Coronary artery disease, autosomal dominant 2

Summary

Coronary artery disease, autosomal dominant 2 (MONDO:0012586) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	coronary artery disease, autosomal dominant 2
Mondo ID	MONDO:0012586
MeSH	C567045
OMIM	610947
UMLS	C1970440
MedGen	370259
Is cancer (heuristic)	no

Also known as: ADCAD2 · coronary artery disease caused by mutation in LRP6 · coronary artery disease, autosomal dominant 2 · coronary artery disease, autosomal dominant type 2 · coronary artery disease, autosomal dominant, 2 · LRP6 coronary artery disease

Data availability: 21 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › arterial disorder › coronary artery disorder › coronary artery disease, autosomal dominant 2

Related subtypes (11): coronary vasospasm, postoperative ventricular dysfunction, coronary aneurysm, coronary stenosis, coronary thrombosis, intermediate coronary syndrome, coronary artery disease, autosomal dominant, 1, coronary artery congenital malformation, coronary atherosclerosis, nonobstructive coronary artery disease, fibromuscular dysplasia of the coronary arteries

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

21 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
6267	NM_002336.3(LRP6):c.1831C>T (p.Arg611Cys)	LRP6	Pathogenic	criteria provided, single submitter
689556	NM_002336.3(LRP6):c.2218C>T (p.Gln740Ter)	LRP6	Pathogenic	criteria provided, single submitter
2464538	NM_002336.3(LRP6):c.4525C>T (p.Pro1509Ser)	LRP6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732299	NM_002336.3(LRP6):c.752A>G (p.Asn251Ser)	LRP6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1524709	NM_004341.5(CAD):c.1408G>A (p.Asp470Asn)	CAD	Uncertain significance	criteria provided, multiple submitters, no conflicts
3067838	NM_004341.5(CAD):c.3719G>T (p.Arg1240Leu)	CAD	Uncertain significance	criteria provided, single submitter
3067863	NM_004341.5(CAD):c.5077G>A (p.Glu1693Lys)	CAD	Uncertain significance	criteria provided, single submitter
3068176	NM_004341.5(CAD):c.5734_5757dup (p.His1919_Ser1920insProGlnThrSerProLeuLeuHis)	CAD	Uncertain significance	criteria provided, single submitter
1394380	NM_002336.3(LRP6):c.2203G>A (p.Asp735Asn)	LRP6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2056656	NM_002336.3(LRP6):c.3107A>G (p.Asn1036Ser)	LRP6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2198245	NM_002336.3(LRP6):c.1625G>A (p.Gly542Asp)	LRP6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382045	NM_002336.3(LRP6):c.553A>T (p.Asn185Tyr)	LRP6	Uncertain significance	criteria provided, single submitter
3891598	NM_002336.3(LRP6):c.2221G>C (p.Val741Leu)	LRP6	Uncertain significance	criteria provided, single submitter
3891599	NM_002336.3(LRP6):c.3391C>T (p.Leu1131Phe)	LRP6	Uncertain significance	criteria provided, single submitter
3891600	NM_002336.3(LRP6):c.3875A>G (p.Gln1292Arg)	LRP6	Uncertain significance	criteria provided, single submitter
66054	NM_002336.3(LRP6):c.1298A>G (p.Asn433Ser)	LRP6	Uncertain significance	criteria provided, single submitter
66055	NM_002336.3(LRP6):c.1418G>A (p.Arg473Gln)	LRP6	Uncertain significance	criteria provided, single submitter
66056	NM_002336.3(LRP6):c.1079G>A (p.Arg360His)	LRP6	Uncertain significance	criteria provided, multiple submitters, no conflicts
816933	NM_002336.3(LRP6):c.1118A>G (p.Tyr373Cys)	LRP6	Uncertain significance	criteria provided, single submitter
723536	NM_002336.3(LRP6):c.3192A>G (p.Val1064=)	LRP6	Benign	criteria provided, multiple submitters, no conflicts
723537	NM_002336.3(LRP6):c.2382C>T (p.Asn794=)	LRP6	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
LRP6	Limited	Unknown	coronary artery disease, autosomal dominant 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRP6	Orphanet:1810	Autosomal dominant hypohidrotic ectodermal dysplasia
LRP6	Orphanet:99798	Oligodontia
CAD	Orphanet:448010	CAD-CDG

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
LRP6	HGNC:6698	ENSG00000070018	O75581	Low-density lipoprotein receptor-related protein 6	gencc,clinvar
CAD	HGNC:1424	ENSG00000084774	P27708	Multifunctional protein CAD	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRP6	Low-density lipoprotein receptor-related protein 6	Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes.
CAD	Multifunctional protein CAD	Multifunctional protein that encodes the first 3 enzymatic activities of the de novo pyrimidine pathway: carbamoylphosphate synthetase (CPSase; EC 6.3.5.5), aspartate transcarbamylase (ATCase; EC 2.1.3.2) and dihydroorotase (DHOase; EC 3.5…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRP6	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt
CAD	Enzyme (other)	yes	2.1.3.2	Asp_carbamoyltransf, Dihydroorotase_CS, CarbamoylP_synth_ssu_N

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
calcaneal tendon	1
corpus callosum	1
ventricular zone	1
body of uterus	1
right lobe of liver	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRP6	139	ubiquitous	marker	calcaneal tendon, corpus callosum, ventricular zone
CAD	223	ubiquitous	marker	body of uterus, stromal cell of endometrium, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAD	3,613
LRP6	2,525

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAD	P27708	55
LRP6	O75581	30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Pyrimidine biosynthesis	1	1903.3×	0.006	CAD
Signaling by RNF43 mutants	1	634.4×	0.008	LRP6
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	356.9×	0.008	LRP6
Signaling by WNT in cancer	1	300.5×	0.008	LRP6
Regulation of FZD by ubiquitination	1	259.6×	0.008	LRP6
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.010	LRP6
TCF dependent signaling in response to WNT	1	58.9×	0.024	LRP6
Signaling by WNT	1	56.0×	0.024	LRP6
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.043	LRP6
Disease	1	6.5×	0.162	LRP6
Signal Transduction	1	5.1×	0.187	LRP6

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
‘de novo’ UMP biosynthetic process	1	2808.7×	0.005	CAD
L-citrulline biosynthetic process	1	2106.5×	0.005	CAD
UDP biosynthetic process	1	1685.2×	0.005	CAD
‘de novo’ pyrimidine nucleobase biosynthetic process	1	1404.3×	0.005	CAD
response to caffeine	1	1203.7×	0.005	CAD
UTP biosynthetic process	1	936.2×	0.005	CAD
neural crest formation	1	936.2×	0.005	LRP6
response to amine	1	936.2×	0.005	CAD
response to cortisol	1	842.6×	0.005	CAD
neural crest cell differentiation	1	766.0×	0.005	LRP6
negative regulation of smooth muscle cell apoptotic process	1	702.2×	0.005	LRP6
L-glutamine metabolic process	1	648.1×	0.005	CAD
midbrain dopaminergic neuron differentiation	1	601.9×	0.005	LRP6
cellular response to cholesterol	1	421.3×	0.006	LRP6
dopaminergic neuron differentiation	1	312.1×	0.008	LRP6
animal organ regeneration	1	300.9×	0.008	CAD
response to testosterone	1	234.1×	0.009	CAD
response to starvation	1	234.1×	0.009	CAD
positive regulation of cell cycle	1	221.7×	0.009	LRP6
lactation	1	210.7×	0.009	CAD
response to peptide hormone	1	195.9×	0.009	LRP6
cellular response to epidermal growth factor stimulus	1	159.0×	0.011	CAD
response to insulin	1	115.4×	0.014	CAD
liver development	1	110.9×	0.014	CAD
female pregnancy	1	105.3×	0.014	CAD
canonical Wnt signaling pathway	1	76.6×	0.018	LRP6
xenobiotic metabolic process	1	74.6×	0.018	CAD
positive regulation of cytosolic calcium ion concentration	1	58.5×	0.022	LRP6
protein localization to plasma membrane	1	54.4×	0.023	LRP6
cell-cell adhesion	1	50.8×	0.024	LRP6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRP6	0	0
CAD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CAD	17	Binding:16, ADMET:1
LRP6	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAD	2.1.3.2, 3.5.2.3, 6.3.5.5	aspartate carbamoyltransferase, dihydroorotase, carbamoyl-phosphate synthase (glutamine-hydrolysing)

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	1	CAD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LRP6

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)
LRP6	9	—
CAD	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.