PRPSAP2

Chr 17

phosphoribosyl pyrophosphate synthetase associated protein 2

Also known as: PAP41

NCBI Gene: 5636 ENSG00000141127 UniProt: O60256 OMIM: 603762

The protein plays a negative regulatory role in 5-phosphoribose 1-diphosphate synthesis, a key step in purine and pyrimidine nucleotide biosynthesis. Mutations cause Arts syndrome, an X-linked disorder characterized by profound intellectual disability, early-onset sensorineural hearing loss, delayed growth, and increased susceptibility to infections. The gene shows tolerance to loss-of-function variants (pLI 0.003), which is consistent with X-linked inheritance where males are primarily affected.

OMIM ResearchSummary from UniProt

This gene encodes a protein that associates with the enzyme phosphoribosylpyrophosphate synthetase (PRS). PRS catalyzes the formation of phosphoribosylpyrophosphate which is a substrate for synthesis of purine and pyrimidine nucleotides, histidine, tryptophan and NAD. PRS exists as a complex with two catalytic subunits and two associated subunits. This gene encodes a non-catalytic associated subunit of PRS. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.77

Clinical Summary— PRPSAP2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

26 VUS of 42 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.003

Z-score 2.25

OE 0.41 (0.23–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.60Z-score

OE missense 0.50 (0.42–0.58)

106 obs / 212.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.41 (0.23–0.77)

0≤0.351.4

Missense OE?0.50 (0.42–0.58)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 7 / 17.0Missense obs/exp: 106 / 212.9Syn Z: 0.33

This gene — mechanism propensity

0.7326th %ile

GOF

0.6248th %ile

LOF

0.3162th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

ClinVar Variant Classifications

42 submitted variants in ClinVar

ClinVar

Classification Summary

VUS26

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	26	0	26
Likely Benign	0	1	1
Benign	0	0	0
Total	26	1	27

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 123) ClinVar copy-number / structural variants overlap PRPSAP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →