tyrosinemia type III

Summary

tyrosinemia type III (MONDO:0010162) is a disease caused by HPD (GenCC Strong), with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HPD (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 374
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	tyrosinemia type III
Mondo ID	MONDO:0010162
OMIM	276710
Orphanet	69723
DOID	DOID:0050727
SNOMED CT	415764005
UMLS	C0268623
MedGen	78694
GARD	0010332
MedDRA	10069461
Is cancer (heuristic)	no

Also known as: 4-alpha hydroxyphenylpyruvate dioxygenase deficiency · 4-alpha hydroxyphenylpyruvic acid oxidase deficiency · tyrosinemia due to 4-hydroxyphenylpyruvate dioxygenase deficiency · tyrosinemia due to 4-hydroxyphenylpyruvic acid oxidase deficiency · tyrosinemia due to HPD deficiency · tyrosinemia type 3 · tyrosinemia type III · tyrosinemia, type III · TYRSN3

Data availability: 374 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: 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 › inborn disorder of phenylalanine and tyrosine metabolism › disorder of tyrosine metabolism › tyrosinemia › tyrosinemia type III

Related subtypes (3): tyrosinemia type II, tyrosinemia type I, transient tyrosinemia of the newborn

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

374 retrieved; paginated sample, class counts are floors:

236 likely benign, 60 uncertain significance, 32 pathogenic, 12 likely pathogenic, 12 conflicting classifications of pathogenicity, 11 benign, 6 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
529445	NM_000159.4(GCDH):c.479A>G (p.Gln160Arg)	GCDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333313	NM_002150.3(HPD):c.463del (p.Gln155fs)	HPD	Pathogenic	criteria provided, single submitter
1574	NM_002150.3(HPD):c.774T>G (p.Tyr258Ter)	HPD	Pathogenic	no assertion criteria provided
1575	NM_002150.3(HPD):c.600C>G (p.Tyr200Ter)	HPD	Pathogenic	no assertion criteria provided
2110723	NM_002150.3(HPD):c.184dup (p.Ile62fs)	HPD	Pathogenic	criteria provided, single submitter
2128171	NM_002150.3(HPD):c.91C>T (p.Gln31Ter)	HPD	Pathogenic	criteria provided, single submitter
2153024	NM_002150.3(HPD):c.613C>T (p.Gln205Ter)	HPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429187	NM_002150.3(HPD):c.248del (p.Gly83fs)	HPD	Pathogenic	criteria provided, multiple submitters, no conflicts
2921754	NM_002150.3(HPD):c.715_724del (p.Pro239fs)	HPD	Pathogenic	criteria provided, single submitter
2922293	NM_002150.3(HPD):c.852_853dup (p.Gly285fs)	HPD	Pathogenic	criteria provided, single submitter
2932690	NM_002150.3(HPD):c.850_853del (p.Arg284fs)	HPD	Pathogenic	criteria provided, single submitter
2946803	NM_002150.3(HPD):c.146del (p.Gly49fs)	HPD	Pathogenic	criteria provided, single submitter
2948128	NM_002150.3(HPD):c.865_866del (p.Leu289fs)	HPD	Pathogenic	criteria provided, single submitter
2950625	NM_002150.3(HPD):c.142del (p.Arg48fs)	HPD	Pathogenic	criteria provided, single submitter
3244248	NC_000012.11:g.(?122284748)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244249	NC_000012.11:g.(?122296573)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244250	NC_000012.11:g.(?122294469)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244251	NC_000012.11:g.(?122292589)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244252	NC_000012.11:g.(?122277634)(122287716_?)del	HPD	Pathogenic	criteria provided, single submitter
3244253	NC_000012.11:g.(?122286885)(122287716_?)del	HPD	Pathogenic	criteria provided, single submitter
3244254	NC_000012.11:g.(?122284839)(122288809_?)del	HPD	Pathogenic	criteria provided, single submitter
3339459	NM_002150.3(HPD):c.442dup (p.Glu148fs)	HPD	Pathogenic	criteria provided, single submitter
3574324	NM_002150.3(HPD):c.673C>T (p.Arg225Ter)	HPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3753445	NM_002150.3(HPD):c.274G>T (p.Gly92Ter)	HPD	Pathogenic	criteria provided, single submitter
3753543	NM_002150.3(HPD):c.65_66del (p.Val22fs)	HPD	Pathogenic	criteria provided, single submitter
3754946	NM_002150.3(HPD):c.535del (p.Glu179fs)	HPD	Pathogenic	criteria provided, single submitter
4687140	NC_000012.11:g.(?122277432)(122296766_?)del	HPD	Pathogenic	criteria provided, single submitter
529472	NC_000012.12:g.(?121843690)(121847234_?)del	HPD	Pathogenic	criteria provided, single submitter
642856	NM_002150.3(HPD):c.158dup (p.Ser54fs)	HPD	Pathogenic	criteria provided, single submitter
832353	NC_000012.12:g.(?121846842)(121849810_?)del	HPD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
HPD	Strong	Autosomal recessive	tyrosinemia type III	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPD	Orphanet:2118	Hawkinsinuria
HPD	Orphanet:69723	Tyrosinemia type 3
GCDH	Orphanet:25	Glutaryl-CoA dehydrogenase deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HPD	HGNC:5147	ENSG00000158104	P32754	4-hydroxyphenylpyruvate dioxygenase	gencc,clinvar
GCDH	HGNC:4189	ENSG00000105607	Q92947	Glutaryl-CoA dehydrogenase, mitochondrial	clinvar
TIALD	HGNC:56938	ENSG00000256811		transcript inducer of AURKA lysosomal degradation	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HPD	4-hydroxyphenylpyruvate dioxygenase	Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.
GCDH	Glutaryl-CoA dehydrogenase, mitochondrial	Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HPD	Enzyme (other)	yes	1.13.11.27	Glyas_Fos-R_dOase_dom, 4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase
GCDH	Enzyme (other)	yes	1.3.8.6	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C
TIALD	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	3
right lobe of liver	3
adult mammalian kidney	1
apex of heart	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPD	163	broad	marker	right lobe of liver, liver, adult mammalian kidney
GCDH	259	ubiquitous	marker	right lobe of liver, liver, apex of heart
TIALD	97		yes	right lobe of liver, liver, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCDH	2,573
HPD	1,766
TIALD	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HPD	P32754	4
GCDH	Q92947	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Tyrosine catabolism	1	1142.0×	0.002	HPD
Lysine catabolism	1	571.0×	0.002	GCDH

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 L-tryptophan metabolic process	1	2808.7×	0.001	GCDH
L-tyrosine catabolic process	1	1404.3×	0.001	HPD
L-phenylalanine catabolic process	1	1053.2×	0.001	HPD
fatty-acyl-CoA biosynthetic process	1	936.2×	0.001	GCDH
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	702.2×	0.001	GCDH

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
HPD	NITISINONE
GCDH	BALSALAZIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HPD	1	4
GCDH	1	4
TIALD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITISINONE	4	HPD
BALSALAZIDE	4	GCDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GCDH	15	Binding:14, ADMET:1
HPD	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HPD	1.13.11.27	4-hydroxyphenylpyruvate dioxygenase
GCDH	1.3.8.6	glutaryl-CoA dehydrogenase (ETF)

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

2 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)
NITISINONE	4	HPD
BALSALAZIDE	4	GCDH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	HPD, GCDH
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	1	TIALD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TIALD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies
NCT04196959	Not specified	COMPLETED	Evaluation of TYR Sphere