Acrodysostosis 1 with or without hormone resistance

Summary

Acrodysostosis 1 with or without hormone resistance (MONDO:0007044) is a disease caused by PRKAR1A (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: PRKAR1A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 122

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Acrodysostosis 1 with or without hormone resistance
Mondo ID	MONDO:0007044
OMIM	101800
NCIT	C136464
UMLS	C3276228
MedGen	477858
GARD	0015030
Is cancer (heuristic)	no

Also known as: ACRDYS1 · Acrodysostosis 1 · Acrodysostosis 1 with or without hormone resistance · Acrodysostosis 1, with or without hormone resistance · ADOHR

Data availability: 122 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › mandibulofacial dysostosis › acrodysostosis › Acrodysostosis 1 with or without hormone resistance

Related subtypes (1): acrodysostosis 2 with or without hormone resistance

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

122 retrieved; paginated sample, class counts are floors:

77 uncertain significance, 13 benign, 13 conflicting classifications of pathogenicity, 10 benign/likely benign, 4 pathogenic, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12675	NM_002734.5(PRKAR1A):c.709-7_709-2del	PRKAR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279877	NM_002734.5(PRKAR1A):c.46C>T (p.Arg16Ter)	PRKAR1A	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
29909	NM_002734.5(PRKAR1A):c.1004G>C (p.Arg335Pro)	PRKAR1A	Pathogenic	no assertion criteria provided
29910	NM_002734.5(PRKAR1A):c.980T>C (p.Ile327Thr)	PRKAR1A	Pathogenic	criteria provided, single submitter
3362248	NM_002734.5(PRKAR1A):c.982G>A (p.Ala328Thr)	PRKAR1A	Likely pathogenic	criteria provided, single submitter
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
638687	NM_002734.5(PRKAR1A):c.620A>G (p.Tyr207Cys)	PRKAR1A	Likely pathogenic	no assertion criteria provided
1434726	NM_002734.5(PRKAR1A):c.549+20A>G	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239382	NM_002734.5(PRKAR1A):c.221G>A (p.Arg74His)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324781	NM_002734.5(PRKAR1A):c.103A>G (p.Ile35Val)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324782	NM_002734.5(PRKAR1A):c.309G>A (p.Glu103=)	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
429590	NM_002734.5(PRKAR1A):c.545C>T (p.Thr182Met)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
469069	NM_002734.5(PRKAR1A):c.596G>A (p.Ser199Asn)	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
579659	NM_002734.5(PRKAR1A):c.331G>A (p.Ala111Thr)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
647875	NM_002734.5(PRKAR1A):c.535C>G (p.Gln179Glu)	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
833813	NM_002734.5(PRKAR1A):c.-11C>T	PRKAR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892521	NM_002734.5(PRKAR1A):c.770-8T>G	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
3333127	NM_017983.7(WIPI1):c.889A>G (p.Met297Val)	ARSG	Uncertain significance	criteria provided, single submitter
3582761	NM_001276290.1(PRKAR1A):c.1012T>C (p.Ter338Gln)	FAM20A	Uncertain significance	criteria provided, single submitter
1019850	NM_002734.5(PRKAR1A):c.790C>T (p.Arg264Cys)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039853	NM_002734.5(PRKAR1A):c.1057C>A (p.Pro353Thr)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057221	NM_002734.5(PRKAR1A):c.658A>G (p.Asn220Asp)	PRKAR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
12674	NM_002734.5(PRKAR1A):c.220C>T (p.Arg74Cys)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 8 · 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	Definitive	Autosomal dominant	acrodysostosis with multiple hormone resistance	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
ARSG	Orphanet:231183	Usher syndrome type 3

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

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
ARSG	HGNC:24102	ENSG00000141337	Q96EG1	Arylsulfatase G	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.
ARSG	Arylsulfatase G	Displays arylsulfatase activity at acidic pH towards artificial substrates, such as p-nitrocatechol sulfate and also, but with a lower activity towards p-nitrophenyl sulfate and 4-methylumbelliferyl sulfate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Phosphatase	1	28.0×	0.071
Other/Unknown	2	1.2×	0.587

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
ARSG	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

Expression context

Cohort genes with no expression data: 0.

3 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)	3
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
blood	1
monocyte	1
stromal cell of endometrium	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
ARSG	135	ubiquitous	marker	blood, stromal cell of endometrium, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAR1A	3,586
ARSG	1,175
FAM20A	736

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAM20A	Q96MK3	4
PRKAR1A	P10644	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSG	Q96EG1	91.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. Enrichment computed across 3 evidence-associated genes (3 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 3 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	317.2×	0.026	PRKAR1A
The activation of arylsulfatases	1	292.8×	0.026	ARSG
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	292.8×	0.026	PRKAR1A
PKA activation in glucagon signalling	1	223.9×	0.026	PRKAR1A
PKA activation	1	211.5×	0.026	PRKAR1A
PKA-mediated phosphorylation of CREB	1	190.3×	0.026	PRKAR1A
DARPP-32 events	1	158.6×	0.026	PRKAR1A
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	141.0×	0.026	ARSG
Anti-inflammatory response favouring Leishmania parasite infection	1	131.3×	0.026	PRKAR1A
Leishmania parasite growth and survival	1	131.3×	0.026	PRKAR1A
Calmodulin induced events	1	126.9×	0.026	PRKAR1A
CaM pathway	1	126.9×	0.026	PRKAR1A
Ca-dependent events	1	122.8×	0.026	PRKAR1A
Aquaporin-mediated transport	1	122.8×	0.026	PRKAR1A
Glucagon signaling in metabolic regulation	1	115.3×	0.026	PRKAR1A
G-protein mediated events	1	108.8×	0.026	PRKAR1A
DAG and IP3 signaling	1	105.7×	0.026	PRKAR1A
Glycosphingolipid metabolism	1	100.2×	0.026	ARSG
Response of endothelial cells to shear stress	1	100.2×	0.026	PRKAR1A
FCGR3A-mediated IL10 synthesis	1	97.6×	0.026	PRKAR1A
Glycosphingolipid catabolism	1	97.6×	0.026	ARSG
Signaling by ALK in cancer	1	90.6×	0.026	PRKAR1A
Opioid Signalling	1	88.5×	0.026	PRKAR1A
PLC beta mediated events	1	88.5×	0.026	PRKAR1A
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	88.5×	0.026	PRKAR1A
Vasopressin regulates renal water homeostasis via Aquaporins	1	88.5×	0.026	PRKAR1A
Cellular responses to mechanical stimuli	1	86.5×	0.026	PRKAR1A
ADORA2B mediated anti-inflammatory cytokines production	1	84.6×	0.026	PRKAR1A
GPER1 signaling	1	82.8×	0.026	PRKAR1A
Regulation of insulin secretion	1	73.2×	0.028	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 3 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	1123.5×	0.012	FAM20A
enamel mineralization	1	401.2×	0.012	FAM20A
sulfur compound metabolic process	1	374.5×	0.012	ARSG
negative regulation of activated T cell proliferation	1	351.1×	0.012	PRKAR1A
glial cell differentiation	1	295.6×	0.012	ARSG
cellular response to glucagon stimulus	1	280.9×	0.012	PRKAR1A
vascular endothelial cell response to laminar fluid shear stress	1	244.2×	0.012	PRKAR1A
homeostasis of number of cells	1	224.7×	0.012	ARSG
biomineral tissue development	1	216.1×	0.012	FAM20A
negative regulation of inflammatory response to antigenic stimulus	1	200.6×	0.012	PRKAR1A
negative regulation of cAMP/PKA signal transduction	1	200.6×	0.012	PRKAR1A
cardiac muscle cell proliferation	1	193.7×	0.012	PRKAR1A
renal water homeostasis	1	170.2×	0.012	PRKAR1A
mesoderm formation	1	165.2×	0.012	PRKAR1A
calcium ion homeostasis	1	147.8×	0.013	FAM20A
sarcomere organization	1	127.7×	0.014	PRKAR1A
lysosome organization	1	102.1×	0.016	ARSG
positive regulation of protein phosphorylation	1	92.1×	0.016	FAM20A
positive regulation of insulin secretion	1	85.1×	0.016	PRKAR1A
retina development in camera-type eye	1	85.1×	0.016	ARSG
response to bacterium	1	64.6×	0.021	FAM20A
neuron apoptotic process	1	61.7×	0.021	ARSG
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	37.7×	0.032	PRKAR1A
gene expression	1	26.6×	0.043	ARSG
chemical synaptic transmission	1	25.8×	0.043	PRKAR1A
negative regulation of gene expression	1	23.0×	0.046	PRKAR1A
intracellular signal transduction	1	12.7×	0.079	PRKAR1A
regulation of transcription by RNA polymerase II	1	3.9×	0.236	PRKAR1A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
ARSG	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
ARSG	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	ARSG
E	Difficult family or no structure, no drug	2	PRKAR1A, FAM20A

Undrugged target profiles

3 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	—
ARSG	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.