Cardioacrofacial dysplasia 1

Summary

Cardioacrofacial dysplasia 1 (MONDO:0030876) is a disease caused by PRKACA (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PRKACA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardioacrofacial dysplasia 1
Mondo ID	MONDO:0030876
OMIM	619142
UMLS	C5436885
MedGen	1777656
Is cancer (heuristic)	no

Also known as: CAFD1 · cardioacrofacial dysplasia 1

Data availability: 10 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 › cardioacrofacial dysplasia › cardioacrofacial dysplasia 1

Related subtypes (1): cardioacrofacial dysplasia 2

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

10 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
989460	NM_002730.4(PRKACA):c.409G>A (p.Gly137Arg)	PRKACA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3368216	NM_002730.4(PRKACA):c.601G>A (p.Gly201Ser)	PRKACA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2435242	NM_002730.4(PRKACA):c.627G>T (p.Glu209Asp)	PRKACA	Uncertain significance	criteria provided, single submitter
2672233	NM_002730.4(PRKACA):c.1022A>G (p.Asn341Ser)	PRKACA	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065085	NM_002730.4(PRKACA):c.875T>C (p.Ile292Thr)	PRKACA	Uncertain significance	criteria provided, single submitter
3237396	NM_002730.4(PRKACA):c.323A>C (p.Glu108Ala)	PRKACA	Uncertain significance	criteria provided, single submitter
3583508	NM_002730.4(PRKACA):c.225C>T (p.Leu75=)	PRKACA	Uncertain significance	criteria provided, single submitter
3600469	NM_002730.4(PRKACA):c.47-404C>T	PRKACA	Uncertain significance	criteria provided, single submitter
3600495	NM_002730.4(PRKACA):c.47-322G>A	PRKACA	Uncertain significance	criteria provided, single submitter
3603291	NM_002730.4(PRKACA):c.327C>A (p.Phe109Leu)	PRKACA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
PRKACA	Strong	Autosomal dominant	cardioacrofacial dysplasia 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKACA	Orphanet:289	Ellis Van Creveld syndrome
PRKACA	Orphanet:401920	Fibrolamellar hepatocellular carcinoma

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
PRKACA	HGNC:9380	ENSG00000072062	P17612	cAMP-dependent protein kinase catalytic subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKACA	cAMP-dependent protein kinase catalytic subunit alpha	Phosphorylates a large number of substrates in the cytoplasm and the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKACA	Kinase	yes	2.7.11.11	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS

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
apex of heart	1
gastrocnemius	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKACA	143	ubiquitous	marker	gastrocnemius, apex of heart, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKACA	8,270

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKACA	P17612	54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 113. 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
Loss of phosphorylation of MECP2 at T308	1	2855.0×	0.010	PRKACA
PKA-mediated phosphorylation of key metabolic factors	1	2284.0×	0.010	PRKACA
HDL assembly	1	1427.5×	0.010	PRKACA
Loss of function of MECP2 in Rett syndrome	1	1427.5×	0.010	PRKACA
Pervasive developmental disorders	1	1427.5×	0.010	PRKACA
Disorders of Developmental Biology	1	1427.5×	0.010	PRKACA
Disorders of Nervous System Development	1	1427.5×	0.010	PRKACA
ROBO receptors bind AKAP5	1	1268.9×	0.010	PRKACA
Regulation of glycolysis by fructose 2,6-bisphosphate metabolism	1	951.7×	0.010	PRKACA
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	878.5×	0.010	PRKACA
Glucose metabolism	1	878.5×	0.010	PRKACA
Rap1 signalling	1	713.8×	0.010	PRKACA
Plasma lipoprotein assembly	1	713.8×	0.010	PRKACA
PKA activation in glucagon signalling	1	671.8×	0.010	PRKACA
Triglyceride metabolism	1	671.8×	0.010	PRKACA
PKA activation	1	634.4×	0.010	PRKACA
PKA-mediated phosphorylation of CREB	1	571.0×	0.010	PRKACA
CD209 (DC-SIGN) signaling	1	519.1×	0.010	PRKACA
Triglyceride catabolism	1	475.8×	0.010	PRKACA
DARPP-32 events	1	475.8×	0.010	PRKACA
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.010	PRKACA
Leishmania parasite growth and survival	1	393.8×	0.010	PRKACA
Calmodulin induced events	1	380.7×	0.010	PRKACA
CaM pathway	1	380.7×	0.010	PRKACA
Ca-dependent events	1	368.4×	0.010	PRKACA
Aquaporin-mediated transport	1	368.4×	0.010	PRKACA
Regulation of MECP2 expression and activity	1	368.4×	0.010	PRKACA
Glucagon signaling in metabolic regulation	1	346.1×	0.010	PRKACA
G-protein mediated events	1	326.3×	0.010	PRKACA
DAG and IP3 signaling	1	317.2×	0.010	PRKACA

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
protein localization to lipid droplet	1	4213.0×	0.003	PRKACA
negative regulation of glycolytic process through fructose-6-phosphate	1	2808.7×	0.003	PRKACA
high-density lipoprotein particle assembly	1	1685.2×	0.003	PRKACA
regulation of bicellular tight junction assembly	1	1685.2×	0.003	PRKACA
mitochondrial protein catabolic process	1	1532.0×	0.003	PRKACA
regulation of protein processing	1	1532.0×	0.003	PRKACA
negative regulation of protein localization to chromatin	1	1532.0×	0.003	PRKACA
cellular response to parathyroid hormone stimulus	1	1404.3×	0.003	PRKACA
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.003	PRKACA
cAMP/PKA signal transduction	1	1404.3×	0.003	PRKACA
regulation of osteoblast differentiation	1	1296.3×	0.003	PRKACA
cellular response to epinephrine stimulus	1	1296.3×	0.003	PRKACA
positive regulation of cholesterol biosynthetic process	1	1123.5×	0.003	PRKACA
cellular response to cold	1	1053.2×	0.003	PRKACA
intracellular potassium ion homeostasis	1	991.3×	0.003	PRKACA
regulation of cardiac muscle contraction	1	887.0×	0.003	PRKACA
cellular response to glucagon stimulus	1	842.6×	0.003	PRKACA
regulation of cardiac conduction	1	842.6×	0.003	PRKACA
dorsal/ventral neural tube patterning	1	802.5×	0.003	PRKACA
positive regulation of protein export from nucleus	1	802.5×	0.003	PRKACA
positive regulation of gluconeogenesis	1	766.0×	0.003	PRKACA
regulation of proteasomal protein catabolic process	1	766.0×	0.003	PRKACA
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.003	PRKACA
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.003	PRKACA
sperm capacitation	1	674.1×	0.003	PRKACA
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.003	PRKACA
negative regulation of interleukin-2 production	1	581.1×	0.003	PRKACA
regulation of microtubule cytoskeleton organization	1	543.6×	0.003	PRKACA
renal water homeostasis	1	510.7×	0.003	PRKACA
protein export from nucleus	1	510.7×	0.003	PRKACA

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
PRKACA	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKACA	29	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	PRKACA
BARICITINIB	4	PRKACA
CAPIVASERTIB	4	PRKACA
MIDOSTAURIN	4	PRKACA
FASUDIL	3	PRKACA
AFURESERTIB	3	PRKACA
LINIFANIB	3	PRKACA
ENZASTAURIN	3	PRKACA
ALISERTIB	3	PRKACA
LESTAURTINIB	3	PRKACA
RUBOXISTAURIN	3	PRKACA
UCN-01	2	PRKACA
BMS-754807	2	PRKACA
ELLAGIC ACID	2	PRKACA
SAR-407899 FREE BASE	2	PRKACA
CENISERTIB	2	PRKACA
UPROSERTIB	2	PRKACA
BMS-690514	2	PRKACA
BMS-777607	2	PRKACA
R-406	2	PRKACA
AT-9283	2	PRKACA
PF-00562271	1	PRKACA
PF-03758309	1	PRKACA
AT-13148	1	PRKACA
CYC-116	1	PRKACA
PD-0166285	1	PRKACA
GSK-690693	1	PRKACA
Y-39983	1	PRKACA
AST-487	1	PRKACA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKACA	606	Binding:598, Functional:7, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKACA	2.7.11.11	cAMP-dependent protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKACA	606

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

29 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)
PONATINIB	4	PRKACA
BARICITINIB	4	PRKACA
CAPIVASERTIB	4	PRKACA
MIDOSTAURIN	4	PRKACA
FASUDIL	3	PRKACA
AFURESERTIB	3	PRKACA
LINIFANIB	3	PRKACA
ENZASTAURIN	3	PRKACA
ALISERTIB	3	PRKACA
LESTAURTINIB	3	PRKACA
RUBOXISTAURIN	3	PRKACA
UCN-01	2	PRKACA
BMS-754807	2	PRKACA
ELLAGIC ACID	2	PRKACA
SAR-407899 FREE BASE	2	PRKACA
CENISERTIB	2	PRKACA
UPROSERTIB	2	PRKACA
BMS-690514	2	PRKACA
BMS-777607	2	PRKACA
R-406	2	PRKACA
AT-9283	2	PRKACA
PF-00562271	1	PRKACA
PF-03758309	1	PRKACA
AT-13148	1	PRKACA
CYC-116	1	PRKACA
PD-0166285	1	PRKACA
GSK-690693	1	PRKACA
Y-39983	1	PRKACA
AST-487	1	PRKACA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKACA
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.