Hypoalphalipoproteinemia, primary, 1

Summary

Hypoalphalipoproteinemia, primary, 1 (MONDO:0011393) is a disease caused by ABCA1 (GenCC Definitive), with 4 cohort genes and 5 clinical trials. Top therapeutic interventions include romosozumab and zoledronic acid anhydrous.

At a glance

• Causal gene: ABCA1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 291
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoalphalipoproteinemia, primary, 1
Mondo ID	MONDO:0011393
OMIM	604091
DOID	DOID:0080957
UMLS	C5231558
MedGen	1684828
GARD	0024796
Is cancer (heuristic)	no

Also known as: familial HDL deficiency · FHA · FHD · HDL deficiency, familial, 1 · HDLD · hypoalphalipoproteinemia, familial

Data availability: 291 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 › inborn errors of metabolism › hypoalphalipoproteinemia, primary, 1

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, 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

291 retrieved; paginated sample, class counts are floors:

111 uncertain significance, 91 conflicting classifications of pathogenicity, 41 benign, 34 benign/likely benign, 6 likely pathogenic, 4 likely benign, 3 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
364389	NM_005502.4(ABCA1):c.5398A>C (p.Asn1800His)	ABCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9486	NM_005502.4(ABCA1):c.2077CTT[1] (p.Leu694del)	ABCA1	Pathogenic	no assertion criteria provided
9504	NM_005502.4(ABCA1):c.3849_3852del (p.Pro1284fs)	ABCA1	Pathogenic	no assertion criteria provided
9502	NM_005502.4(ABCA1):c.6026T>C (p.Phe2009Ser)	NIPSNAP3B	Pathogenic	no assertion criteria provided
1064620	NM_005502.4(ABCA1):c.5237+3A>C	ABCA1	Likely pathogenic	criteria provided, single submitter
1803827	NM_005502.4(ABCA1):c.844C>T (p.Arg282Ter)	ABCA1	Likely pathogenic	criteria provided, single submitter
1803885	NM_005502.4(ABCA1):c.4539T>A (p.Tyr1513Ter)	ABCA1	Likely pathogenic	criteria provided, single submitter
2683744	NM_005502.4(ABCA1):c.1857_1858delinsAT (p.Met619_Gln620delinsIleTer)	ABCA1	Likely pathogenic	criteria provided, single submitter
3779318	NM_005502.4(ABCA1):c.2745_2754del (p.Val916fs)	ABCA1	Likely pathogenic	criteria provided, single submitter
3892960	NM_005502.4(ABCA1):c.5383-2A>T	ABCA1	Likely pathogenic	criteria provided, single submitter
1326278	NM_005502.4(ABCA1):c.6599G>A (p.Arg2200Gln)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1329701	NM_005502.4(ABCA1):c.5492C>T (p.Ala1831Val)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1355168	NM_005502.4(ABCA1):c.6118A>G (p.Lys2040Glu)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1402805	NM_005502.4(ABCA1):c.1390G>A (p.Val464Met)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1445865	NM_005502.4(ABCA1):c.1765G>A (p.Val589Ile)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1657879	NM_005502.4(ABCA1):c.2543-3C>T	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2077232	NM_005502.4(ABCA1):c.3584G>A (p.Arg1195Gln)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225290	NM_005502.4(ABCA1):c.2660G>T (p.Cys887Phe)	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364324	NM_005502.4(ABCA1):c.*3087C>T	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364327	NM_005502.4(ABCA1):c.*2907A>C	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364331	NM_005502.4(ABCA1):c.*2611A>G	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364332	NM_005502.4(ABCA1):c.*2486T>C	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364334	NM_005502.4(ABCA1):c.*2409T>C	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364337	NM_005502.4(ABCA1):c.*2089G>A	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364342	NM_005502.4(ABCA1):c.*1768T>A	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364343	NM_005502.4(ABCA1):c.*1767G>T	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364348	NM_005502.4(ABCA1):c.*1476A>G	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364356	NM_005502.4(ABCA1):c.*1260C>G	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364357	NM_005502.4(ABCA1):c.*1218A>G	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364358	NM_005502.4(ABCA1):c.*1211G>A	ABCA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
ABCA1	Definitive	Autosomal dominant	hypoalphalipoproteinemia, primary, 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:93560	AApoAI amyloidosis

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	gencc,clinvar
NIPSNAP3B	HGNC:23641	ENSG00000165028	Q9BS92	Protein NipSnap homolog 3B	clinvar
APOA1-AS	HGNC:40079	ENSG00000235910		APOA1 antisense RNA	clinvar
APOA1	HGNC:600	ENSG00000118137	P02647	Apolipoprotein A-I	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCA1	Phospholipid-transporting ATPase ABCA1	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.
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: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Transporter	1	19.4×	0.101
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
NIPSNAP3B	Other/Unknown	no		Dimeric_a/b-barrel, NIPSNAP, NipSnap_domain
APOA1-AS	Other/Unknown	no
APOA1	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
left adrenal gland	1
skin of hip	1
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
colonic epithelium	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
jejunal mucosa	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCA1	272	ubiquitous	marker	adrenal tissue, skin of hip, left adrenal gland
NIPSNAP3B	210	broad	marker	biceps brachii, skeletal muscle tissue of biceps brachii, heart right ventricle
APOA1-AS	131		marker	corpus callosum, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium
APOA1	170	broad	marker	jejunal mucosa, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOA1	3,608
ABCA1	3,551
NIPSNAP3B	471
APOA1-AS	0

