PDE8A

Chr 15

phosphodiesterase 8A

Also known as: HsT19550

NCBI Gene: 5151 ENSG00000073417 UniProt: O60658

PDE8A encodes a cyclic nucleotide phosphodiesterase that hydrolyzes cAMP, regulating cellular responses to extracellular signals and maintaining basal cAMP levels important for germ cell development. The gene is highly constrained against loss-of-function variants (LOEUF 0.532), but no definitive human disease phenotypes have been established from mutations in this gene. Clinical significance of PDE8A variants in pediatric neurological conditions remains to be determined.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE8 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

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

0.53

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.000

Z-score 4.00

OE 0.35 (0.23–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.10Z-score

OE missense 0.85 (0.78–0.93)

377 obs / 442.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.23–0.53)

0≤0.351.4

Missense OE?0.85 (0.78–0.93)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 15 / 43.4Missense obs/exp: 377 / 442.0Syn Z: 1.60

Background carrier burden — how many people carry a rare variant somewhere in PDE8A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

1,089 rare PASS variants

Rare truncating (LoF)

1 in 1,700

140 rare PASS variants

Rare synonymous (reference)

1 in 150

386 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PDE8A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 1,700
South Asian	~43k	1 in 48	1 in 1,200
Remaining (unassigned)	~30k	1 in 65	1 in 5,000
European (Finnish)	~27k	1 in 200	≈ 1 in 13,000
Admixed American	~22k	1 in 85	1 in 2,800
African / African American	~21k	1 in 66	1 in 900
East Asian	~20k	1 in 48	1 in 2,800
Ashkenazi Jewish	~13k	1 in 240	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 52	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 22 coding exons well covered in gnomAD exomes; exons 1, 2, 4, 5, 7 and 3 more marginal. Genomes: 21 of 22 (exon 20 below).? see exons ↓