XPR1

Chr 1AD

xenotropic and polytropic retrovirus receptor 1

Also known as: IBGC6, SLC53A1, SYG1, X3

NCBI Gene: 9213 ENSG00000143324 UniProt: Q9UBH6 OMIM: 605237

XPR1 encodes an inorganic phosphate transporter that mediates phosphate export across the plasma membrane, playing a major role in cellular phosphate homeostasis and preventing intracellular phosphate accumulation. Mutations cause autosomal dominant idiopathic basal ganglia calcification-6, which primarily affects the brain's basal ganglia structures. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.156), indicating intolerance to protein-truncating mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— XPR1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — XPR1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.16LOEUF

pLI 1.000

Z-score 5.60

OE 0.05 (0.02–0.16)

Highly constrained

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

Missense Constraint

3.23Z-score

OE missense 0.55 (0.49–0.61)

218 obs / 400.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.16)

0≤0.351.4

Missense OE0.55 (0.49–0.61)

0≤0.61.4

Synonymous OE0.92

0≤1.21.6

LoF obs/exp: 2 / 40.4Missense obs/exp: 218 / 400.0Syn Z: 0.72

0.4190th %ile

GOF

0.6248th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.16

DN1 literature citation

Literature Evidence

DNRemarkably, expression of Leu145Pro XPR1 specifically decreased the phosphate efflux of endogenous XPR1 (Fig. 1b), whereas we observed no effect on the expression of the phosphate importers PiT1 and PiT2 or on phosphate uptake (Supplementary Fig. 3), supporting a trans dominant-negative effect of thPMID:25938945

LOFAdditionally, XPR1 deficiency seriously affected Pi efflux and XPR1 mutations seemed to have an effect through haploinsufficiency mechanism.PMID:28766044

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.