Cardioacrofacial dysplasia 2

Summary

Cardioacrofacial dysplasia 2 (MONDO:0030877) is a disease caused by PRKACB (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PRKACB (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 2
Mondo ID	MONDO:0030877
OMIM	619143
UMLS	C5436886
MedGen	1731253
Is cancer (heuristic)	no

Also known as: CAFD2 · cardioacrofacial dysplasia 2 · cardioacrofacial dysplasia 2, autosomal dominant, somatic mosaicism

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 2

Related subtypes (1): cardioacrofacial dysplasia 1

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:

5 pathogenic, 4 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1805125	NM_182948.4(PRKACB):c.404A>T (p.His135Leu)	PRKACB	Pathogenic	criteria provided, single submitter
989456	NM_182948.4(PRKACB):c.844G>C (p.Gly282Arg)	PRKACB	Pathogenic	no assertion criteria provided
989457	NM_182948.4(PRKACB):c.302C>T (p.Ser101Leu)	PRKACB	Pathogenic	no assertion criteria provided
989458	NM_182948.4(PRKACB):c.404A>G (p.His135Arg)	PRKACB	Pathogenic	no assertion criteria provided
989459	NM_182948.4(PRKACB):c.403C>A (p.His135Asn)	PRKACB	Pathogenic	no assertion criteria provided
4291969	NM_182948.4(PRKACB):c.997A>G (p.Lys333Glu)	PRKACB	Likely pathogenic	criteria provided, single submitter
1687603	NM_182948.4(PRKACB):c.640G>C (p.Asp214His)	PRKACB	Uncertain significance	criteria provided, single submitter
2921164	NM_182948.4(PRKACB):c.1016T>C (p.Ile339Thr)	PRKACB	Uncertain significance	criteria provided, single submitter
3777147	NM_182948.4(PRKACB):c.758T>G (p.Leu253Trp)	PRKACB	Uncertain significance	criteria provided, single submitter
3899335	NM_182948.4(PRKACB):c.752A>G (p.Glu251Gly)	PRKACB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
PRKACB	Strong	Autosomal dominant	cardioacrofacial dysplasia 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKACB	Orphanet:289	Ellis Van Creveld syndrome

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
PRKACB	HGNC:9381	ENSG00000142875	P22694	cAMP-dependent protein kinase catalytic subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKACB	cAMP-dependent protein kinase catalytic subunit beta	Mediates cAMP-dependent signaling triggered by receptor binding to GPCRs.

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)
PRKACB	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
Brodmann (1909) area 23	1
endothelial cell	1
parietal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKACB	293	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, parietal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKACB	7,400

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKACB	P22694	95.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 79. 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
PKA-mediated phosphorylation of key metabolic factors	1	2284.0×	0.009	PRKACB
HDL assembly	1	1427.5×	0.009	PRKACB
ROBO receptors bind AKAP5	1	1268.9×	0.009	PRKACB
Regulation of glycolysis by fructose 2,6-bisphosphate metabolism	1	951.7×	0.009	PRKACB
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	878.5×	0.009	PRKACB
Glucose metabolism	1	878.5×	0.009	PRKACB
Rap1 signalling	1	713.8×	0.009	PRKACB
Plasma lipoprotein assembly	1	713.8×	0.009	PRKACB
PKA activation in glucagon signalling	1	671.8×	0.009	PRKACB
Triglyceride metabolism	1	671.8×	0.009	PRKACB
PKA activation	1	634.4×	0.009	PRKACB
PKA-mediated phosphorylation of CREB	1	571.0×	0.009	PRKACB
CD209 (DC-SIGN) signaling	1	519.1×	0.009	PRKACB
Triglyceride catabolism	1	475.8×	0.009	PRKACB
DARPP-32 events	1	475.8×	0.009	PRKACB
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.009	PRKACB
Leishmania parasite growth and survival	1	393.8×	0.009	PRKACB
Calmodulin induced events	1	380.7×	0.009	PRKACB
CaM pathway	1	380.7×	0.009	PRKACB
Ca-dependent events	1	368.4×	0.009	PRKACB
Aquaporin-mediated transport	1	368.4×	0.009	PRKACB
Glucagon signaling in metabolic regulation	1	346.1×	0.009	PRKACB
G-protein mediated events	1	326.3×	0.009	PRKACB
DAG and IP3 signaling	1	317.2×	0.009	PRKACB
Response of endothelial cells to shear stress	1	300.5×	0.009	PRKACB
FCGR3A-mediated IL10 synthesis	1	292.8×	0.009	PRKACB
Glycolysis	1	285.5×	0.009	PRKACB
Opioid Signalling	1	265.6×	0.009	PRKACB
PLC beta mediated events	1	265.6×	0.009	PRKACB
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.009	PRKACB

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
high-density lipoprotein particle assembly	1	1685.2×	0.004	PRKACB
regulation of protein processing	1	1532.0×	0.004	PRKACB
dorsal/ventral neural tube patterning	1	802.5×	0.004	PRKACB
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.004	PRKACB
renal water homeostasis	1	510.7×	0.005	PRKACB
negative regulation of smoothened signaling pathway	1	455.5×	0.005	PRKACB
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	337.0×	0.005	PRKACB
negative regulation of TORC1 signaling	1	324.1×	0.005	PRKACB
positive regulation of insulin secretion	1	255.3×	0.006	PRKACB
neural tube closure	1	187.2×	0.007	PRKACB
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.010	PRKACB
protein phosphorylation	1	68.0×	0.016	PRKACB
signal transduction	1	16.1×	0.062	PRKACB

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
PRKACB	CAPIVASERTIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKACB	19	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPIVASERTIB	4	PRKACB
DASATINIB	4	PRKACB
MIDOSTAURIN	4	PRKACB
FASUDIL	3	PRKACB
AFURESERTIB	3	PRKACB
ENZASTAURIN	3	PRKACB
LESTAURTINIB	3	PRKACB
RUBOXISTAURIN	3	PRKACB
UCN-01	2	PRKACB
BMS-754807	2	PRKACB
ELLAGIC ACID	2	PRKACB
UPROSERTIB	2	PRKACB
BMS-690514	2	PRKACB
R-406	2	PRKACB
AT-9283	2	PRKACB
PF-03758309	1	PRKACB
AT-13148	1	PRKACB
GSK-690693	1	PRKACB
AST-487	1	PRKACB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKACB	391	Binding:385, Functional:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKACB	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
PRKACB	391

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

19 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)
CAPIVASERTIB	4	PRKACB
DASATINIB	4	PRKACB
MIDOSTAURIN	4	PRKACB
FASUDIL	3	PRKACB
AFURESERTIB	3	PRKACB
ENZASTAURIN	3	PRKACB
LESTAURTINIB	3	PRKACB
RUBOXISTAURIN	3	PRKACB
UCN-01	2	PRKACB
BMS-754807	2	PRKACB
ELLAGIC ACID	2	PRKACB
UPROSERTIB	2	PRKACB
BMS-690514	2	PRKACB
R-406	2	PRKACB
AT-9283	2	PRKACB
PF-03758309	1	PRKACB
AT-13148	1	PRKACB
GSK-690693	1	PRKACB
AST-487	1	PRKACB

Druggability pyramid

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

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