PRPS1

Chr XXLRX-linked

phosphoribosyl pyrophosphate synthetase 1

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

NCBI Gene: 5631ENSG00000147224UniProt: P60891

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]

Primary Disease Associations & Inheritance

Arts syndromeMIM #301835
XLR
Charcot-Marie-Tooth disease, X-linked recessive, 5MIM #311070
XLR
Deafness, X-linked 1MIM #304500
X-linked
Gout, PRPS-relatedMIM #300661
XLR
Phosphoribosylpyrophosphate synthetase superactivityMIM #300661
XLR
425
ClinVar variants
111
Pathogenic / LP
0.92
pLI score· haploinsufficient
0
Active trials
Clinical Summary— PRPS1
🧬
Gene-Disease Validity (ClinGen)
phosphoribosylpyrophosphate synthetase superactivity · XLLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
111 Pathogenic / Likely Pathogenic· 128 VUS of 425 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.08 (0.05–0.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91
0≤1.21.6
LoF obs/exp: 0 / 7.9Missense obs/exp: 10 / 129.5Syn Z: 0.48

ClinVar Variant Classifications

425 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic88
Likely Pathogenic23
VUS128
Likely Benign159
Benign20
Conflicting7
88
Pathogenic
23
Likely Pathogenic
128
VUS
159
Likely Benign
20
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
83
0
88
Likely Pathogenic
1
20
2
0
23
VUS
4
88
36
0
128
Likely Benign
0
1
58
100
159
Benign
0
0
16
4
20
Conflicting
—7
Total8111195104425

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

View in ClinVar →

Protein Context — Lollipop Plot

PRPS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PRPS1-related deafness

definitive
Monoallelic X HemizygousUndeterminedUncertain
Dev. DisordersEar
G2P ↗

PRPS1-related retinal dystrophy

definitive
Monoallelic X HeterozygousUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

PRPS1-related Arts syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

PRPS1-related phosphoribosylpyrophosphate synthetase superactivity

definitive
Monoallelic X HemizygousGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

PRPS1-related Charcot-Marie-Tooth disease

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Arts syndrome

MIM #301835

Molecular basis of disorder known

X-linked recessive

Charcot-Marie-Tooth disease, X-linked recessive, 5

MIM #311070

Molecular basis of disorder known

X-linked recessive

Deafness, X-linked 1

MIM #304500

Molecular basis of disorder known

X-linked

Gout, PRPS-related

MIM #300661

Molecular basis of disorder known

X-linked recessive

Phosphoribosylpyrophosphate synthetase superactivity

MIM #300661

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — PRPS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy.
Liu XZ et al.·Int J Audiol
2013Review
Nonsyndromic X-linked hearing loss.
Song MH et al.·Front Biosci (Elite Ed)
2012Review
Disorders of purine biosynthesis metabolism.
Dewulf JP et al.·Mol Genet Metab
2022Review
Identification and Functional Characterization of a Novel PRPS1 Variant in X-Linked Nonsyndromic Hearing Loss: Insights From Zebrafish and Cellular Models.
Wan Y et al.·Hum Mutat
2025Functional
PRPS1 mutations: four distinct syndromes and potential treatment.
de Brouwer AP et al.·Am J Hum Genet
2010Review
NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells.
Somazu S et al.·J Cell Mol Med
2021
PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review.
Mercati O et al.·Eur J Med Genet
2020Review
PRPS1-associated retinopathy: a diagnostic odyssey.
Alzahem TA et al.·Ophthalmic Genet
2024Case report
A novel mutation in gene of PRPS1 in a young Chinese woman with X-linked gout: a case report and review of the literature.
Yang BY et al.·Clin Rheumatol
2020Review
[PRPS1 Expression in Children with Acute Leukemia and Its Clinical Significance].
Ma YM et al.·Zhongguo Shi Yan Xue Ye Xue Za Zhi
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
Kim JH et al.·Int J Stem Cells
2026
In silico identification of deleterious NT5C2 and PRPS1 mutations driving thiopurine resistance in relapsed acute lymphoblastic leukemia.
Sharma R et al.·Cancer Genet
2026
CLOCK promotes proliferation of glioblastoma cells through acetylating PRPS1/2.
Liu J et al.·J Neurooncol
2025
Generation and Auditory Phenotypic Characterization of Prps1 p.Ala87Thr Mouse Knock-In Model for Human DFNX1 Deafness.
Yan D et al.·Clin Genet
2025🔓 Open AccessFunctional
NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma.
Xiong G et al.·Cell Death Differ
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools