Aortic aneurysm, familial thoracic 8

Summary

Aortic aneurysm, familial thoracic 8 (MONDO:0014187) is a disease caused by PRKG1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PRKG1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 628

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic aneurysm, familial thoracic 8
Mondo ID	MONDO:0014187
OMIM	615436
UMLS	C3809513
MedGen	815843
GARD	0015966
Is cancer (heuristic)	no

Also known as: AAT8 · aortic aneurysm, familial thoracic 8 · aortic aneurysm, familial thoracic type 8 · familial thoracic aortic aneurysm and aortic dissection caused by mutation in PRKG1 · PRKG1 familial thoracic aortic aneurysm and aortic dissection

Data availability: 628 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 › familial thoracic aortic aneurysm and aortic dissection › aortic aneurysm, familial thoracic 8

Related subtypes (8): aortic aneurysm, familial thoracic 4, aortic aneurysm, familial thoracic 2, aortic aneurysm, familial thoracic 6, aortic aneurysm, familial thoracic 7, aortic aneurysm, familial thoracic 9, aortic aneurysm, familial thoracic 10, aortic aneurysm, familial thoracic 1, aortic aneurysm, familial thoracic 12

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

600 retrieved; paginated sample, class counts are floors:

303 likely benign, 237 uncertain significance, 24 benign/likely benign, 19 conflicting classifications of pathogenicity, 16 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
65477	NM_006258.4(PRKG1):c.575G>A (p.Arg192Gln)	PRKG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1003881	NM_006258.4(PRKG1):c.698+4G>A	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1059696	NM_006258.4(PRKG1):c.2043A>T (p.Gly681=)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1113097	NM_006258.4(PRKG1):c.1710-4G>A	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1352452	NM_006258.4(PRKG1):c.75C>A (p.Ile25=)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1756512	NM_006258.4(PRKG1):c.699C>T (p.Ser233=)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210010	NM_006258.4(PRKG1):c.1466A>T (p.Tyr489Phe)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2199506	NM_006258.4(PRKG1):c.1896A>G (p.Lys632=)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264097	NM_006258.4(PRKG1):c.1811A>C (p.Asn604Thr)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264425	NM_006258.4(PRKG1):c.1173+4G>A	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451057	NM_006258.4(PRKG1):c.1106A>G (p.Asn369Ser)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477773	NM_006258.4(PRKG1):c.1576T>C (p.Phe526Leu)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477776	NM_006258.4(PRKG1):c.2014G>A (p.Asp672Asn)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477778	NM_006258.4(PRKG1):c.421A>C (p.Lys141Gln)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477782	NM_006258.4(PRKG1):c.893C>T (p.Thr298Ile)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
507180	NM_006258.4(PRKG1):c.1962T>C (p.Ser654=)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
512811	NM_006258.4(PRKG1):c.777T>C (p.Asn259=)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520133	NM_006258.4(PRKG1):c.1928G>A (p.Arg643Lys)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
648390	NM_006258.4(PRKG1):c.839C>T (p.Thr280Met)	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
680113	NM_006258.4(PRKG1):c.1076+19_1076+20insTGGCCTT	PRKG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2425547	NC_000010.10:g.(?53227463)(53769653_?)dup	CSTF2T	Uncertain significance	criteria provided, single submitter
1023392	NC_000010.10:g.(?54011320)(54530789_?)dup	DKK1	Uncertain significance	criteria provided, single submitter
1023391	NC_000010.10:g.(?53564335)(53564460_?)del	PRKG1	Uncertain significance	criteria provided, single submitter
1023487	NM_006258.4(PRKG1):c.805A>G (p.Arg269Gly)	PRKG1	Uncertain significance	criteria provided, single submitter
1034732	NM_006258.4(PRKG1):c.1166T>C (p.Val389Ala)	PRKG1	Uncertain significance	criteria provided, single submitter
1041937	NM_006258.4(PRKG1):c.478+5G>A	PRKG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1044634	NM_006258.4(PRKG1):c.2052A>G (p.Ile684Met)	PRKG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1049118	NM_006258.4(PRKG1):c.815C>A (p.Thr272Asn)	PRKG1	Uncertain significance	criteria provided, single submitter
1051422	NM_006258.4(PRKG1):c.160C>G (p.Arg54Gly)	PRKG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1056988	NM_006258.4(PRKG1):c.1173+3A>G	PRKG1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PRKG1	Strong	Unknown	familial thoracic aortic aneurysm and aortic dissection	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKG1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
DKK1	Orphanet:268882	Arnold-Chiari malformation type I
DKK1	Orphanet:85193	Idiopathic juvenile osteoporosis

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
PRKG1	HGNC:9414	ENSG00000185532	Q13976	cGMP-dependent protein kinase 1	gencc,clinvar
CSTF2T	HGNC:17086	ENSG00000177613	Q9H0L4	Cleavage stimulation factor subunit 2 tau variant	clinvar
DKK1	HGNC:2891	ENSG00000107984	O94907	Dickkopf-related protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKG1	cGMP-dependent protein kinase 1	Serine/threonine protein kinase that acts as a key mediator of the nitric oxide (NO)/cGMP signaling pathway.
CSTF2T	Cleavage stimulation factor subunit 2 tau variant	May play a significant role in AAUAAA-independent mRNA polyadenylation in germ cells.
DKK1	Dickkopf-related protein 1	Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6.

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKG1	Kinase	yes	2.7.11.12	cNMP-bd_dom, Prot_kinase_dom, AGC-kinase_C
CSTF2T	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, CSTF2_hinge
DKK1	Other/Unknown	no		Dickkopf_N, DKK1-4, Dkk1_Cys2

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
biceps brachii	1
saphenous vein	1
skeletal muscle tissue of biceps brachii	1
choroid plexus epithelium	1
endothelial cell	1
germinal epithelium of ovary	1
decidua	1
endometrium epithelium	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKG1	247	ubiquitous	marker	saphenous vein, biceps brachii, skeletal muscle tissue of biceps brachii
CSTF2T	283	ubiquitous	marker	endothelial cell, germinal epithelium of ovary, choroid plexus epithelium
DKK1	195	ubiquitous	marker	decidua, endometrium epithelium, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DKK1	3,058
CSTF2T	2,868
PRKG1	110

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKG1	Q13976	26
DKK1	O94907	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CSTF2T	Q9H0L4	60.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Signaling by LRP5 mutants	1	543.8×	0.013	DKK1
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	380.7×	0.013	DKK1
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	237.9×	0.013	DKK1
Rap1 signalling	1	237.9×	0.013	PRKG1
cGMP effects	1	237.9×	0.013	PRKG1
Processing of Intronless Pre-mRNAs	1	190.3×	0.014	CSTF2T
Beta-catenin independent WNT signaling	1	97.6×	0.023	PRKG1
RNA Polymerase II Transcription Termination	1	73.2×	0.024	CSTF2T
Maturation of DENV proteins	1	70.5×	0.024	PRKG1
mRNA 3’-end processing	1	65.6×	0.024	CSTF2T
Ca2+ pathway	1	59.5×	0.024	PRKG1
TCF dependent signaling in response to WNT	1	39.2×	0.033	DKK1
Signaling by WNT	1	37.3×	0.033	PRKG1
mRNA Polyadenylation	1	29.3×	0.039	CSTF2T
Dengue Virus-Host Interactions	1	15.2×	0.069	CSTF2T
Signal Transduction	1	3.4×	0.267	PRKG1

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
forebrain development	2	234.1×	0.001	PRKG1, DKK1
regulation of endodermal cell fate specification	1	5617.3×	0.002	DKK1
positive regulation of Wnt signaling pathway, calcium modulating pathway	1	5617.3×	0.002	DKK1
negative regulation of Wnt-Frizzled-LRP5/6 complex assembly	1	5617.3×	0.002	DKK1
positive regulation of midbrain dopaminergic neuron differentiation	1	5617.3×	0.002	DKK1
negative regulation of presynapse assembly	1	5617.3×	0.002	DKK1
negative regulation of inositol phosphate biosynthetic process	1	2808.7×	0.003	PRKG1
negative regulation of mesodermal cell fate specification	1	1872.4×	0.003	DKK1
Wnt signaling pathway involved in somitogenesis	1	1872.4×	0.003	DKK1
regulation of dopaminergic neuron differentiation	1	1872.4×	0.003	DKK1
negative regulation of glutamate secretion	1	1123.5×	0.004	PRKG1
regulation of testosterone biosynthetic process	1	1123.5×	0.004	PRKG1
relaxation of vascular associated smooth muscle	1	936.2×	0.004	PRKG1
regulation of receptor internalization	1	802.5×	0.004	DKK1
cell growth involved in cardiac muscle cell development	1	802.5×	0.004	PRKG1
motor learning	1	802.5×	0.004	DKK1
bone growth	1	802.5×	0.004	PRKG1
synapse pruning	1	802.5×	0.004	DKK1
negative regulation of cardiac muscle cell differentiation	1	802.5×	0.004	DKK1
heart induction	1	702.2×	0.004	DKK1
positive regulation of Wnt signaling pathway, planar cell polarity pathway	1	624.1×	0.004	DKK1
negative regulation of vascular associated smooth muscle cell migration	1	561.7×	0.005	PRKG1
heart valve development	1	510.7×	0.005	DKK1
endocardial cushion development	1	468.1×	0.005	DKK1
negative regulation of platelet aggregation	1	468.1×	0.005	PRKG1
positive regulation of circadian rhythm	1	401.2×	0.005	PRKG1
collateral sprouting	1	401.2×	0.005	PRKG1
regulation of vascular permeability	1	374.5×	0.006	PRKG1
obsolete cGMP-mediated signaling	1	267.5×	0.008	PRKG1
regulation of neuron apoptotic process	1	234.1×	0.008	DKK1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PRKG1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKG1	15	4
CSTF2T	0	0
DKK1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	PRKG1
PACRITINIB	4	PRKG1
CAPIVASERTIB	4	PRKG1
NINTEDANIB	4	PRKG1
MIDOSTAURIN	4	PRKG1
IPATASERTIB	3	PRKG1
LINIFANIB	3	PRKG1
ENZASTAURIN	3	PRKG1
LESTAURTINIB	3	PRKG1
SAR-407899 FREE BASE	2	PRKG1
CENISERTIB	2	PRKG1
SOTRASTAURIN	2	PRKG1
KW-2449	1	PRKG1
PF-03758309	1	PRKG1
GSK-690693	1	PRKG1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKG1	356	Binding:355, Functional:1
DKK1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKG1	2.7.11.12	cGMP-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
PRKG1	356

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

15 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)
FEDRATINIB	4	PRKG1
PACRITINIB	4	PRKG1
CAPIVASERTIB	4	PRKG1
NINTEDANIB	4	PRKG1
MIDOSTAURIN	4	PRKG1
IPATASERTIB	3	PRKG1
LINIFANIB	3	PRKG1
ENZASTAURIN	3	PRKG1
LESTAURTINIB	3	PRKG1
SAR-407899 FREE BASE	2	PRKG1
CENISERTIB	2	PRKG1
SOTRASTAURIN	2	PRKG1
KW-2449	1	PRKG1
PF-03758309	1	PRKG1
GSK-690693	1	PRKG1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKG1
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	CSTF2T, DKK1

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)
CSTF2T	0	—
DKK1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.