FAR1

Chr 11ADAR

fatty acyl-CoA reductase 1

Also known as: CSPSD, MLSTD2, PFCRD, SDR10E1

NCBI Gene: 84188 ENSG00000197601 UniProt: Q8WVX9 OMIM: 616107

This peroxisomal membrane protein catalyzes the reduction of fatty acyl-CoA to fatty alcohols, which are essential substrates for synthesizing ether lipids and plasmalogens. Mutations cause a spectrum of neurological disorders including severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spastic paraparesis. The condition follows both autosomal dominant and autosomal recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cataracts, spastic paraparesis, and speech delayMIM #619338

Peroxisomal fatty acyl-CoA reductase 1 disorderMIM #616154

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.30LOEUF

pLI 0.985

Z-score 4.18

OE 0.12 (0.05–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.30Z-score

OE missense 0.44 (0.38–0.52)

124 obs / 279.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.12 (0.05–0.30)

0≤0.351.4

Missense OE?0.44 (0.38–0.52)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 3 / 26.0Missense obs/exp: 124 / 279.4Syn Z: 0.53

Background carrier burden — how many people carry a rare variant somewhere in FAR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 270

404 rare PASS variants

Rare truncating (LoF)

1 in 6,600

53 rare PASS variants

Rare synonymous (reference)

1 in 150

221 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FAR1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 270	1 in 8,400
South Asian	~43k	1 in 180	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 190	≈ 1 in 7,400
European (Finnish)	~27k	1 in 380	≈ 1 in 13,000
Admixed American	~22k	1 in 150	≈ 1 in 11,000
African / African American	~21k	1 in 140	≈ 1 in 6,900
East Asian	~20k	1 in 240	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 360	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 11 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 11.? see exons ↓