Pigmented nodular adrenocortical disease, primary, 1

Summary

Pigmented nodular adrenocortical disease, primary, 1 (MONDO:0012509) is a disease caused by PRKAR1A (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PRKAR1A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 25
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pigmented nodular adrenocortical disease, primary, 1
Mondo ID	MONDO:0012509
MeSH	C566469
OMIM	610489
DOID	DOID:0070546
UMLS	C1864846
MedGen	400627
GARD	0018620
Is cancer (heuristic)	no

Also known as: pigmented nodular adrenocortical disease, primary, 1 · pigmented nodular adrenocortical disease, primary, type 1 · PPNAD1 · primary pigmented nodular adrenocortical disease caused by mutation in PRKAR1A · PRKAR1A primary pigmented nodular adrenocortical disease

Data availability: 25 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, 1

Related subtypes (4): pigmented nodular adrenocortical disease, primary, 2, 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

25 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 5 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12671	PRKAR1A, 16-BP DEL	PRKAR1A	Pathogenic	no assertion criteria provided
12675	NM_002734.5(PRKAR1A):c.709-7_709-2del	PRKAR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29907	NM_002734.5(PRKAR1A):c.1102C>T (p.Arg368Ter)	PRKAR1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3383348	NM_002734.5(PRKAR1A):c.891+1G>A	PRKAR1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
433148	NM_002734.5(PRKAR1A):c.1003C>T (p.Arg335Cys)	PRKAR1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
12670	NM_002734.5(PRKAR1A):c.-7+1G>A	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434726	NM_002734.5(PRKAR1A):c.549+20A>G	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406171	NM_002734.5(PRKAR1A):c.1024C>T (p.Arg342Cys)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
536890	NM_002734.5(PRKAR1A):c.1025G>A (p.Arg342His)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
945916	NM_002734.5(PRKAR1A):c.238G>T (p.Asp80Tyr)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3582761	NM_001276290.1(PRKAR1A):c.1012T>C (p.Ter338Gln)	FAM20A	Uncertain significance	criteria provided, single submitter
1039853	NM_002734.5(PRKAR1A):c.1057C>A (p.Pro353Thr)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1423807	NM_002734.5(PRKAR1A):c.550G>A (p.Val184Ile)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1425542	NM_002734.5(PRKAR1A):c.691T>C (p.Tyr231His)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3582724	NM_002734.5(PRKAR1A):c.78C>G (p.Asn26Lys)	PRKAR1A	Uncertain significance	criteria provided, single submitter
486156	NM_002734.5(PRKAR1A):c.914G>A (p.Arg305His)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
536899	NM_002734.5(PRKAR1A):c.478G>A (p.Ala160Thr)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
580520	NM_002734.5(PRKAR1A):c.464C>T (p.Ser155Leu)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
638955	NM_002734.5(PRKAR1A):c.25A>G (p.Ser9Gly)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
644694	NM_002734.5(PRKAR1A):c.424GAT[1] (p.Asp143del)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
827371	NM_002734.5(PRKAR1A):c.797C>T (p.Thr266Met)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1562854	NM_002734.5(PRKAR1A):c.503-13dup	PRKAR1A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1588288	NM_002734.5(PRKAR1A):c.502+12_502+13del	PRKAR1A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
41044	NM_002734.5(PRKAR1A):c.204G>A (p.Leu68=)	PRKAR1A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
413782	NM_002734.5(PRKAR1A):c.381T>C (p.Ala127=)	PRKAR1A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 7 · 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
PRKAR1A	Strong	Autosomal dominant	pigmented nodular adrenocortical disease, primary, 1	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKAR1A	Orphanet:1359	Carney complex
PRKAR1A	Orphanet:1501	Adrenocortical carcinoma
PRKAR1A	Orphanet:520	Acute promyelocytic leukemia
PRKAR1A	Orphanet:615	Familial atrial myxoma
PRKAR1A	Orphanet:647772	Isolated primary pigmented nodular adrenocortical disease
PRKAR1A	Orphanet:950	Acrodysostosis
FAM20A	Orphanet:1031	Enamel-renal syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRKAR1A	HGNC:9388	ENSG00000108946	P10644	cAMP-dependent protein kinase type I-alpha regulatory subunit	gencc,clinvar
FAM20A	HGNC:23015	ENSG00000108950	Q96MK3	Pseudokinase FAM20A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKAR1A	cAMP-dependent protein kinase type I-alpha regulatory subunit	Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.
FAM20A	Pseudokinase FAM20A	Pseudokinase that acts as an allosteric activator of the Golgi serine/threonine protein kinase FAM20C and is involved in biomineralization of teeth.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKAR1A	Other/Unknown	no		cNMP-bd_dom, cAMP_dep_PK_reg_su_I/II_a/b, cAMP_dep_PK_reg_su
FAM20A	Other/Unknown	no		FAM20_C, FAM20

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
lateral nuclear group of thalamus	1
mucosa of paranasal sinus	1
right lobe of liver	1
smooth muscle tissue	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKAR1A	295	ubiquitous	marker	mucosa of paranasal sinus, germinal epithelium of ovary, lateral nuclear group of thalamus
FAM20A	196	broad	marker	right lobe of liver, smooth muscle tissue, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAR1A	3,586
FAM20A	736

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAM20A	Q96MK3	4
PRKAR1A	P10644	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ALK mutants bind TKIs	1	475.8×	0.017	PRKAR1A
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	439.2×	0.017	PRKAR1A
PKA activation in glucagon signalling	1	335.9×	0.017	PRKAR1A
PKA activation	1	317.2×	0.017	PRKAR1A
PKA-mediated phosphorylation of CREB	1	285.5×	0.017	PRKAR1A
DARPP-32 events	1	237.9×	0.017	PRKAR1A
Anti-inflammatory response favouring Leishmania parasite infection	1	196.9×	0.017	PRKAR1A
Leishmania parasite growth and survival	1	196.9×	0.017	PRKAR1A
Calmodulin induced events	1	190.3×	0.017	PRKAR1A
CaM pathway	1	190.3×	0.017	PRKAR1A
Ca-dependent events	1	184.2×	0.017	PRKAR1A
Aquaporin-mediated transport	1	184.2×	0.017	PRKAR1A
Glucagon signaling in metabolic regulation	1	173.0×	0.017	PRKAR1A
G-protein mediated events	1	163.1×	0.017	PRKAR1A
DAG and IP3 signaling	1	158.6×	0.017	PRKAR1A
Response of endothelial cells to shear stress	1	150.3×	0.017	PRKAR1A
FCGR3A-mediated IL10 synthesis	1	146.4×	0.017	PRKAR1A
Signaling by ALK in cancer	1	135.9×	0.017	PRKAR1A
Opioid Signalling	1	132.8×	0.017	PRKAR1A
PLC beta mediated events	1	132.8×	0.017	PRKAR1A
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	132.8×	0.017	PRKAR1A
Vasopressin regulates renal water homeostasis via Aquaporins	1	132.8×	0.017	PRKAR1A
Cellular responses to mechanical stimuli	1	129.8×	0.017	PRKAR1A
ADORA2B mediated anti-inflammatory cytokines production	1	126.9×	0.017	PRKAR1A
GPER1 signaling	1	124.1×	0.017	PRKAR1A
Regulation of insulin secretion	1	109.8×	0.019	PRKAR1A
Post NMDA receptor activation events	1	102.0×	0.020	PRKAR1A
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.020	PRKAR1A
Signaling by Hedgehog	1	92.1×	0.020	PRKAR1A
Hedgehog ‘off’ state	1	89.2×	0.020	PRKAR1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tooth eruption	1	1685.2×	0.008	FAM20A
enamel mineralization	1	601.9×	0.008	FAM20A
negative regulation of activated T cell proliferation	1	526.6×	0.008	PRKAR1A
cellular response to glucagon stimulus	1	421.3×	0.008	PRKAR1A
vascular endothelial cell response to laminar fluid shear stress	1	366.4×	0.008	PRKAR1A
biomineral tissue development	1	324.1×	0.008	FAM20A
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.008	PRKAR1A
negative regulation of cAMP/PKA signal transduction	1	300.9×	0.008	PRKAR1A
cardiac muscle cell proliferation	1	290.6×	0.008	PRKAR1A
renal water homeostasis	1	255.3×	0.008	PRKAR1A
mesoderm formation	1	247.8×	0.008	PRKAR1A
calcium ion homeostasis	1	221.7×	0.008	FAM20A
sarcomere organization	1	191.5×	0.008	PRKAR1A
positive regulation of protein phosphorylation	1	138.1×	0.011	FAM20A
positive regulation of insulin secretion	1	127.7×	0.011	PRKAR1A
response to bacterium	1	96.8×	0.014	FAM20A
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.022	PRKAR1A
chemical synaptic transmission	1	38.6×	0.030	PRKAR1A
negative regulation of gene expression	1	34.5×	0.032	PRKAR1A
intracellular signal transduction	1	19.1×	0.054	PRKAR1A
regulation of transcription by RNA polymerase II	1	5.8×	0.164	PRKAR1A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKAR1A	0	0
FAM20A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PRKAR1A	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	PRKAR1A, FAM20A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRKAR1A	2	—
FAM20A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00668291	Not specified	COMPLETED	Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the CARNEY Complex (CNC)