PDE8A

Chr 15

phosphodiesterase 8A

Also known as: HsT19550

NCBI Gene: 5151 ENSG00000073417 UniProt: O60658 OMIM: 602972

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.53

Clinical Summary— PDE8A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

102 VUS of 132 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?

0.53LOEUF

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

This gene — mechanism propensity

0.7130th %ile

GOF

0.76top 25%

LOF

0.3161th %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

132 submitted variants in ClinVar

ClinVar

Classification Summary

VUS102

Likely Benign5

102

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	102	102
Likely Benign	5	5
Benign	0	0
Total	107	107

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 61) ClinVar copy-number / structural variants overlap PDE8A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →