GeneBe

FAH

protein-coding

fumarylacetoacetate hydrolase

Gene summary

Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; L-tyrosine catabolic process; and homogentisate catabolic process. Predicted to act upstream of or within L-arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_000137.4

Inheritance

AR

ClinVar variants

P:203U:201B:209

Top phenotype

Tyrosinemia, type I

gnomAD constraint

pLI —, LoF o/e 1.01

Max pathogenic AF

—

Genomic locus

chr15:80,152,490-80,186,946

External References & Databases

Ensembl (ENSG00000103876)NCBI Gene (2184)OMIM (613871)HGNC:3579GenCCUniProt (P16930)AlphaFoldClinVar (FAH)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~34.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tyrosinemia type ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: PanelApp Australia

tyrosinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: Myriad Women's Health

tyrosinemia type ISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: Orphanet

tyrosinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: ClinGen

FAH was first reported in relation to autosomal recessive Tyrosinemia Type I in 1992 (Phaneuf et al. PMID: 1401056). At least 84 variants (including many missense, nonsense and splicing defects, as well as deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 16 probands in 5 publications (PMIDs: 22884142, 8318997, 7550234, 7942842, 8162054). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Summary of Experimental Evidence: 5 POINTS The gene-disease association is supported by the biochemical function of FAH, which catalyzes the cleavage of fumarylacetoacetate to fumarate and acetoacetate (PMID: 7296877); its absence results in the accumulation of fumarylacetoacetate and maleylacetoacetate, which are alkylating agents presumed responsible for the liver damage observed in Tyrosinemia Type I. Expression of FAH occurs primarily in the liver (and to a lesser degree kidneys and adrenals), which is the primary organ system affected by Tyrosinemia I, and is absent or reduced in acute and chronic patients respectively (PMID: 2378356). Mouse models have been generated both by targeted disruption of FAH and ENU-induced mutation (PMIDs: 8253378, 1129059). Both of these mouse models have been rescued by a variety of methods, including adenoviral vectors to introduce the human FAH gene and CRISPR to correct the mouse gene (PMIDs: 9095403, 26829318). In summary, FAH is definitively associated with autosomal recessive Tyrosinemia Type I. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

tyrosinemia type ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: Labcorp Genetics (formerly Invitae)

tyrosinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: Natera

tyrosinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: Ambry Genetics

tyrosinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: G2P

tyrosinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010161

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Tyrosinemia, type IAR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Oncologic; Renal

Intervention: Biochemical; Oncologic

Rationale: Dietary (controlled intake of phenylalanine and tyrosine) and medical (eg, nitsinone) treatment can be beneficial, and may reduce risks related to manifestations (eg, hepatocellular carcinoma) that are part of the natural history in untreated individuals; Some individuals require liver transplantation

Refs: 14085846; 14271358; 6016174; 2536631; 2153931; 2378357; 1383656; 1440864; 8028615; 7977370; 7603784; 8829657; 9101289; 9728331; 10603099; 11575602; 12203990; 15759101; 20301688; 22554029Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FAH variants in ClinVar

17 Conditions Cataloged
Tyrosinemia type ITotal: 761
not providedTotal: 120
FAH-related disorderTotal: 90
not specifiedTotal: 69
Inborn genetic diseasesTotal: 45
FAH-related disordersTotal: 13
TyrosinemiaTotal: 3
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000137.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
11
clinvar
192
clinvar
4
clinvar
 208
missense
7
clinvar
37
clinvar
187
clinvar
12
clinvar
1
clinvar
 244
nonsense
21
clinvar
20
clinvar
1
clinvar
 42
start loss
2
clinvar
3
clinvar
 5
frameshift
25
clinvar
31
clinvar
1
clinvar
 57
splice donor/acceptor (+/-2bp)
11
clinvar
45
clinvar
1
clinvar
 57
Total661372012045613

Highest pathogenic variant AF is 0.00037998284

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000137.4RefSeqNP_000128.114MANE Select
ENST00000561421.6EnsemblENSP00000453347.214MANE Select
NM_001374377.1RefSeqNP_001361306.114Standard
NM_001374380.1RefSeqNP_001361309.114Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Tyrosine metabolism - Homo sapiens (human)
  • Tyrosinemia, transient, of the newborn
  • Dopamine beta-hydroxylase deficiency
  • Disulfiram Action Pathway
  • Phenylalanine and Tyrosine Metabolism

Biological Process

  • arginine catabolic process
  • L-phenylalanine catabolic process
  • tyrosine catabolic process
  • homogentisate catabolic process

Molecular Function

  • fumarylacetoacetase activity
  • protein binding
  • metal ion binding

Cellular Component

  • cytosol
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000407106
Coding exons
14
Length
34457
Individuals with no LoFs
125619
Homozygous LoFs
0
Heterozygous LoFs
129
Defined
125748
p
0.000513
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.03292442431.010.00001432765
Missense (PolyPhen)8897.4010.903481110
Synonymous-0.61310496.31.080.00000645806
Loss of Function-0.05812524.71.010.00000128268

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000490.00049rare
Latino/Admixed American0.000610.00061rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.000750.00074rare
European (Non-Finnish)0.000660.00066rare
South Asian0.000230.00023rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec
0.243

Intolerance Scores

LoFtool
0.239
RVIS EVS
-0.91
RVIS percentile EVS
10.03

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.981

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.