Hypercholesterolemia, familial, 4

Summary

Hypercholesterolemia, familial, 4 (MONDO:0011374) is a disease caused by LDLRAP1 (GenCC Strong), with 3 cohort genes and 2 clinical trials.

At a glance

• Causal gene: LDLRAP1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 509
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercholesterolemia, familial, 4
Mondo ID	MONDO:0011374
MeSH	C566331
OMIM	603813
DOID	DOID:0090105
NCIT	C128114
UMLS	C1863512
MedGen	400313
GARD	0018614
Is cancer (heuristic)	no

Also known as: ARH · ARH1 · ARH2 · autosomal recessive hypercholesterolemia 1 · autosomal recessive hypercholesterolemia 2 · FHCB1 · FHCB2 · hypercholesterolemia, autosomal recessive · hypercholesterolemia, autosomal recessive, 1 · hypercholesterolemia, autosomal recessive, 2

Data availability: 509 ClinVar variants · 3 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hypercholesterolemia, familial, 4

Related subtypes (92): thiopurine metabolic disease, hypercalcemia, infantile, hypermanganesemia with dystonia, abdominal obesity-metabolic syndrome, plasma protein metabolism disease, inherited lipid metabolism disorder, lysosomal storage disease, striatonigral degeneration, inborn metal metabolism disorder, inborn vitamin metabolic disorder, chondrocalcinosis 2, Ehlers-Danlos syndrome, spondylodysplastic type, fish eye disease, aromatase excess syndrome, spondyloepiphyseal dysplasia with congenital joint dislocations, hypertriglyceridemia 1, autosomal dominant myoglobinuria, diastrophic dysplasia, hemolytic anemia due to diphosphoglycerate mutase deficiency, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, inherited threoninemia, inborn glycerol kinase deficiency, achondrogenesis type IB, diabetes mellitus, noninsulin-dependent, 1, diabetes mellitus, noninsulin-dependent, 2, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, diabetes mellitus, noninsulin-dependent, 3, hypoalphalipoproteinemia, primary, 1, autosomal recessive proximal renal tubular acidosis, diabetes mellitus, noninsulin-dependent, 4, normophosphatemic familial tumoral calcinosis, apolipoprotein c-III deficiency, hypotonia-failure to thrive-microcephaly syndrome, chondrodysplasia with joint dislocations, gPAPP type, gluthathione peroxidase deficiency, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diabetes mellitus, noninsulin-dependent, 5, congenital disorder of glycosylation, monogenic diabetes, 2-hydroxyglutaric aciduria, familial hypoparathyroidism, familial intrahepatic cholestasis, inborn aminoacylase deficiency, disorder of lysosomal-related organelles, inborn disorder of porphyrin metabolism, disorder of metabolite absorption and transport, autosomal dominant proximal renal tubular acidosis, neurodegeneration with brain iron accumulation, ferro-cerebro-cutaneous syndrome, familial hypocalciuric hypercalcemia, hypophosphatasia, hereditary amyloidosis, peroxisomal disease, inborn disorder of amino acid and other organic acid metabolism, inborn carbohydrate metabolic disorder, inborn disorder of energy metabolism, inborn disorder of biogenic amine metabolism and transport, inborn disorder of purine or pyrimidine metabolism, spondyloepimetaphyseal dysplasia, PAPSS2 type, hereditary lipodystrophy, hereditary recurrent myoglobinuria, DNA repair disease, 4-hydroxyphenylacetic aciduria, 5-nucleotidase syndrome, antigen-peptide-transporter 2 deficiency, APO A-i deficiency, cardiomyopathy hypogonadism metabolic anomalies, deficiency of coenzyme q cytochrome c reductase, defective apolipoprotein b-100, sulfide quinone oxidoreductase deficiency, congenital disorder of deglycosylation, hypoalphalipoproteinemia, primary, 2, uridine-cytidineuria, NAD(P)HX dehydratase deficiency, inborn disorder of aspartate family metabolism, weinstein kliman scully syndrome, glycoprotein metabolism disease, inherited thyroid metabolism disease, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 3, combined ApoA-I and ApoC-III deficiency, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, tumoral calcinosis, hyperphosphatemic, familial, 1, Waldenstrom macroglobulinemia, mucopolysaccharidosis or mucopolysaccharidosis-like disorder, disorder of peptide and amine metabolism, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis, Lane Hamilton syndrome, SQSTM1-related multisystem proteinopathy, hypertriglyceridemia 2, autosomal dominant dopa-responsive dystonia

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

509 retrieved; paginated sample, class counts are floors:

284 likely benign, 108 uncertain significance, 37 pathogenic, 33 conflicting classifications of pathogenicity, 15 benign, 14 likely pathogenic, 12 pathogenic/likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
251752	NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln)	LDLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072018	NM_015627.3(LDLRAP1):c.402del (p.Ser135fs)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074905	NM_015627.3(LDLRAP1):c.400C>T (p.Gln134Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
1324659	NM_015627.3(LDLRAP1):c.344+1G>A	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1366160	NM_015627.3(LDLRAP1):c.113del (p.Thr38fs)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373822	NM_015627.3(LDLRAP1):c.143del (p.Phe48fs)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1394189	NM_015627.3(LDLRAP1):c.104G>A (p.Trp35Ter)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399626	NM_015627.3(LDLRAP1):c.604del (p.Ser202fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
1455119	NM_015627.3(LDLRAP1):c.89-2A>G	LDLRAP1	Pathogenic	criteria provided, single submitter
1456558	NM_015627.3(LDLRAP1):c.547del (p.Asp183fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
1457973	NM_015627.3(LDLRAP1):c.439del (p.Leu147fs)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1471714	NM_015627.3(LDLRAP1):c.460-1G>A	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2154296	NM_015627.3(LDLRAP1):c.301_304del (p.Asp101fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
2437212	NM_015627.3(LDLRAP1):c.66G>A (p.Trp22Ter)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2697613	NM_015627.3(LDLRAP1):c.17C>A (p.Ser6Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
2698048	NM_015627.3(LDLRAP1):c.567_570del (p.Gly190fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
2789329	NM_015627.3(LDLRAP1):c.466del (p.Ala156fs)	LDLRAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2804597	NM_015627.3(LDLRAP1):c.178C>T (p.Gln60Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
2831407	NM_015627.3(LDLRAP1):c.442_443del (p.Cys148fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
2832489	NM_015627.3(LDLRAP1):c.105G>A (p.Trp35Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
2835248	NM_015627.3(LDLRAP1):c.516G>A (p.Trp172Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
2850621	NM_015627.3(LDLRAP1):c.58C>T (p.Gln20Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
2855236	NM_015627.3(LDLRAP1):c.148del (p.Leu50fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
296981	NM_015627.3(LDLRAP1):c.487C>T (p.Gln163Ter)	LDLRAP1	Pathogenic	criteria provided, single submitter
3247771	NC_000001.10:g.(?25870190)(25870297_?)del	LDLRAP1	Pathogenic	criteria provided, single submitter
3247772	NC_000001.10:g.(?25883624)(25883778_?)del	LDLRAP1	Pathogenic	criteria provided, single submitter
3247773	NC_000001.10:g.(?25889115)(25889664_?)del	LDLRAP1	Pathogenic	criteria provided, single submitter
3611168	NM_015627.3(LDLRAP1):c.226del (p.Ala76fs)	LDLRAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3633064	NM_015627.3(LDLRAP1):c.55_79del (p.Lys19fs)	LDLRAP1	Pathogenic	criteria provided, single submitter
3720184	NM_015627.3(LDLRAP1):c.207del (p.Ala70fs)	LDLRAP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
LDLRAP1	Strong	Autosomal recessive	hypercholesterolemia, familial, 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LDLRAP1	Orphanet:391665	Homozygous familial hypercholesterolemia
LDLR	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
LDLRAP1	HGNC:18640	ENSG00000157978	Q5SW96	Low density lipoprotein receptor adapter protein 1	gencc,clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar
PAFAH2	HGNC:8579	ENSG00000158006	Q99487	Platelet-activating factor acetylhydrolase 2, cytoplasmic	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LDLRAP1	Low density lipoprotein receptor adapter protein 1	Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts).
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.
PAFAH2	Platelet-activating factor acetylhydrolase 2, cytoplasmic	Catalyzes the hydrolyze of the acetyl group at the sn-2 position of platelet-activating factor (PAF) and its analogs, leading to their inactivation.

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LDLRAP1	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Adapter_Engulfment-Domain
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
PAFAH2	Enzyme (other)	yes	3.1.1.47	PAF_acetylhydro_eukaryote, AB_hydrolase_fold

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adrenal tissue	1
lower lobe of lung	1
right adrenal gland	1
body of pancreas	1
colonic epithelium	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LDLRAP1	271	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland
PAFAH2	210	ubiquitous	marker	body of pancreas, colonic epithelium, pancreas

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LDLR	1,426
LDLRAP1	1,055
PAFAH2	748

Intra-cohort edges

A	B	Sources
LDLR	LDLRAP1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LDLR	P01130	36
LDLRAP1	Q5SW96	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PAFAH2	Q99487	91.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Chylomicron clearance	2	1522.7×	1e-05	LDLRAP1, LDLR
LDL clearance	2	362.5×	9e-05	LDLRAP1, LDLR
Plasma lipoprotein clearance	2	317.2×	9e-05	LDLRAP1, LDLR
Plasma lipoprotein assembly, remodeling, and clearance	2	152.3×	3e-04	LDLRAP1, LDLR
Metabolism of vitamins and cofactors	2	77.7×	1e-03	LDLRAP1, LDLR
Cargo recognition for clathrin-mediated endocytosis	2	69.8×	1e-03	LDLRAP1, LDLR
Clathrin-mediated endocytosis	2	56.8×	0.001	LDLRAP1, LDLR
Transport of RCbl within the body	1	475.8×	0.005	LDLRAP1
Membrane Trafficking	2	24.7×	0.005	LDLRAP1, LDLR
Vesicle-mediated transport	2	23.2×	0.005	LDLRAP1, LDLR
Vitamin D (calciferol) metabolism	1	292.8×	0.007	LDLRAP1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	211.5×	0.008	LDLRAP1
Transport of small molecules	2	16.8×	0.008	LDLRAP1, LDLR
Metabolism of fat-soluble vitamins	1	126.9×	0.012	LDLR
Platelet homeostasis	1	92.8×	0.016	PAFAH2
Visual phototransduction	1	86.5×	0.016	LDLR
Retinoid metabolism and transport	1	82.8×	0.016	LDLR
Metabolism of water-soluble vitamins and cofactors	1	60.4×	0.020	LDLRAP1
Metabolism of steroids	1	45.9×	0.024	LDLRAP1
Metabolism	2	7.7×	0.024	LDLRAP1, LDLR
Sensory Perception	1	31.7×	0.033	LDLR
Metabolism of lipids	1	10.5×	0.092	LDLRAP1

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
receptor-mediated endocytosis involved in cholesterol transport	2	5617.3×	1e-06	LDLRAP1, LDLR
low-density lipoprotein particle clearance	2	660.9×	7e-05	LDLRAP1, LDLR
cholesterol transport	2	488.5×	9e-05	LDLRAP1, LDLR
receptor-mediated endocytosis	2	147.8×	7e-04	LDLRAP1, LDLR
cholesterol metabolic process	2	130.6×	8e-04	LDLRAP1, LDLR
cholesterol homeostasis	2	104.0×	1e-03	LDLRAP1, LDLR
regulation of phosphatidylcholine catabolic process	1	2808.7×	0.002	LDLR
regulation of protein binding	1	2808.7×	0.002	LDLRAP1
positive regulation of receptor-mediated endocytosis involved in cholesterol transport	1	2808.7×	0.002	LDLRAP1
lipid metabolic process	2	61.1×	0.002	LDLR, PAFAH2
negative regulation of astrocyte activation	1	1872.4×	0.002	LDLR
plasma lipoprotein particle clearance	1	1404.3×	0.003	LDLR
positive regulation of low-density lipoprotein particle clearance	1	1404.3×	0.003	LDLRAP1
negative regulation of receptor recycling	1	1123.5×	0.003	LDLR
positive regulation of lysosomal protein catabolic process	1	1123.5×	0.003	LDLR
cholesterol import	1	936.2×	0.003	LDLR
high-density lipoprotein particle clearance	1	802.5×	0.003	LDLR
lipoprotein catabolic process	1	802.5×	0.003	LDLR
regulation of protein metabolic process	1	702.2×	0.003	LDLR
negative regulation of protein metabolic process	1	702.2×	0.003	LDLR
positive regulation of cholesterol metabolic process	1	702.2×	0.003	LDLRAP1
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.003	LDLR
negative regulation of microglial cell activation	1	702.2×	0.003	LDLR
negative regulation of low-density lipoprotein particle clearance	1	510.7×	0.004	LDLR
response to caloric restriction	1	510.7×	0.004	LDLR
intestinal cholesterol absorption	1	468.1×	0.004	LDLR
positive regulation of triglyceride biosynthetic process	1	432.1×	0.004	LDLR
amyloid precursor protein metabolic process	1	432.1×	0.004	LDLRAP1
negative regulation of amyloid fibril formation	1	432.1×	0.004	LDLR
regulation of cholesterol metabolic process	1	374.5×	0.004	LDLR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
LDLR	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LDLR	1	4
LDLRAP1	0	0
PAFAH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NILOTINIB	4	LDLR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LDLR	55	Binding:54, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAFAH2	3.1.1.47	1-alkyl-2-acetylglycerophosphocholine esterase

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	LDLR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LDLR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PAFAH2
E	Difficult family or no structure, no drug	1	LDLRAP1

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)
LDLRAP1	0	—
PAFAH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH
NCT06535542	Not specified	RECRUITING	Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis