HPRT1

Chr X

hypoxanthine phosphoribosyltransferase 1

Also known as: HGPRT, HPRT

NCBI Gene: 3251 ENSG00000165704 UniProt: P00492

The protein catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate, playing a central role in purine nucleotide generation through the purine salvage pathway. Mutations cause Lesch-Nyhan syndrome (characterized by neurologic dysfunction, cognitive impairment, and self-injurious behavior) or HPRT-related hyperuricemia with gout, following X-linked recessive inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.94, LOEUF 0.34), reflecting its essential cellular function.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a transferase, which catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate. This enzyme plays a central role in the generation of purine nucleotides through the purine salvage pathway. Mutations in this gene result in Lesch-Nyhan syndrome or gout.[provided by RefSeq, Jun 2009]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.34

Clinical Summary— HPRT1

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Gene-Disease Validity (ClinGen)

Lesch-Nyhan syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

104 unique Pathogenic / Likely Pathogenic· 59 VUS of 320 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HPRT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.937

Z-score 2.75

OE 0.00 (0.00–0.34)

Highly constrained

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

Missense Constraint?

2.32Z-score

OE missense 0.26 (0.18–0.38)

20 obs / 77.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.34)

0≤0.351.4

Missense OE?0.26 (0.18–0.38)

0≤0.61.4

Synonymous OE?0.59

0≤1.21.6

LoF obs/exp: 0 / 8.8Missense obs/exp: 20 / 77.4Syn Z: 1.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHPRT1-related Lesch-Nyhan syndromeLOFXLR

This gene — mechanism propensity

0.2997th %ile

GOF

0.3689th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 44% of P/LP variants are LoF · LOEUF 0.34 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

320 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic73

Likely Pathogenic31

VUS59

Likely Benign83

Benign20

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	21	15	0	73
Likely Pathogenic	9	19	3	0	31
VUS	4	47	7	1	59
Likely Benign	0	1	53	29	83
Benign	0	0	16	4	20
Conflicting	—				4
Total	50	88	94	34	270

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

View in ClinVar →

98 pathogenic / likely-pathogenic (of 108) ClinVar copy-number / structural variants overlap HPRT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →