Pigmented nodular adrenocortical disease, primary, 2

Summary

Pigmented nodular adrenocortical disease, primary, 2 (MONDO:0012505) is a disease caused by PDE11A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PDE11A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 47

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pigmented nodular adrenocortical disease, primary, 2
Mondo ID	MONDO:0012505
MeSH	C566472
OMIM	610475
DOID	DOID:0070547
UMLS	C1864851
MedGen	355843
GARD	0015489
Is cancer (heuristic)	no

Also known as: PDE11A primary pigmented nodular adrenocortical disease · pigmented nodular adrenocortical disease, primary, 2 · pigmented nodular adrenocortical disease, primary, type 2 · PPNAD2 · primary pigmented nodular adrenocortical disease caused by mutation in PDE11A

Data availability: 47 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › primary pigmented nodular adrenocortical disease › pigmented nodular adrenocortical disease, primary, 2

Related subtypes (4): pigmented nodular adrenocortical disease, primary, 1, pigmented nodular adrenocortical disease, primary, 3, pigmented nodular adrenocortical disease, primary, 4, isolated primary pigmented nodular adrenocortical disease

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

47 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 11 benign, 7 conflicting classifications of pathogenicity, 6 likely pathogenic, 2 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
225431	NM_016953.4(PDE11A):c.2268_2272del (p.Ser757fs)	PDE11A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225433	NM_016953.4(PDE11A):c.1811C>G (p.Ser604Ter)	PDE11A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324867	NM_016953.4(PDE11A):c.1270_1280del (p.Ser424fs)	PDE11A	Likely pathogenic	criteria provided, single submitter
1324868	NM_016953.4(PDE11A):c.1585C>T (p.Gln529Ter)	PDE11A	Likely pathogenic	criteria provided, single submitter
1333997	NM_016953.4(PDE11A):c.1913_1915delinsG (p.Gln638fs)	PDE11A	Likely pathogenic	criteria provided, single submitter
2432520	NM_016953.4(PDE11A):c.1149T>A (p.Tyr383Ter)	PDE11A	Likely pathogenic	criteria provided, single submitter
3780107	NM_016953.4(PDE11A):c.2056C>T (p.Gln686Ter)	PDE11A	Likely pathogenic	criteria provided, single submitter
4081584	NM_016953.4(PDE11A):c.1243C>T (p.Gln415Ter)	PDE11A	Likely pathogenic	criteria provided, single submitter
208602	NM_016953.4(PDE11A):c.171del (p.Thr58fs)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225432	NM_001077197.2(PDE11A):c.20_21del (p.Arg7fs)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451903	NM_016953.4(PDE11A):c.137del (p.Gln46fs)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5286	NM_016953.4(PDE11A):c.919C>T (p.Arg307Ter)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
718046	NM_016953.4(PDE11A):c.2647G>A (p.Ala883Thr)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
725065	NM_016953.4(PDE11A):c.1660del (p.Cys554fs)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
725066	NM_016953.4(PDE11A):c.1655T>C (p.Ile552Thr)	PDE11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028036	NM_016953.4(PDE11A):c.2618T>C (p.Ile873Thr)	PDE11A	Uncertain significance	criteria provided, single submitter
1031979	NM_016953.4(PDE11A):c.493C>A (p.Pro165Thr)	PDE11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333996	NM_016953.4(PDE11A):c.1774G>A (p.Val592Ile)	PDE11A	Uncertain significance	criteria provided, single submitter
1333998	NM_016953.4(PDE11A):c.2290C>T (p.Leu764Phe)	PDE11A	Uncertain significance	criteria provided, single submitter
1333999	NM_016953.4(PDE11A):c.2336T>C (p.Leu779Pro)	PDE11A	Uncertain significance	criteria provided, single submitter
1342528	NM_016953.4(PDE11A):c.2678C>A (p.Pro893Gln)	PDE11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
225434	NM_016953.4(PDE11A):c.985C>T (p.Arg329Ter)	PDE11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432528	NM_016953.4(PDE11A):c.126_127del (p.His42fs)	PDE11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434619	NM_016953.4(PDE11A):c.2044A>G (p.Thr682Ala)	PDE11A	Uncertain significance	criteria provided, single submitter
2434620	NM_016953.4(PDE11A):c.2422C>T (p.Arg808Ter)	PDE11A	Uncertain significance	criteria provided, single submitter
2460027	NM_016953.4(PDE11A):c.2599C>T (p.Arg867Trp)	PDE11A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2502294	NM_016953.4(PDE11A):c.2436G>A (p.Met812Ile)	PDE11A	Uncertain significance	criteria provided, single submitter
3891921	NM_016953.4(PDE11A):c.2125A>G (p.Arg709Gly)	PDE11A	Uncertain significance	criteria provided, single submitter
3891922	NM_016953.4(PDE11A):c.1409_1422del (p.Leu470fs)	PDE11A	Uncertain significance	criteria provided, single submitter
4056704	NM_016953.4(PDE11A):c.2052del (p.Gln686fs)	PDE11A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PDE11A	Strong	Autosomal dominant	pigmented nodular adrenocortical disease, primary, 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE11A	Orphanet:1359	Carney complex
PDE11A	Orphanet:647772	Isolated primary pigmented nodular adrenocortical disease
PDE11A	Orphanet:647782	Isolated micronodular adrenocortical disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PDE11A	HGNC:8773	ENSG00000128655	Q9HCR9	Dual 3’,5’-cyclic-AMP and -GMP phosphodiesterase 11A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE11A	Dual 3’,5’-cyclic-AMP and -GMP phosphodiesterase 11A	Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE11A	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, GAF, HD/PDEase_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
deltoid	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE11A	166	broad	marker	deltoid, quadriceps femoris, vastus lateralis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDE11A	778

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDE11A	Q9HCR9	79.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
cGMP effects	1	713.8×	0.003	PDE11A
G alpha (s) signalling events	1	73.2×	0.014	PDE11A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of receptor guanylyl cyclase signaling pathway	1	2808.7×	0.001	PDE11A
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.002	PDE11A
signal transduction	1	16.1×	0.062	PDE11A

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PDE11A	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE11A	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE11A
SILDENAFIL	4	PDE11A
TADALAFIL	4	PDE11A
DIPYRIDAMOLE	4	PDE11A
ZAPRINAST	2	PDE11A
JNJ-42396302	1	PDE11A
LENRISPODUN PHOSPHATE	1	PDE11A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PDE11A	142	Binding:135, ADMET:5, Functional:1, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE11A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PDE11A	142

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VARDENAFIL	4	PDE11A
SILDENAFIL	4	PDE11A
TADALAFIL	4	PDE11A
DIPYRIDAMOLE	4	PDE11A
ZAPRINAST	2	PDE11A
JNJ-42396302	1	PDE11A
LENRISPODUN PHOSPHATE	1	PDE11A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE11A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.