PPARA

Chr 22

peroxisome proliferator activated receptor alpha

Also known as: NR1C1, PPAR, PPAR-alpha, PPARalpha, hPPAR

NCBI Gene: 5465 ENSG00000186951 UniProt: Q07869 OMIM: 170998

PPARA encodes a nuclear transcription factor that serves as a key regulator of lipid metabolism and the peroxisomal beta-oxidation pathway of fatty acids. Mutations cause autosomal recessive PPARA-related disorder, characterized by episodic myoglobinuria with or without motor neuropathy, typically presenting in childhood or adulthood during periods of metabolic stress. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Peroxisome proliferators include hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers; this term arises because they induce an increase in the size and number of peroxisomes. Peroxisomes are subcellular organelles found in plants and animals that contain enzymes for respiration and for cholesterol and lipid metabolism. The action of peroxisome proliferators is thought to be mediated via specific receptors, called PPARs, which belong to the steroid hormone receptor superfamily. PPARs affect the expression of target genes involved in cell proliferation, cell differentiation and in immune and inflammation responses. Three closely related subtypes (alpha, beta/delta, and gamma) have been identified. This gene encodes the subtype PPAR-alpha, which is a nuclear transcription factor. Multiple alternatively spliced transcript variants have been described for this gene, although the full-length nature of only two has been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

261

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.63

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.030

Z-score 2.73

OE 0.32 (0.17–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.81Z-score

OE missense 0.69 (0.62–0.78)

192 obs / 276.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.17–0.63)

0≤0.351.4

Missense OE?0.69 (0.62–0.78)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 6 / 18.7Missense obs/exp: 192 / 276.8Syn Z: -0.76

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

501 rare PASS variants

Rare truncating (LoF)

1 in 3,500

58 rare PASS variants

Rare synonymous (reference)

1 in 150

255 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPARA. 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 140	1 in 3,700
South Asian	~43k	1 in 100	1 in 4,800
Remaining (unassigned)	~30k	1 in 120	1 in 4,300
European (Finnish)	~27k	1 in 420	1 in 4,400
Admixed American	~22k	1 in 170	≈ 1 in 4,500
African / African American	~21k	1 in 160	≈ 1 in 4,900
East Asian	~20k	1 in 180	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 350	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 190	≈ 1 in 2,900

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): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