HPRT1

Chr XXLR

hypoxanthine phosphoribosyltransferase 1

Also known as: HGPRT, HPRT

NCBI Gene: 3251 ENSG00000165704 UniProt: P00492 OMIM: 308000

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hyperuricemia, HPRT-relatedMIM #300323

XLR

Lesch-Nyhan syndromeMIM #300322

XLR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Lesch-Nyhan syndrome · XL · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.34

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — HPRT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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

Background carrier burden — how many people carry a rare variant somewhere in HPRT1?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 2,200

71 rare PASS variants

Rare truncating (LoF)

1 in 3,100

11 rare PASS variants

Rare synonymous (reference)

1 in 1,600

56 rare PASS variants

Rare missense and truncating variants are carried at similar rates in HPRT1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~559k	1 in 2,100	1 in 2,500
South Asian	~36k	1 in 2,100	none seen
Remaining (unassigned)	~31k	1 in 1,900	1 in 3,400
Admixed American	~23k	1 in 3,500	≈ 1 in 23,000
African / African American	~21k	1 in 2,900	1 in 3,200
East Asian	~20k	1 in 1,300	none seen
Ashkenazi Jewish	~13k	≈ 1 in 12,000	none seen
Middle Eastern	~2,753	≈ 1 in 2,700	≈ 1 in 1,300

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): 7 of 9 coding exons well covered in gnomAD exomes; exons 4, 5 marginal. Genomes: all 9.? see exons ↓