citrullinemia, type II, adult-onset

Summary

citrullinemia, type II, adult-onset (MONDO:0011326) is a disease caused by SLC25A13 (GenCC Strong), with 2 cohort genes and 3 clinical trials.

At a glance

• Causal gene: SLC25A13 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 132
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	citrullinemia, type II, adult-onset
Mondo ID	MONDO:0011326
OMIM	603471
DOID	DOID:0070342
GARD	0024789
Is cancer (heuristic)	no

Also known as: adult-onset citrullinemia type 2 · adult-onset citrullinemia type II · citrin deficiency · citrullinemia type 2 · citrullinemia type II · citrullinemia, adult-onset type II · citrullinemia, type II, adult-onset · CTLN2

Data availability: 132 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: 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 › citrin deficiency › citrullinemia type II › citrullinemia, type II, adult-onset

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

132 retrieved; paginated sample, class counts are floors:

49 likely pathogenic, 31 pathogenic/likely pathogenic, 27 pathogenic, 13 conflicting classifications of pathogenicity, 10 uncertain significance, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339499	NM_054012.4(ASS1):c.364-2A>G	ASS1	Pathogenic	criteria provided, multiple submitters, no conflicts
21510	NM_014251.3(SLC25A13):c.15G>A (p.Lys5=)	LOC129998833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067978	NM_014251.3(SLC25A13):c.1231-1G>A	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069536	NM_014251.3(SLC25A13):c.1311C>A (p.Cys437Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074032	NM_014251.3(SLC25A13):c.276del (p.Phe92fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074885	NM_014251.3(SLC25A13):c.1677C>G (p.Tyr559Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075398	NM_014251.3(SLC25A13):c.1063C>G (p.Arg355Gly)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
1076508	NM_014251.3(SLC25A13):c.429_430del (p.Arg144fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323603	NM_014251.3(SLC25A13):c.1173T>G (p.Tyr391Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361947	NM_014251.3(SLC25A13):c.127C>T (p.Arg43Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362972	NM_014251.3(SLC25A13):c.528dup (p.Arg177fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388183	NM_014251.3(SLC25A13):c.1453-2A>T	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
1450311	NM_014251.3(SLC25A13):c.970C>T (p.Gln324Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451917	NM_014251.3(SLC25A13):c.1095del (p.Phe365fs)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
1451920	NM_014251.3(SLC25A13):c.754G>A (p.Glu252Lys)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458046	NM_014251.3(SLC25A13):c.605_608dup (p.Val204fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459278	NM_014251.3(SLC25A13):c.1658_1661dup (p.Gln556fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459462	NM_014251.3(SLC25A13):c.229G>T (p.Glu77Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1929400	NM_014251.3(SLC25A13):c.1769C>A (p.Ser590Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2075890	NM_014251.3(SLC25A13):c.1311+1G>C	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
21508	NM_014251.3(SLC25A13):c.1078C>T (p.Arg360Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21513	NM_014251.3(SLC25A13):c.1801G>T (p.Glu601Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
21514	NM_014251.3(SLC25A13):c.1813C>T (p.Arg605Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21515	NM_014251.3(SLC25A13):c.550C>T (p.Arg184Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
21517	NM_014251.3(SLC25A13):c.615+5G>A	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
2193074	NM_014251.3(SLC25A13):c.990C>A (p.Tyr330Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225472	NM_014251.3(SLC25A13):c.852_855del (p.Met285fs)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
252920	NM_014251.3(SLC25A13):c.775C>T (p.Gln259Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
2678809	NM_014251.3(SLC25A13):c.1676dup (p.Tyr559Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678817	NM_014251.3(SLC25A13):c.1453-1G>C	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
SLC25A13	Strong	Autosomal recessive	citrullinemia, type II, adult-onset	5

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
ASS1	Orphanet:247546	Acute neonatal citrullinemia type I
ASS1	Orphanet:247573	Late-onset citrullinemia type I

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

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)
SLC25A13	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair
ASS1	Enzyme (other)	yes	6.3.4.5	Arginosuc_synth, Rossmann-like_a/b/a_fold, Arginosuc_synth_CS

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
secondary oocyte	1
palpebral conjunctiva	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
ASS1	292	ubiquitous	marker	right lobe of liver, palpebral conjunctiva, liver

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
SLC25A13	Q9UJS0	1
ASS1	P00966	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	SLC25A13, ASS1
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	SLC25A13, ASS1
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
SLC25A13	0	0
ASS1	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
SLC25A13	1	Binding:1
ASS1	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	SLC25A13, ASS1
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)
SLC25A13	1	—
ASS1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06895746	Not specified	ACTIVE_NOT_RECRUITING	Multi-omics Study in Citrin Deficiency
NCT07055269	Not specified	ACTIVE_NOT_RECRUITING	Liver Metabolic Functions in Patients With Citrin Deficiency and Healthy Subjects
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening