Hypoalphalipoproteinemia, primary, 2

Summary

Hypoalphalipoproteinemia, primary, 2 (MONDO:0032766) is a disease caused by APOA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: APOA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 69

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoalphalipoproteinemia, primary, 2
Mondo ID	MONDO:0032766
OMIM	618463
DOID	DOID:0080958
UMLS	C5551172
MedGen	1789263
GARD	0025738
Is cancer (heuristic)	no

Also known as: ApoA-I and apoC-III deficiency, combined · HYPOALPHALIPOPROTEINEMIA, PRIMARY, 2 · hypoalphalipoproteinemia, primary, 2, with or without corneal clouding

Data availability: 69 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hypoalphalipoproteinemia, primary, 2

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, hypercholesterolemia, familial, 4, 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, 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

Subtypes (1): hypoalphalipoproteinemia, primary, 2, intermediate

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

69 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 8 conflicting classifications of pathogenicity, 7 pathogenic, 6 likely benign, 5 benign/likely benign, 4 benign, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17917	NM_000039.3(APOA1):c.148G>C (p.Gly50Arg)	APOA1	Pathogenic	criteria provided, multiple submitters, no conflicts
17921	NM_000039.3(APOA1):c.678del (p.Leu227fs)	APOA1	Pathogenic	no assertion criteria provided
17922	NM_000039.3(APOA1):c.322C>T (p.Gln108Ter)	APOA1	Pathogenic	no assertion criteria provided
17924	NM_000039.3(APOA1):c.67C>T (p.Gln23Ter)	APOA1	Pathogenic	criteria provided, multiple submitters, no conflicts
17926	NM_000039.3(APOA1):c.166C>T (p.Gln56Ter)	APOA1	Pathogenic	no assertion criteria provided
17929	NM_000039.3(APOA1):c.539T>A (p.Val180Glu)	APOA1	Pathogenic	no assertion criteria provided
17930	NM_000039.3(APOA1):c.43+1G>C	APOA1	Pathogenic	no assertion criteria provided
565272	NM_000039.3(APOA1):c.532_533dup (p.His179fs)	APOA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1163527	NM_000039.3(APOA1):c.296T>C (p.Leu99Pro)	APOA1-AS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341582	NM_000039.3(APOA1):c.542A>G (p.Asp181Gly)	APOA1	Likely pathogenic	criteria provided, single submitter
1687354	NM_000039.3(APOA1):c.364C>T (p.Gln122Ter)	APOA1	Likely pathogenic	criteria provided, single submitter
1900584	NM_000039.3(APOA1):c.44-5C>G	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302503	NM_000039.3(APOA1):c.498C>A (p.Ser166Arg)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302510	NM_000039.3(APOA1):c.28G>A (p.Val10Met)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3231928	NM_000039.3(APOA1):c.42G>A (p.Thr14=)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504196	NM_000039.3(APOA1):c.85dup (p.Gln29fs)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636899	NM_000039.3(APOA1):c.388AAG[1] (p.Lys131del)	APOA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302508	NM_000039.3(APOA1):c.168G>A (p.Gln56=)	APOA1-AS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879223	NM_000039.3(APOA1):c.178T>G (p.Ser60Ala)	APOA1-AS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301313	NM_000039.3(APOA1):c.752T>A (p.Val251Asp)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1338197	NM_000039.3(APOA1):c.80C>A (p.Pro27His)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1371350	NM_000039.3(APOA1):c.794_796dup (p.Asn265_Thr266insAsn)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1461988	NM_000039.3(APOA1):c.379G>A (p.Asp127Asn)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1501391	NM_000039.3(APOA1):c.127G>A (p.Val43Met)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1513939	NM_000039.3(APOA1):c.271G>T (p.Val91Leu)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
17912	NM_000039.3(APOA1):c.664G>A (p.Glu222Lys)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
17920	NM_000039.3(APOA1):c.101G>T (p.Arg34Leu)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1907392	NM_000039.3(APOA1):c.537T>G (p.His179Gln)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1977672	NM_000039.3(APOA1):c.389A>G (p.Lys130Arg)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2332981	NM_000039.3(APOA1):c.508G>A (p.Glu170Lys)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
APOA1	Strong	Autosomal recessive	hypoalphalipoproteinemia, primary, 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:93560	AApoAI amyloidosis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOA1	HGNC:600	ENSG00000118137	P02647	Apolipoprotein A-I	gencc,clinvar
APOA1-AS	HGNC:40079	ENSG00000235910		APOA1 antisense RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOA1	Apolipoprotein A-I	Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOA1	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
APOA1-AS	Other/Unknown	no

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
jejunal mucosa	1
liver	1
right lobe of liver	1
colonic epithelium	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOA1	170	broad	marker	jejunal mucosa, right lobe of liver, liver
APOA1-AS	131		marker	corpus callosum, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOA1	3,608
APOA1-AS	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOA1	P02647	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 2 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
Defective ABCA1 causes TGD	1	5710.0×	0.006	APOA1
HDL clearance	1	2284.0×	0.006	APOA1
HDL assembly	1	1427.5×	0.006	APOA1
Chylomicron assembly	1	1142.0×	0.006	APOA1
Chylomicron remodeling	1	1142.0×	0.006	APOA1
HDL remodeling	1	1142.0×	0.006	APOA1
Scavenging by Class B Receptors	1	1038.2×	0.006	APOA1
Scavenging of heme from plasma	1	878.5×	0.006	APOA1
Plasma lipoprotein assembly	1	713.8×	0.007	APOA1
ABC transporters in lipid homeostasis	1	601.0×	0.007	APOA1
Scavenging by Class A Receptors	1	601.0×	0.007	APOA1
Binding and Uptake of Ligands by Scavenger Receptors	1	543.8×	0.007	APOA1
Plasma lipoprotein remodeling	1	475.8×	0.007	APOA1
Plasma lipoprotein clearance	1	475.8×	0.007	APOA1
ABC transporter disorders	1	439.2×	0.007	APOA1
Metabolism of fat-soluble vitamins	1	380.7×	0.007	APOA1
Dengue virus activates/modulates innate and adaptive immune responses	1	335.9×	0.008	APOA1
Visual phototransduction	1	259.6×	0.010	APOA1
Retinoid metabolism and transport	1	248.3×	0.010	APOA1
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.010	APOA1
Heme signaling	1	215.5×	0.010	APOA1
Maturation of DENV proteins	1	211.5×	0.010	APOA1
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.012	APOA1
Regulation of lipid metabolism by PPARalpha	1	141.0×	0.013	APOA1
Disorders of transmembrane transporters	1	139.3×	0.013	APOA1
ABC-family protein mediated transport	1	121.5×	0.014	APOA1
Metabolism of vitamins and cofactors	1	116.5×	0.014	APOA1
Platelet activation, signaling and aggregation	1	105.7×	0.015	APOA1
Amyloid fiber formation	1	102.9×	0.015	APOA1
Post-translational protein phosphorylation	1	100.2×	0.015	APOA1

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
protein oxidation	1	5617.3×	0.001	APOA1
peptidyl-methionine modification	1	5617.3×	0.001	APOA1
regulation of intestinal cholesterol absorption	1	4213.0×	0.001	APOA1
positive regulation of phospholipid efflux	1	4213.0×	0.001	APOA1
acylglycerol homeostasis	1	3370.4×	0.001	APOA1
negative regulation of cell adhesion molecule production	1	3370.4×	0.001	APOA1
cellular response to lipoprotein particle stimulus	1	3370.4×	0.001	APOA1
negative regulation of cytokine production involved in immune response	1	2808.7×	0.001	APOA1
glucocorticoid metabolic process	1	2808.7×	0.001	APOA1
negative regulation of very-low-density lipoprotein particle remodeling	1	2808.7×	0.001	APOA1
lipoprotein biosynthetic process	1	2808.7×	0.001	APOA1
vitamin transport	1	2808.7×	0.001	APOA1
negative regulation of response to cytokine stimulus	1	2808.7×	0.001	APOA1
cholesterol import	1	2808.7×	0.001	APOA1
high-density lipoprotein particle clearance	1	2407.4×	0.001	APOA1
positive regulation of cholesterol metabolic process	1	2106.5×	0.001	APOA1
negative regulation of heterotypic cell-cell adhesion	1	1872.4×	0.001	APOA1
amyloid-beta formation	1	1872.4×	0.001	APOA1
high-density lipoprotein particle assembly	1	1685.2×	0.001	APOA1
regulation of Cdc42 protein signal transduction	1	1404.3×	0.002	APOA1
blood vessel endothelial cell migration	1	1404.3×	0.002	APOA1
phospholipid efflux	1	1123.5×	0.002	APOA1
phospholipid homeostasis	1	991.3×	0.002	APOA1
reverse cholesterol transport	1	936.2×	0.002	APOA1
phosphatidylcholine biosynthetic process	1	802.5×	0.002	APOA1
high-density lipoprotein particle remodeling	1	802.5×	0.002	APOA1
cholesterol transport	1	732.7×	0.002	APOA1
adrenal gland development	1	674.1×	0.002	APOA1
negative chemotaxis	1	648.1×	0.003	APOA1
positive regulation of cholesterol efflux	1	624.1×	0.003	APOA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APOA1	0	0
APOA1-AS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
APOA1	2	Binding:2

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	APOA1, APOA1-AS

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)
APOA1	2	—
APOA1-AS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.