FAH

Summary

FAH (fumarylacetoacetate hydrolase, HGNC:3579) is a protein-coding gene on chromosome 15q25.1, encoding Fumarylacetoacetase (P16930).

Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; homogentisate catabolic process; and tyrosine catabolic process. Predicted to act upstream of or within arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I.

Source: NCBI Gene 2184 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tyrosinemia type I (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 913 total — 66 pathogenic, 91 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000137

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3579
Approved symbol	FAH
Name	fumarylacetoacetate hydrolase
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000103876
Ensembl biotype	protein_coding
OMIM	613871
Entrez	2184

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 23 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000261755, ENST00000407106, ENST00000537726, ENST00000539156, ENST00000558022, ENST00000558514, ENST00000558627, ENST00000558767, ENST00000559217, ENST00000559542, ENST00000561353, ENST00000561369, ENST00000561421, ENST00000646551, ENST00000682012, ENST00000683593, ENST00000684363, ENST00000684569, ENST00000874652, ENST00000874653, ENST00000874654, ENST00000874655, ENST00000874656, ENST00000874657, ENST00000874658, ENST00000874659, ENST00000929198, ENST00000929199, ENST00000960159, ENST00000960160, ENST00000960161, ENST00000960162, ENST00000960163, ENST00000960164

RefSeq mRNA: 3 — MANE Select: NM_000137 NM_000137, NM_001374377, NM_001374380

CCDS: CCDS10314

Canonical transcript exons

ENST00000561421 — 14 exons

Exon	Start	End
ENSE00000699985	80175016	80175091
ENSE00000699986	80177537	80177583
ENSE00001104232	80186130	80186349
ENSE00001554054	80152999	80153135
ENSE00003458634	80159756	80159877
ENSE00003525947	80168052	80168149
ENSE00003548632	80181042	80181159
ENSE00003575841	80158060	80158170
ENSE00003577165	80180124	80180225
ENSE00003577707	80168264	80168316
ENSE00003578314	80160410	80160459
ENSE00003617352	80173014	80173144
ENSE00003655158	80162246	80162336
ENSE00003660607	80172149	80172248

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 98.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3131 / max 296.5978, expressed in 1785 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147988	20.7380	1748
147985	4.5918	1577
147986	0.6844	315
147991	0.4820	193
147987	0.4632	165
147989	0.1815	111
147990	0.1205	69
207611	0.0516	22

Top tissues by expression

280 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.70	gold quality
liver	UBERON:0002107	97.57	gold quality
right adrenal gland	UBERON:0001233	96.70	gold quality
right adrenal gland cortex	UBERON:0035827	96.58	gold quality
left adrenal gland cortex	UBERON:0035825	96.53	gold quality
left adrenal gland	UBERON:0001234	96.46	gold quality
adrenal cortex	UBERON:0001235	96.08	gold quality
adipose tissue	UBERON:0001013	95.72	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.27	gold quality
omental fat pad	UBERON:0010414	95.18	gold quality
peritoneum	UBERON:0002358	95.15	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.03	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.89	gold quality
adrenal gland	UBERON:0002369	94.80	gold quality
connective tissue	UBERON:0002384	94.66	gold quality
stromal cell of endometrium	CL:0002255	93.57	gold quality
spinal cord	UBERON:0002240	93.47	gold quality
adult mammalian kidney	UBERON:0000082	93.33	gold quality
right ovary	UBERON:0002118	92.86	gold quality
left ovary	UBERON:0002119	91.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.52	gold quality
descending thoracic aorta	UBERON:0002345	91.16	gold quality
left coronary artery	UBERON:0001626	90.79	gold quality
thoracic aorta	UBERON:0001515	90.55	gold quality
coronary artery	UBERON:0001621	90.54	gold quality
ascending aorta	UBERON:0001496	90.49	gold quality
right uterine tube	UBERON:0001302	90.47	gold quality
right testis	UBERON:0004534	90.33	gold quality
nephron tubule	UBERON:0001231	90.17	gold quality
right coronary artery	UBERON:0001625	89.97	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

16 targeting FAH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-3126-3P	97.17	66.51	468
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-6856-3P	96.47	66.27	781

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 21)

• A missense mutation in the fumarylacetoacetate hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation. (PMID:11476670)
• Data describe the metabolism of fumarylacetoacetate hydrolase mRNA harboring a nonsense mutation, W262X, in lymphoblastoid cell lines derived from hereditary tyrosinemia type I patients. (PMID:15465000)
• identification of an alternative nonsense transcript of the fah gene, which despite being subjected to nonsense-mediated mRNA decay, produces a protein in different human tissues (PMID:15638932)
• An immunopositive liver nodule was found in a patient with tyrosinemia having a mosaic pattern of FAH. (PMID:15759101)
• We detected 11 novel and 6 previously described pathogenic mutations in the fumarylacetoacetase gene in a cohort of 43 patients originating from the Middle East with the acute form hereditary tyrosinemia type I (PMID:21764616)
• Identification of novel mutations in the fumarylacetoacetase gene in Hereditary tyrosinaemia type I. (PMID:22554029)
• Compound mutations (R237X and L375P) in the fumarylacetoacetate hydrolase gene causing tyrosinemia type I in a Chinese patient. (PMID:22884142)
• Four splicing mutations affecting exonic or intronic nucleotides of the FAH gene were identified in two hereditary tyrosinemia type I patients. (PMID:23895425)
• Two siblings have been described with tyrosinemia type 1 complicated by reversible hypertrophic cardiomyopathy in infancy due to a FAH homozygous mutation. (PMID:24016420)
• FAH gene mutation is associated with tyrosinemia type 1. (PMID:26565546)
• Results from whole exome sequencing revealed a novel homozygous missense variant in FAH causing tyrosinemia type I . This novel variant involves the catalytic pocket of the enzyme, but does not result in increased succinylacetone or tyrosine. (PMID:27397503)
• molecular aspects of the FAH gene and its corresponding protein and a complete listing of all the mutations identified to date; highlight of the importance of splicing mutations in hereditary tyrosinemia type 1 (PMID:28755182)
• Altogether these findings elucidate the molecular basis of HT1 caused by the frequent FAH c.1062+5G>A mutation, and demonstrate the compensatory effect of the c.1061C>A change in promoting exon definition, thus unraveling a rare mechanism leading to FAH immune-reactive mosaicism. (PMID:29497141)
• A liver-humanized mouse model of carbamoyl phosphate synthetase 1-deficiency. (PMID:30843237)
• We identified pathogenic variants in 15/16 studied alleles (93.8%). Nine different variants were found. The most commonly detected HT1-causing allele was NM_000137.2(FAH):c.3G > A or p.(?) [rs766882348] (25%, n = 4/16). We also identified a novel missense variant NM_000137.2(FAH):c.36C > A or p.(Phe12Leu) in a homozygous patient with an early and fatal acute form. (PMID:31568711)
• Genetic Analysis of Tyrosinemia Type 1 and Fructose-1, 6 Bisphosphatase Deficiency Affected in Pakistani Cohorts. (PMID:31584309)
• E3 Ubiquitin Ligase APC/C(Cdh1) Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination. (PMID:33218190)
• Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I. (PMID:33670179)
• Survival-Assured Liver Injury Preconditioning (SALIC) Enables Robust Expansion of Human Hepatocytes in Fah(-/-) Rag2(-/-) IL2rg(-/-) Rats. (PMID:34382351)
• Fumarylacetoacetate hydrolase gene as a knockout target for hepatic chimerism and donor liver production. (PMID:34678209)
• The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1). (PMID:36369907)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fah	ENSDARG00000101762
mus_musculus	Fah	ENSMUSG00000030630
rattus_norvegicus	Fah	ENSRNOG00000013223
drosophila_melanogaster	Faa	FBGN0016013
caenorhabditis_elegans		WBGENE00019620

Paralogs (3): FAHD2A (ENSG00000115042), FAHD2B (ENSG00000144199), FAHD1 (ENSG00000180185)

Protein

Protein identifiers

Fumarylacetoacetase — P16930 (reviewed: P16930)

Alternative names: Beta-diketonase, Fumarylacetoacetate hydrolase

All UniProt accessions (7): A0A384P5L6, A0A804HJ13, A0A804HJX2, B7Z4W2, P16930, H0YLC7, H3BNP8

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Homodimer.

Tissue specificity. Mainly expressed in liver and kidney. Lower levels are also detected in many other tissues.

Disease relevance. Tyrosinemia 1 (TYRSN1) [MIM:276700] An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, and hepatorenal manifestations. Typical features include hepatic necrosis, renal tubular injury, episodic weakness, self-mutilation, and seizures. Renal tubular dysfunction is associated with phosphate loss and hypophosphataemic rickets. Progressive liver disease can lead to the development of hepatocellular carcinoma. Dietary treatment with restriction of tyrosine and phenylalanine alleviates the rickets, but liver transplantation has so far been the only definite treatment. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 6/6.

Similarity. Belongs to the FAH family.

Isoforms (2)

UniProt ID	Names	Canonical?
P16930-1	1	yes
P16930-2	2

RefSeq proteins (3): NP_000128, NP_001361306, NP_001361309 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005959	Fumarylacetoacetase	Family
IPR011234	Fumarylacetoacetase-like_C	Domain
IPR015377	Fumarylacetoacetase_N	Domain
IPR036462	Fumarylacetoacetase_N_sf	Homologous_superfamily
IPR036663	Fumarylacetoacetase_C_sf	Homologous_superfamily

Pfam: PF01557, PF09298

Enzyme classification (BRENDA):

• EC 3.7.1.2 — fumarylacetoacetase (BRENDA: 19 organisms, 49 substrates, 36 inhibitors, 15 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-FUMARYLACETOACETATE	0.0014–0.0252	2
3,5-DIOXOHEXANOATE	0.27	1
3-PHENYLPROPIONOPYRUVATE	0.22	1
5-PHENYL-3,5-DIOXOPENTANOATE	0.89	1
6,6-DIMETHYL-3,5-DIOXOHEPTANOATE	0.14	1
ACETOPYRUVATE	0.47	1
BENZOYLPYRUVATE	0.12	1
BUTYROPYRUVATE	0.31	1
FUMARYLACETOACETATE	0.021	1
PIVALOPYRUVATE	0.64	1
PROPIONOPYRUVATE	0.47	1
TRIACETIC ACID	1.38	1

Catalyzed reactions (Rhea), 1 shown:

• 4-fumarylacetoacetate + H2O = acetoacetate + fumarate + H(+) (RHEA:10244)

UniProt features (42 total): sequence variant 22, binding site 12, modified residue 4, initiator methionine 1, chain 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9SX4	X-RAY DIFFRACTION	1.42
9T27	X-RAY DIFFRACTION	1.79
9SZM	X-RAY DIFFRACTION	1.8
9T9X	X-RAY DIFFRACTION	1.81
9SW1	X-RAY DIFFRACTION	1.99
9SQS	X-RAY DIFFRACTION	2.1
9SVW	X-RAY DIFFRACTION	2.15
9SZX	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16930-F1	98.06	0.98

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 133 (proton acceptor)

Ligand- & substrate-binding residues (12): 240; 244; 253; 257; 350; 126; 128; 142; 199; 201; 233; 233

Post-translational modifications (4): 2, 92, 309, 395

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8963684	Tyrosine catabolism

MSigDB gene sets: 348 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, SMITH_TERT_TARGETS_DN, MARTINEZ_RB1_TARGETS_UP, BOYAULT_LIVER_CANCER_SUBCLASS_G12_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GNF2_LCAT

GO Biological Process (6): L-arginine catabolic process (GO:0006527), L-phenylalanine catabolic process (GO:0006559), L-tyrosine catabolic process (GO:0006572), lipid metabolic process (GO:0006629), homogentisate catabolic process (GO:1902000), aromatic amino acid metabolic process (GO:0009072)

GO Molecular Function (5): fumarylacetoacetase activity (GO:0004334), metal ion binding (GO:0046872), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phenylalanine and tyrosine metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-amino acid catabolic process	3
proteinogenic amino acid catabolic process	3
aromatic amino acid catabolic process	2
arginine metabolic process	1
primary metabolic process	1
phenol-containing compound catabolic process	1
benzene-containing compound metabolic process	1
monocarboxylic acid catabolic process	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
hydrolase activity, acting on carbon-carbon bonds, in ketonic substances	1
cation binding	1
molecular_function	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAH	HPD	P32754	987
FAH	TAT	P17735	929
FAH	AFP	P02771	774
FAH	RAG2	P55895	749
FAH	GSTZ1	O43708	744
FAH	FAHD1	Q6P587	742
FAH	HGD	Q93099	736
FAH	ALB	P02768	667
FAH	G6PC1	P35575	661
FAH	PLAU	P00749	661
FAH	NOG	Q13253	575
FAH	IL2RG	P31785	545
FAH	PAH	P00439	542
FAH	RAG1	P15918	531
FAH	OSM	P13725	523

IntAct

44 interactions, top by confidence:

A	B	Type	Score
LAMTOR1	LAMTOR5	psi-mi:“MI:0914”(association)	0.870
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
FAH	TCF4	psi-mi:“MI:0915”(physical association)	0.560
FAH	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	FAH	psi-mi:“MI:0915”(physical association)	0.560
SERTAD1	FAH	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	FAH	psi-mi:“MI:0915”(physical association)	0.560
FAH	SERTAD1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	FAH	psi-mi:“MI:0915”(physical association)	0.560
FAH	KRTAP13-3	psi-mi:“MI:0915”(physical association)	0.560
FAH	CHRDL2	psi-mi:“MI:0915”(physical association)	0.560
FAH	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
EGFR	FAH	psi-mi:“MI:0915”(physical association)	0.550
MPHOSPH6	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DNAJC30	UBA6	psi-mi:“MI:0914”(association)	0.350
DND1	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): KRTAP5-9 (Two-hybrid), TCF4 (Two-hybrid), SERTAD1 (Two-hybrid), ADAMTSL4 (Two-hybrid), KRTAP10-8 (Two-hybrid), FAH (Co-fractionation), FAH (Co-fractionation), FAH (Co-fractionation), PGM1 (Co-fractionation), SORD (Co-fractionation), FAH (Two-hybrid), PLEKHF2 (Two-hybrid), KRTAP13-3 (Two-hybrid), FAH (Proximity Label-MS), EXO1 (Negative Genetic)

ESM2 similar proteins: A0A4P8DJE6, A5PKH3, A7EI75, A7KAL8, A7RZW4, F7W4M2, G2XR75, I1S0J7, O55096, O74638, O93918, P16930, P25093, P32327, P35505, P38095, P38675, P78820, P80576, Q00770, Q02218, Q09WE7, Q0CLK1, Q0GZS3, Q148N0, Q1RMS2, Q1ZXQ1, Q4WHT8, Q4WJ90, Q4WYN6, Q52CS0, Q5AWA2, Q5RCB8, Q5W915, Q5XI78, Q60597, Q60HE2, Q6H7M1, Q6P6Z8, Q6PEI7

Diamond homologs: A5PKH3, P16930, P25093, P35505, Q00770, Q1ZXQ1, Q4WHT8, Q6H7M1, Q8RW90, Q94272, O06724

