PPIL3

Chr 2

peptidylprolyl isomerase like 3

Also known as: CYPJ

NCBI Gene: 53938 ENSG00000240344 UniProt: Q9H2H8 OMIM: 615811

The protein is a peptidylprolyl isomerase that catalyzes cis-trans isomerization of proline bonds in peptides and accelerates protein folding, with potential involvement in pre-mRNA splicing. Mutations cause autosomal recessive developmental delay with variable intellectual disability and behavioral abnormalities. This gene is highly constrained against loss-of-function variants, suggesting that complete loss of protein function is poorly tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the cyclophilin family. Cyclophilins catalyze the cis-trans isomerization of peptidylprolyl imide bonds in oligopeptides. They have been proposed to act either as catalysts or as molecular chaperones in protein-folding events. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.40

Clinical Summary— PPIL3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

16 VUS of 31 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.40LOEUF

pLI 0.902

Z-score 2.54

OE 0.00 (0.00–0.40)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.15Z-score

OE missense 0.95 (0.78–1.17)

66 obs / 69.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.40)

0≤0.351.4

Missense OE?0.95 (0.78–1.17)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 7.5Missense obs/exp: 66 / 69.5Syn Z: -0.31

This gene — mechanism propensity

0.6648th %ile

GOF

0.73top 25%

LOF

0.4430th %ile

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

GOFprediction above median

DNprediction above median

LOFLOEUF 0.40

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

31 submitted variants in ClinVar

ClinVar

Classification Summary

VUS16

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	16	16
Likely Benign	1	1
Benign	0	0
Total	17	17

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap PPIL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →