINIB	4	ABL1
ASCIMINIB	4	ABL1
PAZOPANIB	4	ABL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ABL1	3,282	Binding:3254, ADMET:16, Functional:10, Toxicity:2
ARSA	4	Binding:3, Functional:1
SLC25A13	1	Binding:1
ASS1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASS1	6.3.4.5	argininosuccinate synthase
ABL1	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ABL1	3,282

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PONATINIB	4	ABL1
AFATINIB	4	ABL1
FEDRATINIB	4	ABL1
TIVOZANIB	4	ABL1
LENVATINIB	4	ABL1
AXITINIB	4	ABL1
SORAFENIB	4	ABL1
DASATINIB ANHYDROUS	4	ABL1
IMATINIB MESYLATE	4	ABL1
RUXOLITINIB	4	ABL1
NERATINIB	4	ABL1
INFIGRATINIB PHOSPHATE	4	ABL1
INFIGRATINIB	4	ABL1
IBRUTINIB	4	ABL1
REGORAFENIB	4	ABL1
ENTRECTINIB	4	ABL1
DABRAFENIB	4	ABL1
TOFACITINIB CITRATE	4	ABL1
AFATINIB DIMALEATE	4	ABL1
CABOZANTINIB	4	ABL1
TOFACITINIB	4	ABL1
CERITINIB	4	ABL1
VANDETANIB	4	ABL1
NILOTINIB	4	ABL1
BOSUTINIB	4	ABL1
FILGOTINIB	4	ABL1
TOVORAFENIB	4	ABL1
BRIGATINIB	4	ABL1
ASCIMINIB	4	ABL1
PAZOPANIB	4	ABL1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABL1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	SLC25A13, ARSA, ASS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A13	1	—
ARSA	4	—
ASS1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
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
NCT01610089	Not specified	COMPLETED	Nitric Oxide Flux and Ureagenesis in Argininosuccinate Synthetase Deficiency (ASSD)(Citrullinemia I)
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan