PDE11A

Chr 2AD

phosphodiesterase 11A

Also known as: PPNAD2

NCBI Gene: 50940 ENSG00000128655 UniProt: Q9HCR9 OMIM: 604961

The 3',5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5'-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a member of the PDE protein superfamily. Mutations in this gene are a cause of Cushing disease and adrenocortical hyperplasia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.401 OMIM phenotype

Clinical Summary— PDE11A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 173 VUS of 277 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PDE11A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.40LOEUF

pLI 0.000

Z-score -0.72

OE 1.11 (0.89–1.40)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.00Z-score

OE missense 1.00 (0.93–1.08)

515 obs / 514.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.11 (0.89–1.40)

0≤0.351.4

Missense OE?1.00 (0.93–1.08)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 52 / 46.7Missense obs/exp: 515 / 514.7Syn Z: 0.44

This gene — mechanism propensity

0.7034th %ile

GOF

0.75top 25%

LOF

0.3941th %ile

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

LOF1 literature citation · 92% of P/LP variants are LoF

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.

Literature Evidence

LOFSince patients with PDE11A defects and Cushing syndrome have PDE11A haploinsufficiency, it was particularly pertinent to study this hypomorphic mouse line.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 33127481 ↗

ClinVar Variant Classifications

277 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic12

VUS173

Likely Benign30

Benign31

Conflicting10

Likely Pathogenic

173

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	11	0	1	0	12
VUS	21	148	4	0	173
Likely Benign	2	5	4	19	30
Benign	0	10	9	12	31
Conflicting	—				10
Total	34	163	18	31	256

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap PDE11A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →