GPX4

Chr 19

glutathione peroxidase 4

Also known as: GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx, snPHGPx

NCBI Gene: 2879 ENSG00000167468 UniProt: P36969

The protein is an essential antioxidant peroxidase that directly reduces phospholipid hydroperoxides in membranes and lipoproteins, protecting cells from oxidative damage and preventing ferroptosis (iron-dependent cell death). Mutations cause spondylometaphyseal dysplasia, Sedaghatian type, a severe skeletal dysplasia with autosomal recessive inheritance. This gene shows minimal constraint against loss-of-function variants (pLI 0.00005, LOEUF 1.28), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme has a high preference for lipid hydroperoxides and protects cells against membrane lipid peroxidation and cell death. It is also required for normal sperm development; thus, it has been identified as a 'moonlighting' protein because of its ability to serve dual functions as a peroxidase, as well as a structural protein in mature spermatozoa. Mutations in this gene are associated with Sedaghatian type of spondylometaphyseal dysplasia (SMDS). This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Transcript variants resulting from alternative splicing or use of alternate promoters have been described to encode isoforms with different subcellular localization. [provided by RefSeq, Dec 2018]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtSpondylometaphyseal dysplasia, Sedaghatian type

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

5429

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

—

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (2)

gnomad: Error: gnomAD API error: 400

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in GPX4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

673 rare PASS variants

Rare truncating (LoF)

1 in 580

133 rare PASS variants

Rare synonymous (reference)

1 in 320

194 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GPX4. 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 88	1 in 900
South Asian	~43k	1 in 47	1 in 1,500
Remaining (unassigned)	~30k	1 in 53	1 in 420
European (Finnish)	~26k	1 in 250	1 in 300
Admixed American	~22k	1 in 64	1 in 1,100
African / African American	~21k	1 in 59	1 in 430
East Asian	~20k	1 in 70	1 in 690
Ashkenazi Jewish	~13k	1 in 520	none seen
Middle Eastern	~2,884	1 in 53	1 in 270

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.