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

913 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	66
Likely pathogenic	91
Uncertain significance	221
Likely benign	352
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066400	NM_000137.4(FAH):c.1203C>A (p.Tyr401Ter)	Pathogenic
1071694	NC_000015.9:g.(?80445387)(80478561_?)del	Pathogenic
1071695	NC_000015.9:g.(?80445387)(80445487_?)del	Pathogenic
1071696	NC_000015.9:g.(?80473374)(80478561_?)del	Pathogenic
1071697	NC_000015.9:g.(?80460384)(80460668_?)del	Pathogenic
1071826	NM_000137.4(FAH):c.721A>T (p.Lys241Ter)	Pathogenic
1073240	NM_000137.4(FAH):c.96dup (p.Gly33fs)	Pathogenic
1073593	NC_000015.9:g.(?80464481)(80478561_?)del	Pathogenic
1075997	NM_000137.4(FAH):c.372C>A (p.Tyr124Ter)	Pathogenic
11867	NM_000137.4(FAH):c.1090G>T (p.Glu364Ter)	Pathogenic
11869	NM_000137.4(FAH):c.1009G>A (p.Gly337Ser)	Pathogenic
11871	NM_000137.4(FAH):c.1069G>T (p.Glu357Ter)	Pathogenic
11873	NM_000137.4(FAH):c.786G>A (p.Trp262Ter)	Pathogenic
11874	NM_000137.4(FAH):c.554-1G>T	Pathogenic
1322862	NM_000137.4(FAH):c.697del (p.Asp233fs)	Pathogenic
1328148	NM_000137.4(FAH):c.1062+2T>G	Pathogenic
1380695	NM_000137.4(FAH):c.860del (p.Leu287fs)	Pathogenic
1388069	NM_000137.4(FAH):c.1235T>A (p.Val412Glu)	Pathogenic
1401386	NM_000137.4(FAH):c.667G>T (p.Glu223Ter)	Pathogenic
1453896	NM_000137.4(FAH):c.191del (p.Gln64fs)	Pathogenic
1455586	NM_000137.4(FAH):c.233G>A (p.Trp78Ter)	Pathogenic
1458313	NM_000137.4(FAH):c.484del (p.Arg162fs)	Pathogenic
1459306	NC_000015.9:g.(?80450392)(80454688_?)del	Pathogenic
1460135	NM_000137.4(FAH):c.932del (p.Ala311fs)	Pathogenic
1685807	NM_000137.4(FAH):c.61G>T (p.Val21Phe)	Pathogenic
188751	NM_000137.4(FAH):c.520C>T (p.Arg174Ter)	Pathogenic
1926774	NM_000137.4(FAH):c.1014del (p.Gly337_Cys338insTer)	Pathogenic
1996251	NM_000137.4(FAH):c.963C>G (p.Tyr321Ter)	Pathogenic
21054	NM_000137.4(FAH):c.192G>T (p.Gln64His)	Pathogenic
2422437	NC_000015.9:g.(?80465346)(80465496_?)del	Pathogenic

SpliceAI

2272 predictions. Top by Δscore:

Variant	Effect	Δscore
15:80153131:GCGAC:G	donor_gain	1.0000
15:80153133:GAC:G	donor_gain	1.0000
15:80153136:G:GG	donor_gain	1.0000
15:80158058:A:AG	acceptor_gain	1.0000
15:80158059:G:GA	acceptor_gain	1.0000
15:80158059:GCCAA:G	acceptor_gain	1.0000
15:80159747:T:TA	acceptor_gain	1.0000
15:80159754:A:AG	acceptor_gain	1.0000
15:80159755:G:GA	acceptor_gain	1.0000
15:80159755:GCCT:G	acceptor_gain	1.0000
15:80159872:G:GT	donor_gain	1.0000
15:80159875:GTG:G	donor_gain	1.0000
15:80160408:A:AG	acceptor_gain	1.0000
15:80160409:G:GG	acceptor_gain	1.0000
15:80160409:GT:G	acceptor_gain	1.0000
15:80160409:GTGC:G	acceptor_gain	1.0000
15:80168146:GACT:G	donor_gain	1.0000
15:80168150:G:GG	donor_gain	1.0000
15:80168250:T:TA	acceptor_gain	1.0000
15:80168251:G:A	acceptor_gain	1.0000
15:80168253:T:TA	acceptor_gain	1.0000
15:80168262:A:AG	acceptor_gain	1.0000
15:80168263:G:GA	acceptor_gain	1.0000
15:80168317:G:GA	donor_loss	1.0000
15:80173012:A:AG	acceptor_gain	1.0000
15:80173013:G:GG	acceptor_gain	1.0000
15:80175090:AGG:A	donor_loss	1.0000
15:80175091:GGTA:G	donor_loss	1.0000
15:80175092:GTAT:G	donor_loss	1.0000
15:80175093:T:G	donor_loss	1.0000

AlphaMissense

2773 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:80172240:A:C	D233A	0.998
15:80172240:A:T	D233V	0.998
15:80172242:T:A	W234R	0.998
15:80172242:T:C	W234R	0.998
15:80168312:A:T	E201V	0.997
15:80168306:A:T	E199V	0.996
15:80172241:C:A	D233E	0.996
15:80172241:C:G	D233E	0.996
15:80172245:A:C	S235R	0.996
15:80172247:T:A	S235R	0.996
15:80172247:T:G	S235R	0.996
15:80173017:G:C	R237P	0.996
15:80173027:G:C	Q240H	0.996
15:80173027:G:T	Q240H	0.996
15:80173061:G:T	G252W	0.996
15:80173066:G:C	K253N	0.996
15:80173066:G:T	K253N	0.996
15:80173065:A:C	K253T	0.995
15:80173067:A:C	S254R	0.995
15:80173069:T:A	S254R	0.995
15:80173069:T:G	S254R	0.995
15:80180217:A:C	S352R	0.995
15:80180219:C:A	S352R	0.995
15:80180219:C:G	S352R	0.995
15:80181126:T:C	F383L	0.995
15:80181128:T:A	F383L	0.995
15:80181128:T:G	F383L	0.995
15:80162259:C:A	D126E	0.994
15:80162259:C:G	D126E	0.994
15:80172238:C:A	N232K	0.994

dbSNP variants (sampled 300 via entrez): RS1000029228 (15:80185434 C>T), RS1000108983 (15:80154424 G>A,T), RS1000162073 (15:80170832 A>C,G), RS1000181141 (15:80152963 G>A,C), RS1000349426 (15:80175705 C>T), RS1000392145 (15:80175660 G>A,T), RS1000452037 (15:80181109 A>G), RS1000543874 (15:80179319 T>C), RS1000613767 (15:80174266 C>G,T), RS1000739982 (15:80168709 G>A,T), RS1000876731 (15:80151370 AGGG>A,AGG,AGGGG), RS1000879088 (15:80160247 T>C,G), RS1000934370 (15:80159964 G>A,T), RS1001041948 (15:80166723 G>A), RS1001043619 (15:80184588 C>G,T)

Disease associations

OMIM: gene MIM:613871 | disease phenotypes: MIM:276700, MIM:276200, MIM:276600, MIM:248510

GenCC curated gene-disease

Disease	Classification	Inheritance
tyrosinemia type I	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
tyrosinemia type I	Definitive	AR

Mondo (6): tyrosinemia type I (MONDO:0010161), tyrosinemia (MONDO:0004741), hepatoblastoma (MONDO:0018666), T-substance anomaly (MONDO:0010158), tyrosinemia type II (MONDO:0010160), beta-mannosidosis (MONDO:0009562)

Orphanet (4): Tyrosinemia type 1 (Orphanet:882), Hepatoblastoma (Orphanet:449), Tyrosinemia type 2 (Orphanet:28378), Beta-mannosidosis (Orphanet:118)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000096	Glomerular sclerosis
HP:0000105	Enlarged kidney
HP:0000121	Nephrocalcinosis
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001402	Hepatocellular carcinoma
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001541	Ascites
HP:0001639	Hypertrophic cardiomyopathy
HP:0001744	Splenomegaly
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001945	Fever
HP:0001994	Renal Fanconi syndrome
HP:0002239	Gastrointestinal hemorrhage
HP:0002240	Hepatomegaly
HP:0002249	Melena
HP:0002572	Episodic vomiting
HP:0002590	Paralytic ileus
HP:0002909	Generalized aminoaciduria
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003163	Elevated urinary delta-aminolevulinic acid
HP:0003231	Hypertyrosinemia
HP:0003235	Hypermethioninemia
HP:0003645	Prolonged partial thromboplastin time
HP:0003768	Periodic paralysis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1572	Blood protein levels	4.000000e-75

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D018197	Hepatoblastoma	C04.557.435.380
D020176	Tyrosinemias	C10.228.140.163.100.875; C16.320.565.100.880; C16.320.565.189.875; C18.452.132.100.875; C18.452.648.100.880; C18.452.648.189.875
D044905	beta-Mannosidosis	C16.320.565.202.607.750; C16.320.565.595.577.750; C18.452.648.202.607.750; C18.452.648.595.577.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066391 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.56	Kd	27.49	nM	CHEMBL5653589
7.56	ED50	27.49	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148358: Binding affinity to human FAH incubated for 45 mins by Kinobead based pull down assay	kd	0.0275	uM

CTD chemical–gene interactions

83 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	10
Benzo(a)pyrene	decreases expression, increases expression, affects cotreatment	5
Cyclosporine	decreases expression	4
perfluorooctane sulfonic acid	increases expression	3
Aflatoxin B1	affects expression, decreases methylation, increases methylation	3
bisphenol A	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
perfluorodecanesulfonic acid	increases expression	1
bufotalin	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenate	decreases expression	1
ascorbate-2-phosphate	affects cotreatment, increases expression, affects binding	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tetrahydropalmatine	decreases expression	1
diethyl maleate	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651400	Binding	Binding affinity to human FAH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

13 cell lines: 11 induced pluripotent stem cell, 1 cancer cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C361	TYR1-hiPSC1	Induced pluripotent stem cell	Female
CVCL_C362	TYR1-hiPSC2	Induced pluripotent stem cell	Female
CVCL_C363	TYR1-hiPSC3	Induced pluripotent stem cell	Female
CVCL_C364	TYR1-hiPSC4	Induced pluripotent stem cell	Female
CVCL_C365	TYR1-hiPSC5	Induced pluripotent stem cell	Female
CVCL_C366	TYR1-hiPSC6	Induced pluripotent stem cell	Female
CVCL_C367	TYR1-hiPSC7	Induced pluripotent stem cell	Female
CVCL_E0U5	Ubigene Hep G2 FAH KO	Cancer cell line	Male
CVCL_L937	GM00286	Finite cell line	Male
CVCL_WV77	HT patient 1 line 1	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

69 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT03017326	PHASE3	ACTIVE_NOT_RECRUITING	Paediatric Hepatic International Tumour Trial
NCT03533582	PHASE3	ACTIVE_NOT_RECRUITING	Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
NCT04478292	PHASE3	RECRUITING	A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy
NCT00004333	PHASE2	COMPLETED	Phase II Study of the Enzyme Inhibitor NTBC for Tyrosinemia Type I
NCT01154816	PHASE2	COMPLETED	Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia
NCT02011126	PHASE2	WITHDRAWN	Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT05302921	PHASE2	COMPLETED	Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors
NCT06638931	PHASE2	RECRUITING	Agnostic Therapy in Rare Solid Tumors
NCT07300449	PHASE2	RECRUITING	A Prospective Multicenter Clinical Study of SCCG Protocol and ctDNA 5hmc in Predicting the Chemotherapy Sensitivity and Monitoring the Recurrence and Metastasis of Hepatoblastoma in Children and Adolescents
NCT01331135	PHASE1	COMPLETED	Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
NCT02390843	PHASE1	COMPLETED	Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors
NCT03618381	PHASE1	ACTIVE_NOT_RECRUITING	EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04093648	PHASE1	WITHDRAWN	T Cells co- Expressing a Second Generation Glypican 3-specific Chimeric Antigen Receptor With Cytokines Interleukin-21 and 15 as Immunotherapy for Patients With Liver Cancer (TEGAR)
NCT04308330	PHASE1	RECRUITING	Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies
NCT04337177	PHASE1	ACTIVE_NOT_RECRUITING	Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors
NCT04483778	PHASE1	ACTIVE_NOT_RECRUITING	B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04897321	PHASE1	RECRUITING	B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)
NCT06198296	PHASE1	RECRUITING	Immunotherapy For Adults With GPC3-Positive Solid Tumors Using IL-15 and IL-21 Armored GPC3-CAR T Cells
NCT07148050	PHASE1	RECRUITING	Immunotherapy for Solid Tumor Malignancies in Pediatrics Using Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor T Cells
NCT03284658	Not specified	WITHDRAWN	Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 (BioTyrosin)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04196959	Not specified	COMPLETED	Evaluation of TYR Sphere
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies
NCT04761588	Not specified	COMPLETED	Evaluation of TYR Sphere in France