FAR1
protein-codingfatty acyl-CoA reductase 1, the group of Short chain dehydrogenase/reductase superfamily
Gene summary
The protein encoded by this gene is required for the reduction of fatty acids to fatty alcohols, a process that is required for the synthesis of monoesters and ether lipids. NADPH is required as a cofactor in this reaction, and 16-18 carbon saturated and unsaturated fatty acids are the preferred substrate. This is a peroxisomal membrane protein, and studies suggest that the N-terminus contains a large catalytic domain located on the outside of the peroxisome, while the C-terminus is exposed to the matrix of the peroxisome. Studies indicate that the regulation of this protein is dependent on plasmalogen levels. Mutations in this gene have been associated with individuals affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity (PMID: 25439727). A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Jan 2015]
- MLSTD2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~63.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014510
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0036212
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014510
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014510
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100230
Submitter: ClinGen
The relationship between FAR1 and FAR1 Upregulation, a newly described autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2021. FAR1 encodes a peroxisomal membrane protein that is required for the reduction of fatty acids to fatty alcohols. The disorder is characterized by spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia (PMID: 33239752). The clinical phenotypes seen in affected individuals overlap with those of the autosomal recessive condition, FAR1 deficiency, caused by biallelic variants in FAR1. However, the biochemical phenotypes are in contrast - while FAR1 deficiency is associated with plasmalogen deficiency, FAR1 upregulation is characterized by elevated plasmalogen levels. FAR1 protein levels are subject to plasmalogen-dependent feedback regulation (PMID: 33239752). FAR1 was first reported in relation to autosomal dominant FAR1 Upregulation in 2020 (Ferdinandusseet al, 2020; PMID: 33239752), and so far this is the only report. Variants in this gene that cause FAR1 upregulation (n = 3) all affect the same residue (Arg480) and arise de novo. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (9.2 points): Eighteen unrelated patients from around the world in 1 publication (PMID: 33239752, 37335441, 39074165, 36781603) have been reported with de novo heterozygous variants in FAR1. Of note, all variants reported involve the same codon - Arg480. The mechanism is reported to be gain of function (PMID: 33239752). Summary of experimental data (1 point): FAR1 has a functional role in plasmalogen synthesis as outlined in PMIDs: 15220348 and 24108123. In summary, the evidence to support the gene-disease relationship of FAR1 and FAR1 upregulation is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal GCEP on January 12, 2023. It was reevaluated on June 6, 2025 (SOP v 10). Although additional cases were published (PMIDs: 37335441, 39074165, 36781603), the classification did not change. Lumping and Splitting Considerations: OMIM entities: Cataracts, spastic paraparesis, and speech delay (MIM# 619338), Peroxisomal fatty acyl-CoA reductase 1 disorder (MIM# 616154). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns AND phenotypic presentation. Therefore, we have split curations for the disease entities, FAR1 deficiency and FAR1 upregulation (terms introduced by the peroxisomal GCEP).
Inheritance Pattern: AR
Disease ID:MONDO:0014510
Submitter: ClinGen
*FAR1* was first reported in relation to autosomal recessive fatty acyl-CoA reductase 1 deficiency in 2014 (Buchert et al., PMID: 25439727). 2 nonsense, 1 missense, and 1 in-frame delins variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case level and experimental data: 6.5 points. Variants in this gene have been reported in at least 3 probands in 2 publications (PMID: 25439727, 33586168). The mechanism for disease is loss of function. This gene-disease association is supported by in vitro functional assays and a knock-out mouse model (PMID: 15220348, 24108123, 36781603). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by thePeroxisomal GCEP on Jan 12, 2023. It was reevaluated on June 6, 2025 (SOP v 10). Although a new animal model was published (PMID: 36781603), the classification did not change. Lumping and Splitting Considerations: OMIM entities: Cataracts, spastic paraparesis, and speech delay (MIM# 619338), Peroxisomal fatty acyl-CoA reductase 1 disorder (MIM# 616154). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns AND phenotypic presentation. Therefore, we have split curations for the disease entities, FAR1 deficiency and FAR1 dysregulation (terms introduced by the peroxisomal GCEP).
Inheritance Pattern: AD
Disease ID:MONDO:0100230
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014510
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014510
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FAR1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032228.6. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 104 | 110 | |||
| missense | 2 | 4 | 176 | 4 | 186 | |
| nonsense | 4 | 1 | 5 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | 6 | ||
| Total | 8 | 7 | 187 | 108 | 0 | 310 |
Highest pathogenic variant AF is 0.00000434331
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_115604.1 | 11 | MANE Select | |
| Ensembl | ENSP00000346874.3 | 11 | MANE Select | |
| RefSeq | NP_001428171.1 | 11 | Standard | |
| RefSeq | NP_001428172.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Peroxisome - Homo sapiens (human)
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
- Metabolism of lipids
Biological Process
- ether lipid biosynthetic process
- wax biosynthetic process
- long-chain fatty-acyl-CoA metabolic process
- glycerophospholipid biosynthetic process
- oxidation-reduction process
Molecular Function
- oxidoreductase activity
- fatty-acyl-CoA reductase (alcohol-forming) activity
- alcohol-forming fatty acyl-CoA reductase activity
Cellular Component
- peroxisome
- peroxisomal membrane
- integral component of peroxisomal membrane
- peroxisomal matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354817
- Coding exons
- 11
- Length
- 63677
- Individuals with no LoFs
- 125631
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125635
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.30 | 124 | 279 | 0.444 | 0.0000145 | 3395 |
| Missense (PolyPhen) | 9 | 55.962 | 0.16082 | 714 | ||
| Synonymous | 0.534 | 89 | 95.6 | 0.931 | 0.00000496 | 958 |
| Loss of Function | 4.18 | 3 | 26.0 | 0.116 | 0.00000133 | 315 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000034 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the reduction of saturated and unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols (PubMed:15220348, PubMed:24108123). It plays an essential role in the production of ether lipids/plasmalogens which synthesis requires fatty alcohols (PubMed:20071337, PubMed:24108123). In parallel, it is also required for wax monoesters production since fatty alcohols also constitute a substrate for their synthesis (By similarity). {ECO:0000250|UniProtKB:Q922J9, ECO:0000269|PubMed:15220348, ECO:0000269|PubMed:20071337, ECO:0000269|PubMed:24108123}.;
- Disease
- DISEASE: Peroxisomal fatty acyl-CoA reductase 1 disorder (PFCRD) [MIM:616154]: An autosomal recessive metabolic disorder clinically characterized by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity. {ECO:0000269|PubMed:25439727}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.107
Intolerance Scores
- LoFtool
- 0.345
- RVIS EVS
- -0.21
- RVIS percentile EVS
- 38.58
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.843
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |