PDE5A

Chr 4

phosphodiesterase 5A

Also known as: CGB-PDE, CN5A, PDE5

NCBI Gene: 8654ENSG00000138735UniProt: O76074

The protein specifically hydrolyzes cGMP to 5'-GMP and regulates nitric oxide-generated cGMP, which is important for smooth muscle relaxation in the cardiovascular system. Mutations cause autosomal dominant arterial calcification due to deficiency of CD73 (ACDC), a vascular disorder characterized by calcification of arteries. The gene is highly constrained against loss-of-function variants (pLI ~0, LOEUF 0.51), suggesting intolerance to complete protein loss.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
42
Pubs (1 yr)
22
P/LP submissions
0%
P/LP missense
0.51
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— PDE5A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
22 unique Pathogenic / Likely Pathogenic· 94 VUS of 165 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.51LOEUF
pLI 0.000
Z-score 4.25
OE 0.34 (0.23–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.10Z-score
OE missense 0.72 (0.66–0.79)
327 obs / 452.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.34 (0.23–0.51)
0≤0.351.4
Missense OE0.72 (0.66–0.79)
0≤0.61.4
Synonymous OE0.86
0≤1.21.6
LoF obs/exp: 16 / 47.6Missense obs/exp: 327 / 452.9Syn Z: 1.33
DN
0.6842th %ile
GOF
0.74top 25%
LOF
0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

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

165 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic2
VUS94
Likely Benign14
Benign6
20
Pathogenic
2
Likely Pathogenic
94
VUS
14
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
0
0
2
0
2
VUS
0
88
6
0
94
Likely Benign
0
5
4
5
14
Benign
1
2
0
3
6
Total195328136

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

View in ClinVar →

Protein Context — Lollipop Plot

PDE5A · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients