Hypercholesterolemia, autosomal dominant, 3

Summary

Hypercholesterolemia, autosomal dominant, 3 (MONDO:0011369) is a disease caused by PCSK9 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PCSK9 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,048
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercholesterolemia, autosomal dominant, 3
Mondo ID	MONDO:0011369
MeSH	C566337
OMIM	603776
UMLS	C1863551
MedGen	355007
GARD	0024793
Is cancer (heuristic)	no

Also known as: familial hypercholesterolemia caused by mutation in PCSK9 · HCHOLA3 · hypercholesterolemia, autosomal dominant, 3 · hypercholesterolemia, autosomal dominant, type 3 · hypercholesterolemia, familial, 3 · low density lipoprotein cholesterol level QTL 1 · PCSK9 familial hypercholesterolemia

Data availability: 1,048 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › familial hyperlipidemia › familial hypercholesterolemia › hypercholesterolemia, autosomal dominant, 3

Related subtypes (4): hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, type B, hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency, homozygous familial hypercholesterolemia

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:

278 uncertain significance, 208 likely benign, 72 conflicting classifications of pathogenicity, 16 benign, 16 benign/likely benign, 5 pathogenic/likely pathogenic, 3 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
201127	NM_174936.4(PCSK9):c.644G>A (p.Arg215His)	PCSK9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2027927	NM_174936.4(PCSK9):c.381T>G (p.Ser127Arg)	PCSK9	Pathogenic	criteria provided, single submitter
265939	NM_174936.4(PCSK9):c.1120G>C (p.Asp374His)	PCSK9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2873	NM_174936.4(PCSK9):c.381T>A (p.Ser127Arg)	PCSK9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2874	NM_174936.4(PCSK9):c.646T>C (p.Phe216Leu)	PCSK9	Pathogenic	no assertion criteria provided
2875	NM_174936.4(PCSK9):c.1120G>T (p.Asp374Tyr)	PCSK9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
297692	NM_174936.4(PCSK9):c.94G>A (p.Glu32Lys)	PCSK9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068052	NC_000001.10:g.(?55464850)(55530536_?)dup	BSND	Likely pathogenic	criteria provided, single submitter
1015123	NM_174936.4(PCSK9):c.653G>C (p.Arg218Thr)	PCSK9	Likely pathogenic	criteria provided, single submitter
1120257	NM_174936.4(PCSK9):c.1906A>C (p.Ser636Arg)	PCSK9	Likely pathogenic	criteria provided, single submitter
1035538	NM_174936.4(PCSK9):c.1591C>T (p.Gln531Ter)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1171041	NM_174936.4(PCSK9):c.1323G>A (p.Val441=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1171159	NM_174936.4(PCSK9):c.554_558del (p.Leu185fs)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1324866	NM_174936.4(PCSK9):c.316G>A (p.Gly106Arg)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1524079	NM_174936.4(PCSK9):c.652A>G (p.Arg218Gly)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1746317	NM_174936.4(PCSK9):c.524-5G>A	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1761089	NM_174936.4(PCSK9):c.789C>T (p.Gly263=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1771225	NM_174936.4(PCSK9):c.1378G>A (p.Val460Ile)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1775396	NM_174936.4(PCSK9):c.1567A>G (p.Ile523Val)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1781846	NM_174936.4(PCSK9):c.1879G>A (p.Glu627Lys)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1790140	NM_174936.4(PCSK9):c.235G>A (p.Val79Met)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
189308	NM_174936.4(PCSK9):c.610G>A (p.Asp204Asn)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201128	NM_174936.4(PCSK9):c.1405C>T (p.Arg469Trp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201129	NM_174936.4(PCSK9):c.1486C>T (p.Arg496Trp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2031915	NM_174936.4(PCSK9):c.65_66insGCTCCT (p.Leu23_Gly24insLeuLeu)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2418130	NM_174936.4(PCSK9):c.1394C>G (p.Ser465Trp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242027	NM_174936.4(PCSK9):c.1658A>G (p.His553Arg)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242028	NM_174936.4(PCSK9):c.720C>T (p.Gly240=)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2454168	NM_174936.4(PCSK9):c.147G>C (p.Glu49Asp)	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2497756	NM_174936.4(PCSK9):c.523+1G>A	PCSK9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
PCSK9	Definitive	Autosomal dominant	hypercholesterolemia, autosomal dominant, 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCSK9	Orphanet:391665	Homozygous familial hypercholesterolemia
BSND	Orphanet:89938	Bartter syndrome type 4
BSND	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia

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
PCSK9	HGNC:20001	ENSG00000169174	Q8NBP7	Proprotein convertase subtilisin/kexin type 9	gencc,clinvar
BSND	HGNC:16512	ENSG00000162399	Q8WZ55	Barttin	clinvar
APOB	HGNC:603	ENSG00000084674	P04114	Apolipoprotein B-100	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCSK9	Proprotein convertase subtilisin/kexin type 9	Crucial player in the regulation of plasma cholesterol homeostasis.
BSND	Barttin	Regulatory subunit of anion-selective CLCNKA:BSND and CLCNKB:BSND heteromeric channels involved in basolateral chloride conductance along the nephron to achieve urine concentration and maintain systemic acid-base homeostasis, and in the st…
APOB	Apolipoprotein B-100	Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100).

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCSK9	Protease	yes	3.4.21.61	Peptidase_S8/S53_dom, S8pro/Inhibitor_I9, Peptidase_S8_subtilisin-rel
BSND	Other/Unknown	no		Barttin
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom

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
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
right lobe of liver	1
adult mammalian kidney	1
kidney epithelium	1
metanephros cortex	1
ileal mucosa	1
jejunal mucosa	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCSK9	147	broad	marker	right lobe of liver, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis
BSND	22	tissue_specific	marker	kidney epithelium, adult mammalian kidney, metanephros cortex
APOB	116	broad	marker	jejunal mucosa, liver, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOB	5,244
PCSK9	2,994
BSND	996

Intra-cohort edges

A	B	Sources
APOB	PCSK9	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCSK9	Q8NBP7	65
APOB	P04114	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BSND	Q8WZ55	53.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. 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
LDL clearance	2	362.5×	4e-04	PCSK9, APOB
Post-translational protein phosphorylation	2	66.8×	0.006	PCSK9, APOB
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	57.7×	0.006	PCSK9, APOB
Scavenging by Class H Receptors	1	951.7×	0.008	APOB
VLDL assembly	1	761.3×	0.008	APOB
Chylomicron clearance	1	761.3×	0.008	APOB
Scavenging by Class F Receptors	1	634.4×	0.008	APOB
LDL remodeling	1	634.4×	0.008	APOB
VLDL clearance	1	634.4×	0.008	APOB
Chylomicron assembly	1	380.7×	0.011	APOB
Chylomicron remodeling	1	380.7×	0.011	APOB
Scavenging by Class B Receptors	1	346.1×	0.011	APOB
VLDLR internalisation and degradation	1	237.9×	0.013	PCSK9
Plasma lipoprotein assembly	1	237.9×	0.013	APOB
Platelet sensitization by LDL	1	223.9×	0.013	APOB
Transport of small molecules	2	16.8×	0.013	BSND, APOB
Scavenging by Class A Receptors	1	200.3×	0.013	APOB
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.013	APOB
Regulation of TLR by endogenous ligand	1	165.5×	0.013	APOB
Plasma lipoprotein remodeling	1	158.6×	0.013	APOB
Plasma lipoprotein clearance	1	158.6×	0.013	APOB
Metabolism of fat-soluble vitamins	1	126.9×	0.016	APOB
Platelet homeostasis	1	92.8×	0.021	APOB
Visual phototransduction	1	86.5×	0.022	APOB
Retinoid metabolism and transport	1	82.8×	0.022	APOB
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.023	APOB
Heme signaling	1	71.8×	0.023	APOB
Stimuli-sensing channels	1	45.3×	0.035	BSND
Toll-like Receptor Cascades	1	41.4×	0.037	APOB
Metabolism of vitamins and cofactors	1	38.8×	0.038	APOB

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
low-density lipoprotein particle receptor catabolic process	1	5617.3×	0.003	PCSK9
cholesterol metabolic process	2	130.6×	0.003	PCSK9, APOB
cholesterol homeostasis	2	104.0×	0.003	PCSK9, APOB
negative regulation of sodium ion import across plasma membrane	1	2808.7×	0.004	PCSK9
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	2808.7×	0.004	PCSK9
positive regulation of low-density lipoprotein particle receptor catabolic process	1	1872.4×	0.005	PCSK9
triglyceride mobilization	1	1404.3×	0.005	APOB
negative regulation of receptor recycling	1	1123.5×	0.005	PCSK9
cellular response to lipoprotein particle stimulus	1	1123.5×	0.005	APOB
lipoprotein biosynthetic process	1	936.2×	0.005	APOB
positive regulation of cholesterol storage	1	802.5×	0.005	APOB
lipoprotein catabolic process	1	802.5×	0.005	APOB
negative regulation of low-density lipoprotein particle clearance	1	510.7×	0.007	PCSK9
regulation of cholesterol biosynthetic process	1	510.7×	0.007	APOB
positive regulation of lipid storage	1	468.1×	0.007	APOB
negative regulation of receptor internalization	1	401.2×	0.007	PCSK9
very-low-density lipoprotein particle assembly	1	401.2×	0.007	APOB
low-density lipoprotein particle remodeling	1	351.1×	0.008	APOB
low-density lipoprotein particle clearance	1	330.4×	0.008	APOB
lipoprotein transport	1	330.4×	0.008	APOB
lipoprotein metabolic process	1	312.1×	0.008	PCSK9
positive regulation of macrophage derived foam cell differentiation	1	280.9×	0.008	APOB
triglyceride catabolic process	1	267.5×	0.008	APOB
cholesterol transport	1	244.2×	0.008	APOB
positive regulation of receptor internalization	1	234.1×	0.008	PCSK9
lysosomal transport	1	234.1×	0.008	PCSK9
regulation of neuron apoptotic process	1	234.1×	0.008	PCSK9
artery morphogenesis	1	224.7×	0.008	APOB
protein autoprocessing	1	216.1×	0.008	PCSK9
cholesterol efflux	1	175.5×	0.010	APOB

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
PCSK9	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCSK9	1	4
BSND	0	0
APOB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NILOTINIB	4	PCSK9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PCSK9	202	Binding:201, ADMET:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCSK9	3.4.21.61	Kexin

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PCSK9	202

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

1 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)
NILOTINIB	4	PCSK9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PCSK9
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	BSND, APOB

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)
BSND	0	—
APOB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH