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

The protein encoded by this gene is a receptor for the xenotropic and polytropic classes of murine leukemia viruses. The encoded protein is involved in phosphate homeostasis by mediating phosphate export from the cell. Defects in this gene have been associated with idiopathic basal ganglia calcification-6. [provided by RefSeq, Jun 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 148 VUS of 333 total submissions

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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 OE?0.05 (0.02–0.16)

0≤0.351.4

Missense OE?0.55 (0.49–0.61)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

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

This gene — mechanism propensity

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 th1

LOFAdditionally, XPR1 deficiency seriously affected Pi efflux and XPR1 mutations seemed to have an effect through haploinsufficiency mechanism.2

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

References

ClinVar Variant Classifications

333 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS148

Likely Benign112

Benign50

Conflicting4

Pathogenic

Likely Pathogenic

148

VUS

112

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	1	2	0	0	3
VUS	7	128	9	4	148
Likely Benign	0	3	49	60	112
Benign	0	0	44	6	50
Conflicting	—				4
Total	8	137	102	70	321

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

28 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap XPR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →