PDE2A

Chr 11AR

phosphodiesterase 2A

Also known as: CGS-PDE, IDDPADS, PDE2A1, PED2A4, cGSPDE

NCBI Gene: 5138 ENSG00000186642 UniProt: O00408 OMIM: 602658

The protein functions as a cGMP-activated cyclic nucleotide phosphodiesterase that degrades both cGMP and cAMP second messengers, with higher efficiency for cGMP. Biallelic mutations cause intellectual developmental disorder with paroxysmal dyskinesia or seizures, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.348), indicating intolerance to protein-disrupting changes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables several functions, including 3',5'-cyclic-nucleotide phosphodiesterase activity; anion binding activity; and metal ion binding activity. Involved in several processes, including cellular response to cytokine stimulus; regulation of signal transduction; and regulation of vascular permeability. Located in several cellular components, including cytosol; mitochondrial membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.351 OMIM phenotype

Clinical Summary— PDE2A

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 149 VUS of 379 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.35LOEUF

pLI 0.631

Z-score 5.44

OE 0.21 (0.14–0.35)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.06Z-score

OE missense 0.51 (0.46–0.56)

271 obs / 535.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.21 (0.14–0.35)

0≤0.351.4

Missense OE?0.51 (0.46–0.56)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 12 / 55.9Missense obs/exp: 271 / 535.0Syn Z: 0.38

This gene — mechanism propensity

0.5279th %ile

GOF

0.6930th %ile

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF56% of P/LP variants are LoF · LOEUF 0.35

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

379 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic3

VUS149

Likely Benign170

Benign25

Conflicting2

Pathogenic

Likely Pathogenic

149

VUS

170

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	1	0	6
Likely Pathogenic	2	1	0	0	3
VUS	6	131	10	2	149
Likely Benign	0	4	75	91	170
Benign	0	2	16	7	25
Conflicting	—				2
Total	11	140	102	100	355

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap PDE2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →