Cystathioninuria

Summary

Cystathioninuria (MONDO:0009058) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Canada) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 53
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	7.1	Canada	Validated
Prevalence at birth	1-9 / 100 000	7.1	Canada	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0003153	Cystathioninuria	Obligate (100%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0003286	Cystathioninemia	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cystathioninuria
Mondo ID	MONDO:0009058
OMIM	219500
Orphanet	212
DOID	DOID:0090142
ICD-11	1415819835
NCIT	C129070
SNOMED CT	13003007
UMLS	C0220993
MedGen	66353
GARD	0002428
Is cancer (heuristic)	no

Also known as: cystathionase deficiency · cystathioninuria · cystathioninuria (disease) · gamma-cystathionase deficiency

Data availability: 53 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype · 5 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 › cystathioninuria

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

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

53 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 4 benign, 3 conflicting classifications of pathogenicity, 3 likely benign, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033458	NM_001902.6(CTH):c.1064del (p.Thr355fs)	CTH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2937	NM_001902.6(CTH):c.784_785del (p.Leu262fs)	CTH	Pathogenic	no assertion criteria provided
2940	NM_001902.6(CTH):c.718C>G (p.Gln240Glu)	CTH	Pathogenic	no assertion criteria provided
225330	NM_001902.6(CTH):c.793C>T (p.Arg265Ter)	CTH	Likely pathogenic	criteria provided, single submitter
2939	NM_001902.6(CTH):c.200C>T (p.Thr67Ile)	CTH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298029	NM_001902.6(CTH):c.346+7G>A	CTH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298035	NM_001902.6(CTH):c.864G>A (p.Lys288=)	CTH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2552199	NM_001902.6(CTH):c.473C>T (p.Thr158Ile)	CTH	Uncertain significance	criteria provided, multiple submitters, no conflicts
298026	NM_001902.5(CTH):c.-151T>C	CTH	Uncertain significance	criteria provided, single submitter
298028	NM_001902.6(CTH):c.-3A>G	CTH	Uncertain significance	criteria provided, single submitter
298030	NM_001902.6(CTH):c.381A>G (p.Glu127=)	CTH	Uncertain significance	criteria provided, single submitter
298031	NM_001902.6(CTH):c.430G>C (p.Glu144Gln)	CTH	Uncertain significance	criteria provided, single submitter
298032	NM_001902.6(CTH):c.495G>T (p.Lys165Asn)	CTH	Uncertain significance	criteria provided, single submitter
298033	NM_001902.6(CTH):c.541G>A (p.Asp181Asn)	CTH	Uncertain significance	criteria provided, multiple submitters, no conflicts
298034	NM_001902.6(CTH):c.589-3C>T	CTH	Uncertain significance	criteria provided, single submitter
298036	NM_001902.6(CTH):c.995T>C (p.Leu332Pro)	CTH	Uncertain significance	criteria provided, single submitter
298037	NM_001902.6(CTH):c.1033G>A (p.Glu345Lys)	CTH	Uncertain significance	criteria provided, multiple submitters, no conflicts
298041	NM_001902.6(CTH):c.*98G>A	CTH	Uncertain significance	criteria provided, single submitter
298042	NM_001902.6(CTH):c.*260T>C	CTH	Uncertain significance	criteria provided, single submitter
298043	NM_001902.6(CTH):c.*334T>A	CTH	Uncertain significance	criteria provided, single submitter
298044	NM_001902.6(CTH):c.*370C>T	CTH	Uncertain significance	criteria provided, single submitter
298045	NM_001902.6(CTH):c.*371G>A	CTH	Uncertain significance	criteria provided, single submitter
298049	NM_001902.6(CTH):c.*527A>T	CTH	Uncertain significance	criteria provided, single submitter
298051	NM_001902.6(CTH):c.*545C>T	CTH	Uncertain significance	criteria provided, single submitter
298052	NM_001902.6(CTH):c.*587G>A	CTH	Uncertain significance	criteria provided, single submitter
298054	NM_001902.6(CTH):c.*630G>A	CTH	Uncertain significance	criteria provided, single submitter
298055	NM_001902.6(CTH):c.*631C>T	CTH	Uncertain significance	criteria provided, single submitter
298056	NM_001902.6(CTH):c.*632G>A	CTH	Uncertain significance	criteria provided, single submitter
3587693	NM_001902.6(CTH):c.620T>C (p.Met207Thr)	CTH	Uncertain significance	criteria provided, single submitter
4078427	NM_001902.6(CTH):c.347-2A>G	CTH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
CTH	Moderate	Autosomal recessive	cystathioninuria	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTH	Orphanet:212	Cystathioninuria

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
CTH	HGNC:2501	ENSG00000116761	P32929	Cystathionine gamma-lyase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTH	Cystathionine gamma-lyase	Catalyzes the last step in the trans-sulfuration pathway from L-methionine to L-cysteine in a pyridoxal-5’-phosphate (PLP)-dependent manner, which consists on cleaving the L,L-cystathionine molecule into L-cysteine, ammonia and 2-oxobutano…

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)
CTH	Enzyme (other)	yes	4.4.1.1	Cys/Met-Metab_PyrdxlP-dep_enz, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

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
pigmented layer of retina	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTH	243	ubiquitous	marker	right lobe of liver, liver, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTH	2,987

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTH	P32929	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Cysteine formation from homocysteine	1	5710.0×	5e-04	CTH
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	1427.5×	0.001	CTH
Degradation of cysteine and homocysteine	1	951.7×	0.001	CTH

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
protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine	1	16852.0×	4e-04	CTH
protein sulfhydration	1	16852.0×	4e-04	CTH
obsolete L-cysteine biosynthetic process via L-cystathionine	1	8426.0×	4e-04	CTH
positive regulation of aortic smooth muscle cell differentiation	1	8426.0×	4e-04	CTH
L-cysteine biosynthetic process	1	5617.3×	4e-04	CTH
hydrogen sulfide biosynthetic process	1	5617.3×	4e-04	CTH
obsolete cysteine metabolic process	1	4213.0×	4e-04	CTH
transsulfuration	1	4213.0×	4e-04	CTH
negative regulation of apoptotic signaling pathway	1	561.7×	0.003	CTH
endoplasmic reticulum unfolded protein response	1	295.6×	0.005	CTH
protein homotetramerization	1	237.3×	0.005	CTH
cellular response to leukemia inhibitory factor	1	159.0×	0.007	CTH
lipid metabolic process	1	91.6×	0.012	CTH
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.014	CTH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
CTH	NITROXOLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CTH	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROXOLINE	4	CTH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTH	31	Binding:31

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTH	4.4.1.1	cystathionine gamma-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

1 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)
NITROXOLINE	4	CTH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CTH
B	Phased (≥1) drug, not yet approved	0
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: 0.