PDE5A

Chr 4

phosphodiesterase 5A

Also known as: CGB-PDE, CN5A, PDE5

NCBI Gene: 8654 ENSG00000138735 UniProt: O76074 OMIM: 603310

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.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a cGMP-binding, cGMP-specific phosphodiesterase, a member of the cyclic nucleotide phosphodiesterase family. This phosphodiesterase specifically hydrolyzes cGMP to 5'-GMP. It is involved in the regulation of intracellular concentrations of cyclic nucleotides and is important for smooth muscle relaxation in the cardiovascular system. Alternative splicing of this gene results in three transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

Multiple*

Mechanism· predicted

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 OE?0.34 (0.23–0.51)

0≤0.351.4

Missense OE?0.72 (0.66–0.79)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 16 / 47.6Missense obs/exp: 327 / 452.9Syn Z: 1.33

Background carrier burden — how many people carry a rare variant somewhere in PDE5A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 60

938 rare PASS variants

Rare truncating (LoF)

1 in 590

159 rare PASS variants

Rare synonymous (reference)

1 in 140

354 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PDE5A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.