PRPF3

Chr 1AD

pre-mRNA processing factor 3

Also known as: HPRP3, HPRP3P, PRP3, Prp3p, RP18, SNRNP90

NCBI Gene: 9129 ENSG00000117360 UniProt: O43395 OMIM: 607301

This gene encodes a protein that is an essential component of the U4/U6-U5 tri-snRNP complex required for pre-mRNA splicing and spliceosome assembly. Mutations cause autosomal dominant retinitis pigmentosa 18, a progressive retinal degeneration affecting vision. The gene is highly constrained against loss-of-function variants, indicating intolerance to functional disruption.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The removal of introns from nuclear pre-mRNAs occurs on complexes called spliceosomes, which are made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors. This gene product is one of several proteins that associate with U4 and U6 snRNPs. Mutations in this gene are associated with retinitis pigmentosa-18. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.071 OMIM phenotype

Clinical Summary— PRPF3

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Gene-Disease Validity (ClinGen)

retinitis pigmentosa 18 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 192 VUS of 447 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRPF3

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?

0.07LOEUF

pLI 1.000

Z-score 6.12

OE 0.00 (0.00–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.85Z-score

OE missense 0.44 (0.38–0.50)

160 obs / 367.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.07)

0≤0.351.4

Missense OE?0.44 (0.38–0.50)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 0 / 43.6Missense obs/exp: 160 / 367.6Syn Z: 0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePRPF3-related retinitis pigmentosaOTHERAD

This gene — mechanism propensity

0.4190th %ile

GOF

0.2795th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 33% of P/LP variants are LoF · LOEUF 0.07

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNWe delineate the correlation between specific PRPF31 genotype and RP phenotype, suggesting that, except in cases of complete gene deletion or large-scale deletions, dominant negative effects contribute to phenotype as well as haploinsufficiency.1

GOFThese models suggest that RP18 is not a result of haploinsufficiency but instead arises from a toxic gain of function caused by missense mutations in PRPF3.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

447 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic5

VUS192

Likely Benign167

Benign41

Conflicting13

Pathogenic

Likely Pathogenic

192

VUS

167

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	5	0	0	7
Likely Pathogenic	2	3	0	0	5
VUS	5	163	18	6	192
Likely Benign	0	5	69	93	167
Benign	1	1	35	4	41
Conflicting	—				13
Total	10	177	122	103	425

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap PRPF3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →