Phosphoribosylpyrophosphate synthetase superactivity

Summary

Phosphoribosylpyrophosphate synthetase superactivity (MONDO:0010395) is a disease caused by PRPS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRPS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 46
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0002149	Hyperuricemia	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001679	Abnormal aortic morphology	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	phosphoribosylpyrophosphate synthetase superactivity
Mondo ID	MONDO:0010395
MeSH	C567064
OMIM	300661
Orphanet	3222
DOID	DOID:0111260
SNOMED CT	723454008
UMLS	C1970827
MedGen	370358
GARD	0004337
Is cancer (heuristic)	no

Also known as: gout, PRPS-related, X-linked recessive · phosphoribosylpyrophosphate synthetase superactivity · phosphoribosylpyrophosphate synthetase superactivity, X-linked recessive · PRPP synthetase superactivity · PRPS1 superactivity

Data availability: 46 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of purine or pyrimidine metabolism › inborn disorder of purine metabolism › phosphoribosylpyrophosphate synthetase superactivity

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, adenylosuccinate lyase deficiency, familial juvenile hyperuricemic nephropathy type 1, mitochondrial DNA depletion syndrome 3 (hepatocerebral type), Charcot-Marie-Tooth disease X-linked recessive 5, AICA-ribosiduria, adenosine monophosphate deaminase deficiency, purine nucleoside phosphorylase deficiency, adenine phosphoribosyltransferase deficiency, developmental and epileptic encephalopathy, 35, hypoxanthine-guanine phosphoribosyltransferase deficiency, hereditary xanthinuria, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, hemolytic anemia due to erythrocyte adenosine deaminase overproduction, PAICS deficiency

Subtypes (2): mild phosphoribosylpyrophosphate synthetase superactivity, severe phosphoribosylpyrophosphate synthetase superactivity

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

46 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 9 benign/likely benign, 6 likely pathogenic, 4 pathogenic, 3 benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
446163	NM_002764.4(PRPS1):c.640C>T (p.Arg214Trp)	PRPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9930	NM_002764.4(PRPS1):c.154G>C (p.Asp52His)	PRPS1	Pathogenic	no assertion criteria provided
9931	NM_002764.4(PRPS1):c.385C>A (p.Leu129Ile)	PRPS1	Pathogenic	no assertion criteria provided
9932	NM_002764.4(PRPS1):c.569C>T (p.Ala190Val)	PRPS1	Pathogenic	no assertion criteria provided
9933	NM_002764.4(PRPS1):c.579C>G (p.His193Gln)	PRPS1	Pathogenic	no assertion criteria provided
4540444	NM_002764.4(PRPS1):c.155A>C (p.Asp52Ala)	PRPS1	Likely pathogenic	criteria provided, single submitter
4813860	NM_002764.4(PRPS1):c.377C>T (p.Thr126Ile)	PRPS1	Likely pathogenic	criteria provided, single submitter
804069	NM_002764.4(PRPS1):c.359G>T (p.Gly120Val)	PRPS1	Likely pathogenic	criteria provided, single submitter
807472	NM_002764.4(PRPS1):c.433T>G (p.Leu145Val)	PRPS1	Likely pathogenic	criteria provided, single submitter
9928	NM_002764.4(PRPS1):c.341A>G (p.Asn114Ser)	PRPS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
9929	NM_002764.4(PRPS1):c.547G>C (p.Asp183His)	PRPS1	Likely pathogenic	criteria provided, single submitter
2170185	NM_002764.4(PRPS1):c.531-15C>A	PRPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912516	NM_002764.4(PRPS1):c.*539G>C	PRPS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057937	NM_002764.4(PRPS1):c.611G>A (p.Arg204His)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1320158	NM_002764.4(PRPS1):c.641G>A (p.Arg214Gln)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333893	NM_002764.4(PRPS1):c.497C>T (p.Thr166Ile)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356780	NM_002764.4(PRPS1):c.334G>A (p.Val112Ile)	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500350	NM_002764.4(PRPS1):c.755T>A (p.Ile252Asn)	PRPS1	Uncertain significance	criteria provided, single submitter
3597843	NM_002764.4(PRPS1):c.306+5G>T	PRPS1	Uncertain significance	criteria provided, single submitter
3597844	NM_002764.4(PRPS1):c.913A>G (p.Asn305Asp)	PRPS1	Uncertain significance	criteria provided, single submitter
367703	NM_002764.4(PRPS1):c.*88C>T	PRPS1	Uncertain significance	criteria provided, single submitter
367704	NM_002764.4(PRPS1):c.*159G>A	PRPS1	Uncertain significance	criteria provided, single submitter
367705	NM_002764.4(PRPS1):c.*166G>A	PRPS1	Uncertain significance	criteria provided, single submitter
367707	NM_002764.4(PRPS1):c.*389G>C	PRPS1	Uncertain significance	criteria provided, single submitter
367708	NM_002764.4(PRPS1):c.*538G>C	PRPS1	Uncertain significance	criteria provided, single submitter
367709	NM_002764.4(PRPS1):c.*538G>T	PRPS1	Uncertain significance	criteria provided, single submitter
367711	NM_002764.4(PRPS1):c.*762G>T	PRPS1	Uncertain significance	criteria provided, single submitter
912517	NM_002764.4(PRPS1):c.*539G>T	PRPS1	Uncertain significance	criteria provided, single submitter
912518	NM_002764.4(PRPS1):c.*608C>T	PRPS1	Uncertain significance	criteria provided, single submitter
913589	NM_002764.4(PRPS1):c.*389G>A	PRPS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PRPS1	Definitive	X-linked	phosphoribosylpyrophosphate synthetase superactivity	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRPS1	Orphanet:1187	Lethal ataxia with deafness and optic atrophy
PRPS1	Orphanet:411536	Mild phosphoribosylpyrophosphate synthetase superactivity
PRPS1	Orphanet:411543	Severe phosphoribosylpyrophosphate synthetase superactivity
PRPS1	Orphanet:423479	X-linked intellectual disability-limb spasticity-retinal dystrophy-arginine vasopressin deficiency
PRPS1	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
PRPS1	Orphanet:99014	X-linked Charcot-Marie-Tooth disease type 5

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRPS1	HGNC:9462	ENSG00000147224	P60891	Ribose-phosphate pyrophosphokinase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRPS1	Ribose-phosphate pyrophosphokinase 1	Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRPS1	Kinase	yes	2.7.6.1	PRTase_dom, PRib_PP_synth_CS, Rib-P_diPkinase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRPS1	291	ubiquitous	marker	islet of Langerhans, ventricular zone, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRPS1	881

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRPS1	P60891	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
5-Phosphoribose 1-diphosphate biosynthesis	1	3806.7×	3e-04	PRPS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hypoxanthine biosynthetic process	1	16852.0×	3e-04	PRPS1
pyrimidine nucleotide biosynthetic process	1	8426.0×	3e-04	PRPS1
urate biosynthetic process	1	8426.0×	3e-04	PRPS1
ribonucleoside monophosphate biosynthetic process	1	4213.0×	5e-04	PRPS1
5-phosphoribose 1-diphosphate biosynthetic process	1	3370.4×	5e-04	PRPS1
purine nucleobase metabolic process	1	2407.4×	6e-04	PRPS1
purine nucleotide biosynthetic process	1	1296.3×	9e-04	PRPS1
nervous system development	1	45.9×	0.022	PRPS1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRPS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRPS1	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRPS1	2.7.6.1	ribose-phosphate diphosphokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PRPS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PRPS1	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.