tyrosinemia type II

Summary

tyrosinemia type II (MONDO:0010160) is a disease caused by TAT (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TAT (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 447
• Phenotypes (HPO): 17
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0004337	Abnormality of amino acid metabolism	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tyrosinemia type II
Mondo ID	MONDO:0010160
OMIM	276600
Orphanet	28378
DOID	DOID:0050725
ICD-11	1900229795
NCIT	C129032
SNOMED CT	4887000
UMLS	C0268487
MedGen	75687
GARD	0003105
MedDRA	10069463
Is cancer (heuristic)	no

Also known as: keratosis palmoplantaris-corneal dystrophy syndrome · oculocutaneous tyrosinemia · Richner Hanhart syndrome · Richner-Hanhart syndrome · tyrosinemia due to TAT deficiency · tyrosinemia due to tyrosine aminotransferase deficiency · tyrosinemia type 2 · tyrosinemia type II · tyrosinemia, type II · Tyrosinosis oculocutaneous type · TYRSN2

Data availability: 447 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

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 II

Related subtypes (3): tyrosinemia type I, tyrosinemia type III, 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

447 retrieved; paginated sample, class counts are floors:

283 likely benign, 76 uncertain significance, 38 likely pathogenic, 24 pathogenic, 10 pathogenic/likely pathogenic, 8 conflicting classifications of pathogenicity, 6 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
405	NM_000353.3(TAT):c.[1085G>T;912+2T>G]		Pathogenic	no assertion criteria provided
21054	NM_000137.4(FAH):c.192G>T (p.Gln64His)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
1350262	NM_000353.3(TAT):c.582G>A (p.Trp194Ter)	LOC111413029	Pathogenic	criteria provided, single submitter
2899928	NM_000353.3(TAT):c.648del (p.Pro217fs)	LOC111413029	Pathogenic	criteria provided, single submitter
403	NM_000353.3(TAT):c.668C>G (p.Ser223Ter)	LOC111413029	Pathogenic	no assertion criteria provided
4798409	NM_000353.3(TAT):c.523_524del (p.Leu175fs)	LOC111413029	Pathogenic	criteria provided, single submitter
1071272	NC_000016.9:g.(?71609815)(71610328_?)del	TAT	Pathogenic	criteria provided, single submitter
1074025	NM_000353.3(TAT):c.9dup (p.Tyr4fs)	TAT	Pathogenic	criteria provided, single submitter
1422277	NM_000353.3(TAT):c.308_309delinsAA (p.Ser103Ter)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425300	NM_000353.3(TAT):c.916C>T (p.Arg306Ter)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1440254	NM_000353.3(TAT):c.966del (p.Ile322fs)	TAT	Pathogenic	criteria provided, single submitter
1452969	NM_000353.3(TAT):c.89del (p.Val30fs)	TAT	Pathogenic	criteria provided, single submitter
1454381	NM_000353.3(TAT):c.825del (p.Cys275fs)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1474620	NM_000353.3(TAT):c.707-2A>G	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2019658	NM_000353.3(TAT):c.358del (p.Glu120fs)	TAT	Pathogenic	criteria provided, single submitter
2129086	NM_000353.3(TAT):c.1125+1del	TAT	Pathogenic	criteria provided, single submitter
2679097	NM_000353.3(TAT):c.1224G>T (p.Thr408=)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2703184	NM_000353.3(TAT):c.742G>T (p.Glu248Ter)	TAT	Pathogenic	criteria provided, single submitter
2711453	NM_000353.3(TAT):c.1188_1191del (p.Val397fs)	TAT	Pathogenic	criteria provided, single submitter
2743466	NM_000353.3(TAT):c.825T>A (p.Cys275Ter)	TAT	Pathogenic	criteria provided, single submitter
3643231	NM_000353.3(TAT):c.861G>A (p.Trp287Ter)	TAT	Pathogenic	criteria provided, single submitter
402	NM_000353.3(TAT):c.169C>T (p.Arg57Ter)	TAT	Pathogenic	criteria provided, multiple submitters, no conflicts
404	NM_000353.3(TAT):c.1249C>T (p.Arg417Ter)	TAT	Pathogenic	criteria provided, multiple submitters, no conflicts
406	NM_000353.3(TAT):c.236-5A>G	TAT	Pathogenic	no assertion criteria provided
550062	NM_000353.3(TAT):c.1250G>A (p.Arg417Gln)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550810	NM_000353.3(TAT):c.226dup (p.Leu76fs)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550997	NM_000353.3(TAT):c.355C>T (p.Arg119Trp)	TAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553180	NM_000353.3(TAT):c.1297C>T (p.Arg433Trp)	TAT	Pathogenic	criteria provided, multiple submitters, no conflicts
553660	NM_000353.3(TAT):c.1047del (p.Asn349fs)	TAT	Pathogenic	criteria provided, single submitter
557491	NM_000353.3(TAT):c.177dup (p.Val60fs)	TAT	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
TAT	Definitive	Autosomal recessive	tyrosinemia type II	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TAT	Orphanet:28378	Tyrosinemia type 2
FAH	Orphanet:882	Tyrosinemia type 1

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
TAT	HGNC:11573	ENSG00000198650	P17735	Tyrosine aminotransferase	gencc,clinvar
FAH	HGNC:3579	ENSG00000103876	P16930	Fumarylacetoacetase	clinvar
TAT-AS1	HGNC:51369	ENSG00000260886		TAT antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TAT	Tyrosine aminotransferase	Transaminase involved in tyrosine breakdown.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TAT	Other/Unknown	no		NHTrfase_class1_PyrdxlP-BS, Aminotransferase_I/II_large, Tyrosine_aminoTrfase
FAH	Enzyme (other)	yes	3.7.1.2	Fumarylacetoacetase, Fumarylacetoacetase-like_C, Fumarylacetoacetase_N
TAT-AS1	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	2
right lobe of liver	2
buccal mucosa cell	1
right adrenal gland	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TAT	128	tissue_specific	marker	right lobe of liver, liver, buccal mucosa cell
FAH	255	ubiquitous	marker	right lobe of liver, liver, right adrenal gland
TAT-AS1	112	tissue_specific	yes	left testis, testis, right testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TAT	2,267
FAH	1,872
TAT-AS1	0

Intra-cohort edges

A	B	Sources
FAH	TAT	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAH	P16930	8
TAT	P17735	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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	2	2284.0×	6e-07	TAT, FAH
Phenylalanine and tyrosine metabolism	1	1427.5×	0.001	TAT
Metabolism of amino acids and derivatives	1	33.8×	0.039	TAT
Metabolism	1	5.8×	0.165	TAT

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
L-tyrosine catabolic process	2	2808.7×	2e-06	TAT, FAH
L-phenylalanine catabolic process	2	2106.5×	2e-06	TAT, FAH
homogentisate catabolic process	1	8426.0×	6e-04	FAH
L-arginine catabolic process	1	1404.3×	0.003	FAH
response to mercury ion	1	1203.7×	0.003	TAT
response to cortisol	1	842.6×	0.003	TAT
response to dexamethasone	1	601.9×	0.004	TAT
glutamate metabolic process	1	561.7×	0.004	TAT
2-oxoglutarate metabolic process	1	468.1×	0.004	TAT
response to cAMP	1	255.3×	0.006	TAT
liver regeneration	1	255.3×	0.006	TAT
cellular response to retinoic acid	1	117.0×	0.011	TAT
cellular response to insulin stimulus	1	85.1×	0.014	TAT
response to ethanol	1	73.3×	0.016	TAT
response to oxidative stress	1	65.3×	0.016	TAT
lipid metabolic process	1	45.8×	0.022	FAH

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TAT	0	0
FAH	0	0
TAT-AS1	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
TAT	2	Functional:1, Binding:1
FAH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FAH	3.7.1.2	fumarylacetoacetase

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	1	FAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TAT, TAT-AS1

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)
TAT	2	—
FAH	1	—
TAT-AS1	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