Intra-cohort edges

A	B	Sources
ABCA1	APOA1	biogrid_interaction, intact, string_interaction
ABCA1	NIPSNAP3B	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOA1	P02647	31
ABCA1	O95477	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NIPSNAP3B	Q9BS92	91.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 4 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
Defective ABCA1 causes TGD	2	5710.0×	8e-07	ABCA1, APOA1
HDL assembly	2	1427.5×	1e-05	ABCA1, APOA1
Plasma lipoprotein assembly	2	713.8×	3e-05	ABCA1, APOA1
ABC transporter disorders	2	439.2×	6e-05	ABCA1, APOA1
Plasma lipoprotein assembly, remodeling, and clearance	2	228.4×	2e-04	ABCA1, APOA1
Regulation of lipid metabolism by PPARalpha	2	141.0×	4e-04	ABCA1, APOA1
Disorders of transmembrane transporters	2	139.3×	4e-04	ABCA1, APOA1
PPARA activates gene expression	2	94.4×	7e-04	ABCA1, APOA1
HDL clearance	1	1142.0×	0.005	APOA1
Metabolism of lipids	2	31.6×	0.005	ABCA1, APOA1
Chylomicron assembly	1	571.0×	0.006	APOA1
Chylomicron remodeling	1	571.0×	0.006	APOA1
HDL remodeling	1	571.0×	0.006	APOA1
Transport of small molecules	2	25.1×	0.006	ABCA1, APOA1
Scavenging by Class B Receptors	1	519.1×	0.006	APOA1
Scavenging of heme from plasma	1	439.2×	0.007	APOA1
ABC transporters in lipid homeostasis	1	300.5×	0.009	APOA1
Scavenging by Class A Receptors	1	300.5×	0.009	APOA1
Binding and Uptake of Ligands by Scavenger Receptors	1	271.9×	0.009	APOA1
Plasma lipoprotein remodeling	1	237.9×	0.010	APOA1
Plasma lipoprotein clearance	1	237.9×	0.010	APOA1
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.011	ABCA1
Metabolism of fat-soluble vitamins	1	190.3×	0.011	APOA1
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.012	APOA1
Disease	2	13.1×	0.012	ABCA1, APOA1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.012	ABCA1
Metabolism	2	11.6×	0.013	ABCA1, APOA1
Visual phototransduction	1	129.8×	0.013	APOA1
Retinoid metabolism and transport	1	124.1×	0.014	APOA1
Heme signaling	1	107.7×	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipoprotein biosynthetic process	2	1872.4×	2e-05	ABCA1, APOA1
high-density lipoprotein particle assembly	2	1123.5×	3e-05	ABCA1, APOA1
regulation of Cdc42 protein signal transduction	2	936.2×	3e-05	ABCA1, APOA1
phospholipid efflux	2	749.0×	4e-05	ABCA1, APOA1
phospholipid homeostasis	2	660.9×	4e-05	ABCA1, APOA1
reverse cholesterol transport	2	624.1×	4e-05	ABCA1, APOA1
positive regulation of cholesterol efflux	2	416.1×	8e-05	ABCA1, APOA1
cholesterol efflux	2	351.1×	9e-05	ABCA1, APOA1
cholesterol metabolic process	2	130.6×	6e-04	ABCA1, APOA1
cholesterol homeostasis	2	104.0×	9e-04	ABCA1, APOA1
response to vitamin B3	1	2808.7×	0.002	ABCA1
regulation of high-density lipoprotein particle assembly	1	2808.7×	0.002	ABCA1
positive regulation of high-density lipoprotein particle assembly	1	2808.7×	0.002	ABCA1
protein oxidation	1	1872.4×	0.002	APOA1
peptidyl-methionine modification	1	1872.4×	0.002	APOA1
signal release	1	1872.4×	0.002	ABCA1
peptide secretion	1	1404.3×	0.003	ABCA1
regulation of intestinal cholesterol absorption	1	1404.3×	0.003	APOA1
response to laminar fluid shear stress	1	1404.3×	0.003	ABCA1
positive regulation of phospholipid efflux	1	1404.3×	0.003	APOA1
acylglycerol homeostasis	1	1123.5×	0.003	APOA1
negative regulation of cell adhesion molecule production	1	1123.5×	0.003	APOA1
cellular response to lipoprotein particle stimulus	1	1123.5×	0.003	APOA1
negative regulation of cytokine production involved in immune response	1	936.2×	0.003	APOA1
glucocorticoid metabolic process	1	936.2×	0.003	APOA1
negative regulation of very-low-density lipoprotein particle remodeling	1	936.2×	0.003	APOA1
vitamin transport	1	936.2×	0.003	APOA1
negative regulation of response to cytokine stimulus	1	936.2×	0.003	APOA1
cholesterol import	1	936.2×	0.003	APOA1
high-density lipoprotein particle clearance	1	802.5×	0.003	APOA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
ABCA1	0	0
NIPSNAP3B	0	0
APOA1-AS	0	0
APOA1	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
ABCA1	2	Binding:2
APOA1	2	Binding:2

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

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	ABCA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	NIPSNAP3B, APOA1-AS, APOA1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCA1	2	—
NIPSNAP3B	0	—
APOA1-AS	0	—
APOA1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
Not specified	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06533865	PHASE3	RECRUITING	Romosozumab as an Adjunct to Physiologic Estrogen Replacement in Functional Hypothalamic Amenorrhea
NCT07010146	PHASE2	RECRUITING	Role of Estrogen on Skeletal Outcomes in FHA
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00453219	Not specified	WITHDRAWN	FHA: Characterization of Metabolic Status, Brain Circuitry, and Stress-Reactivity
NCT06571578	Not specified	COMPLETED	High Intensity Interval Inspiratory Training Effect on Ventilatory Functions and Diaphragmatic Excursion in Forward Head Posture

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ROMOSOZUMAB	4	1
ZOLEDRONIC ACID ANHYDROUS	4	1