citrullinemia type I

Summary

citrullinemia type I (MONDO:0008988) is a disease caused by ASS1 (GenCC Definitive), with 2 cohort genes and 7 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: ASS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 373
• Phenotypes (HPO): 28
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.4	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.28	Austria	Validated
Prevalence at birth	1-9 / 100 000	4.5	Korea, Republic of	Validated
Prevalence at birth	1-9 / 1 000 000	0.84	Taiwan, Province of China	Validated
Prevalence at birth	1-9 / 100 000	1.13	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0011966	Elevated plasma citrulline	Very frequent (80-99%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001950	Respiratory alkalosis	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002480	Hepatic encephalopathy	Occasional (5-29%)
HP:0006889	Intellectual disability, borderline	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0000473	Torticollis	Very rare (<1-4%)
HP:0000575	Scotoma	Very rare (<1-4%)
HP:0001251	Ataxia	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0001256	Intellectual disability, mild	Very rare (<1-4%)
HP:0001259	Coma	Very rare (<1-4%)
HP:0001350	Slurred speech	Very rare (<1-4%)
HP:0002020	Gastroesophageal reflux	Very rare (<1-4%)
HP:0002076	Migraine	Very rare (<1-4%)
HP:0002315	Headache	Very rare (<1-4%)
HP:0002516	Increased intracranial pressure	Very rare (<1-4%)
HP:0002789	Tachypnea	Very rare (<1-4%)
HP:0007185	Loss of consciousness	Very rare (<1-4%)
HP:0011448	Ankle clonus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	citrullinemia type I
Mondo ID	MONDO:0008988
OMIM	215700
Orphanet	247525
DOID	DOID:0070340
NCIT	C150601
SNOMED CT	398680004
UMLS	C4721769
MedGen	1648491
GARD	0006114
MedDRA	10058298
Is cancer (heuristic)	no

Also known as: argininosuccinate synthase deficiency · argininosuccinate synthetase deficiency · argininosuccinic acid synthase deficiency · argininosuccinic acid synthetase deficiency · ASS deficiency · citrullinemia · citrullinemia 1 · citrullinemia type 1 · citrullinemia type I · classic citrullinemia · CTLN1 · CTNL1

Data availability: 373 ClinVar variants · 4 GenCC gene-disease records · 32 cell lines.

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 › citrullinemia type I

Related subtypes (1): citrin deficiency

Subtypes (2): acute neonatal citrullinemia type I, adult-onset citrullinemia type I

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

373 retrieved; paginated sample, class counts are floors:

105 uncertain significance, 88 likely pathogenic, 54 pathogenic/likely pathogenic, 42 conflicting classifications of pathogenicity, 40 pathogenic, 21 benign, 17 likely benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424822	NM_000050.4(ASS1):c.[323G>T];[970+5G>A]		Pathogenic	no assertion criteria provided
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
1071097	NM_054012.4(ASS1):c.1048C>T (p.Gln350Ter)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1339499	NM_054012.4(ASS1):c.364-2A>G	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1424757	NM_054012.4(ASS1):c.1117G>T (p.Glu373Ter)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457481	NM_054012.4(ASS1):c.174+1G>A	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
203631	NM_054012.4(ASS1):c.1088G>A (p.Arg363Gln)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2081172	NM_054012.4(ASS1):c.773+4A>C	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208153	NM_054012.4(ASS1):c.571G>A (p.Glu191Lys)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2134004	NM_054012.4(ASS1):c.537G>A (p.Trp179Ter)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136821	NM_054012.4(ASS1):c.271A>C (p.Thr91Pro)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2501087	NM_054012.4(ASS1):c.815G>A (p.Arg272His)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
265958	NM_054012.4(ASS1):c.773+49C>T	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265960	NM_054012.4(ASS1):c.257G>A (p.Arg86His)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265962	NM_054012.4(ASS1):c.970+5G>A	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678946	NM_054012.4(ASS1):c.571G>C (p.Glu191Gln)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679013	NM_054012.4(ASS1):c.364-2A>C	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679029	NM_054012.4(ASS1):c.848del (p.Glu283fs)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2679072	NM_054012.4(ASS1):c.299del (p.Arg100fs)	ASS1	Pathogenic	criteria provided, single submitter
2803980	NM_054012.4(ASS1):c.773+1G>T	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2860934	NM_054012.4(ASS1):c.631C>T (p.Gln211Ter)	ASS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3240656	NM_054012.4(ASS1):c.1194-2A>G	ASS1	Pathogenic	criteria provided, single submitter
3596478	NM_054012.4(ASS1):c.102T>G (p.Tyr34Ter)	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
ASS1	Definitive	Autosomal recessive	citrullinemia type I	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASS1	Orphanet:247546	Acute neonatal citrullinemia type I
ASS1	Orphanet:247573	Late-onset citrullinemia type I
SLC25A13	Orphanet:247585	Citrullinemia type II
SLC25A13	Orphanet:247598	Neonatal intrahepatic cholestasis due to citrin deficiency

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
ASS1	HGNC:758	ENSG00000130707	P00966	Argininosuccinate synthase	gencc,clinvar
SLC25A13	HGNC:10983	ENSG00000004864	Q9UJS0	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 2 · 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
Transporter	1	38.9×	0.051
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASS1	Enzyme (other)	yes	6.3.4.5	Arginosuc_synth, Rossmann-like_a/b/a_fold, Arginosuc_synth_CS
SLC25A13	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
palpebral conjunctiva	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASS1	292	ubiquitous	marker	right lobe of liver, palpebral conjunctiva, liver
SLC25A13	283	ubiquitous	marker	right lobe of liver, liver, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASS1	3,101
SLC25A13	1,895

Intra-cohort edges

A	B	Sources
ASS1	SLC25A13	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASS1	P00966	1
SLC25A13	Q9UJS0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
ASS1 variants cause citrullinemia	1	2855.0×	0.002	ASS1
Metabolism of amino acids and derivatives	2	67.6×	0.002	ASS1, SLC25A13
Malate-aspartate shuttle	1	634.4×	0.005	SLC25A13
Aspartate and asparagine metabolism	1	519.1×	0.005	SLC25A13
Urea cycle	1	439.2×	0.005	ASS1
Metabolism	2	11.6×	0.012	ASS1, SLC25A13
Protein localization	1	95.2×	0.015	SLC25A13
Mitochondrial protein import	1	84.0×	0.015	SLC25A13
Respiratory electron transport	1	47.6×	0.022	SLC25A13
Aerobic respiration and respiratory electron transport	1	44.3×	0.022	SLC25A13

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
obsolete argininosuccinate metabolic process	1	8426.0×	0.002	ASS1
obsolete citrulline metabolic process	1	4213.0×	0.002	ASS1
L-arginine biosynthetic process	1	2808.7×	0.002	ASS1
response to mycotoxin	1	2808.7×	0.002	ASS1
cellular response to oleic acid	1	2808.7×	0.002	ASS1
cellular response to amine stimulus	1	2808.7×	0.002	ASS1
cellular response to ammonium ion	1	1685.2×	0.003	ASS1
negative regulation of leukocyte cell-cell adhesion	1	1404.3×	0.003	ASS1
aspartate metabolic process	1	1053.2×	0.003	ASS1
midgut development	1	1053.2×	0.003	ASS1
cellular response to laminar fluid shear stress	1	1053.2×	0.003	ASS1
malate-aspartate shuttle	1	936.2×	0.003	SLC25A13
diaphragm development	1	936.2×	0.003	ASS1
aspartate transmembrane transport	1	702.2×	0.004	SLC25A13
urea cycle	1	648.1×	0.004	ASS1
mitochondrial transport	1	601.9×	0.004	SLC25A13
response to growth hormone	1	561.7×	0.004	ASS1
ATP biosynthetic process	1	495.6×	0.004	SLC25A13
cellular response to glucagon stimulus	1	421.3×	0.005	ASS1
L-glutamate transmembrane transport	1	401.2×	0.005	SLC25A13
response to zinc ion	1	312.1×	0.006	ASS1
cellular response to dexamethasone stimulus	1	290.6×	0.006	ASS1
positive regulation of nitric oxide biosynthetic process	1	227.7×	0.007	ASS1
cellular respiration	1	216.1×	0.007	SLC25A13
acute-phase response	1	210.7×	0.007	ASS1
gluconeogenesis	1	162.0×	0.009	SLC25A13
response to calcium ion	1	159.0×	0.009	SLC25A13
cellular response to amino acid stimulus	1	153.2×	0.009	ASS1
response to nutrient	1	147.8×	0.009	ASS1
cellular response to cAMP	1	145.3×	0.009	ASS1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ASS1	0	0
SLC25A13	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ASS1	1	Binding:1
SLC25A13	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASS1	6.3.4.5	argininosuccinate synthase

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

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	2	ASS1, SLC25A13
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
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)
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