PRPS1

Chr XXLRX-linked

phosphoribosyl pyrophosphate synthetase 1

Also known as: ARTS, CMTX5, DFN2, DFNX1, PPRibP, PRS-I, PRSI

NCBI Gene: 5631 ENSG00000147224 UniProt: P60891 OMIM: 311850

The PRPS1 protein catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP), which is essential for nucleotide synthesis and purine metabolism. Mutations cause a spectrum of X-linked disorders including Arts syndrome (severe intellectual disability, sensorineural hearing loss, and ataxia), X-linked Charcot-Marie-Tooth disease type 5, X-linked deafness, and PRPS-related gout. This gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.38) and follows X-linked inheritance patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme that catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for purine metabolism and nucleotide biosynthesis. Defects in this gene are a cause of phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive type 5 and Arts Syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismXLR/X-linkedLOEUF 0.385 OMIM phenotypes

Clinical Summary— PRPS1

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Gene-Disease Validity (ClinGen)

phosphoribosylpyrophosphate synthetase superactivity · XLLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

31 unique Pathogenic / Likely Pathogenic· 121 VUS of 411 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRPS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.38LOEUF

pLI 0.915

Z-score 2.61

OE 0.00 (0.00–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.73Z-score

OE missense 0.08 (0.05–0.13)

10 obs / 129.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.38)

0≤0.351.4

Missense OE?0.08 (0.05–0.13)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 0 / 7.9Missense obs/exp: 10 / 129.5Syn Z: 0.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePRPS1-related deafnessOTHERXLR

definitivePRPS1-related retinal dystrophyOTHERmonoallelic_X_heterozygous

definitivePRPS1-related Arts syndromeLOFXLR

definitivePRPS1-related phosphoribosylpyrophosphate synthetase superactivityGOFXLR

definitivePRPS1-related Charcot-Marie-Tooth diseaseLOFXLR

This gene — mechanism propensity

0.4388th %ile

GOF

0.4973th %ile

LOF

0.67top 25%

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

LOFprediction above median · 16% of P/LP variants are LoF · LOEUF 0.38

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

411 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic20

VUS121

Likely Benign156

Benign20

Conflicting6

Pathogenic

Likely Pathogenic

121

VUS

156

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	7	0	0	11
Likely Pathogenic	1	19	0	0	20
VUS	4	94	23	0	121
Likely Benign	0	1	57	98	156
Benign	0	0	16	4	20
Conflicting	—				6
Total	9	121	96	102	334

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

View in ClinVar →

87 pathogenic / likely-pathogenic (of 98) ClinVar copy-number / structural variants overlap PRPS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →