Tangier disease

Summary

Tangier disease (MONDO:0008783) is a disease caused by ABCA1 (GenCC Definitive), with 2 cohort genes and 5 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ABCA1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 287
• Phenotypes (HPO): 22
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		185	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0003146	Hypocholesterolemia	Very frequent (80-99%)
HP:0000656	Ectropion	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002730	Chronic noninfectious lymphadenopathy	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0004943	Accelerated atherosclerosis	Frequent (30-79%)
HP:0005145	Coronary artery stenosis	Frequent (30-79%)
HP:0007133	Progressive peripheral neuropathy	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0030814	Orange discoloured tonsils	Frequent (30-79%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0003396	Syringomyelia	Occasional (5-29%)
HP:0007957	Corneal opacity	Occasional (5-29%)
HP:0100546	Carotid artery stenosis	Occasional (5-29%)
HP:0010829	Impaired temperature sensition	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Tangier disease
Mondo ID	MONDO:0008783
MeSH	D013631
OMIM	205400
Orphanet	31150
DOID	DOID:1388
NCIT	C85182
SNOMED CT	723579009
UMLS	C0039292
MedGen	52644
GARD	0007731
MedDRA	10051875
NORD	1757
Is cancer (heuristic)	no

Also known as: A-alphalipoprotein neuropathy · Alpha high density lipoprotein deficiency disease · Analphalipo-proteinemia · Analphalipoproteinemia · ATP-binding cassette transporter A1 deficiency · cholesterol thesaurismosis · defective adenosine triphosphate-binding cassette transporter A1 · familial high density lipoprotein deficiency disease · familial Hypoalphalipo-proteinemia · HDL lipoprotein deficiency disease · HDLDT1 · Tangier disease · tgd

Data availability: 287 ClinVar variants · 4 GenCC gene-disease records · 6 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 › inherited lipid metabolism disorder › hypolipoproteinemia › Tangier disease

Related subtypes (2): Norum disease, hypobetalipoproteinemia

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

287 retrieved; paginated sample, class counts are floors:

104 uncertain significance, 84 conflicting classifications of pathogenicity, 42 benign, 32 benign/likely benign, 15 pathogenic, 8 likely pathogenic, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3256126	NM_005502.4(ABCA1):c.2302C>T (p.Gln768Ter)	ABCA1	Pathogenic	criteria provided, single submitter
3339293	NM_005502.4(ABCA1):c.1979del (p.Val660fs)	ABCA1	Pathogenic	criteria provided, single submitter
364389	NM_005502.4(ABCA1):c.5398A>C (p.Asn1800His)	ABCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813697	NM_005502.4(ABCA1):c.5449C>T (p.Arg1817Ter)	ABCA1	Pathogenic	criteria provided, single submitter
4813698	NM_005502.4(ABCA1):c.3112C>T (p.Gln1038Ter)	ABCA1	Pathogenic	criteria provided, single submitter
9484	NM_005502.4(ABCA1):c.3738+1G>C	ABCA1	Pathogenic	no assertion criteria provided
9485	NM_005502.4(ABCA1):c.1790A>G (p.Gln597Arg)	ABCA1	Pathogenic	no assertion criteria provided
9487	NM_005502.4(ABCA1):c.1824del (p.Thr609fs)	ABCA1	Pathogenic	no assertion criteria provided
9488	NM_005502.4(ABCA1):c.2804A>G (p.Asn935Ser)	ABCA1	Pathogenic	criteria provided, single submitter
9489	NM_005502.4(ABCA1):c.2810C>T (p.Ala937Val)	ABCA1	Pathogenic	no assertion criteria provided
9492	NM_005502.4(ABCA1):c.1584_1597delinsCGGGCGTGGTGGCAGGAGCTGTAATCCCAGCTACTTGGGAGGCTGAGGCACGAGAATCACTTGAACTCAGGAGGCAGAGGTTGCAGTGAGCTGAGGTCACGCCACTGTAC (p.Glu529_Trp533delinsGlyArgGlyGlyArgSerCysAsnProSerTyrLeuGlyGlyTer)	ABCA1	Pathogenic	no assertion criteria provided
9493	NM_005502.4(ABCA1):c.3343_3344del (p.Ser1115fs)	ABCA1	Pathogenic	no assertion criteria provided
9495	NM_005502.4(ABCA1):c.2725del (p.Arg909fs)	ABCA1	Pathogenic	no assertion criteria provided
9498	NM_005502.4(ABCA1):c.2803A>C (p.Asn935His)	ABCA1	Pathogenic	no assertion criteria provided
9499	NG_007981.1:g.[101177_102434delins36;107248_127198delins21]	ABCA1	Pathogenic	no assertion criteria provided
9505	NM_005502.4(ABCA1):c.1719C>A (p.Tyr573Ter)	ABCA1	Pathogenic	no assertion criteria provided
1803827	NM_005502.4(ABCA1):c.844C>T (p.Arg282Ter)	ABCA1	Likely pathogenic	criteria provided, single submitter
3063714	NM_005502.4(ABCA1):c.3103+1G>C	ABCA1	Likely pathogenic	criteria provided, single submitter
374312	NM_005502.4(ABCA1):c.2803A>G (p.Asn935Asp)	ABCA1	Likely pathogenic	no assertion criteria provided
3892960	NM_005502.4(ABCA1):c.5383-2A>T	ABCA1	Likely pathogenic	criteria provided, single submitter
4849334	NM_005502.4(ABCA1):c.1423C>T (p.Gln475Ter)	ABCA1	Likely pathogenic	criteria provided, single submitter
9483	NM_005502.4(ABCA1):c.4429T>C (p.Cys1477Arg)	ABCA1	Likely pathogenic	criteria provided, single submitter
9496	NM_005502.4(ABCA1):c.4517C>T (p.Ser1506Leu)	ABCA1	Likely pathogenic	criteria provided, single submitter
9494	NM_005502.4(ABCA1):c.6241C>T (p.Arg2081Trp)	NIPSNAP3B	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
ABCA1	Definitive	Autosomal recessive	Tangier disease	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency

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
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	gencc,clinvar
NIPSNAP3B	HGNC:23641	ENSG00000165028	Q9BS92	Protein NipSnap homolog 3B	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.

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
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

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

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
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

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

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCA1	3,551
NIPSNAP3B	471

Intra-cohort edges

A	B	Sources
ABCA1	NIPSNAP3B	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
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: 16. 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×	0.003	ABCA1
HDL assembly	1	1427.5×	0.006	ABCA1
Plasma lipoprotein assembly	1	713.8×	0.007	ABCA1
ABC transporter disorders	1	439.2×	0.008	ABCA1
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.008	ABCA1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.009	ABCA1
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.010	ABCA1
Regulation of lipid metabolism by PPARalpha	1	141.0×	0.013	ABCA1
Disorders of transmembrane transporters	1	139.3×	0.013	ABCA1
Signaling by Nuclear Receptors	1	102.0×	0.015	ABCA1
PPARA activates gene expression	1	94.4×	0.015	ABCA1
Metabolism of lipids	1	31.6×	0.042	ABCA1
Transport of small molecules	1	25.1×	0.049	ABCA1
Disease	1	13.1×	0.087	ABCA1
Metabolism	1	11.6×	0.092	ABCA1
Signal Transduction	1	10.2×	0.098	ABCA1

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
response to vitamin B3	1	4213.0×	0.003	ABCA1
regulation of high-density lipoprotein particle assembly	1	4213.0×	0.003	ABCA1
positive regulation of high-density lipoprotein particle assembly	1	4213.0×	0.003	ABCA1
signal release	1	2808.7×	0.003	ABCA1
peptide secretion	1	2106.5×	0.003	ABCA1
response to laminar fluid shear stress	1	2106.5×	0.003	ABCA1
lipoprotein biosynthetic process	1	1404.3×	0.004	ABCA1
high-density lipoprotein particle assembly	1	842.6×	0.004	ABCA1
export across plasma membrane	1	842.6×	0.004	ABCA1
negative regulation of cholesterol storage	1	766.0×	0.004	ABCA1
regulation of Cdc42 protein signal transduction	1	702.2×	0.004	ABCA1
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.004	ABCA1
intracellular cholesterol transport	1	648.1×	0.004	ABCA1
protein transmembrane transport	1	648.1×	0.004	ABCA1
phospholipid efflux	1	561.7×	0.004	ABCA1
phospholipid homeostasis	1	495.6×	0.004	ABCA1
reverse cholesterol transport	1	468.1×	0.004	ABCA1
cellular response to low-density lipoprotein particle stimulus	1	443.5×	0.004	ABCA1
cellular response to cholesterol	1	421.3×	0.004	ABCA1
phagocytosis, engulfment	1	337.0×	0.005	ABCA1
platelet dense granule organization	1	337.0×	0.005	ABCA1
positive regulation of cholesterol efflux	1	312.1×	0.005	ABCA1
phospholipid translocation	1	312.1×	0.005	ABCA1
cellular response to cytokine stimulus	1	271.8×	0.005	ABCA1
cholesterol efflux	1	263.3×	0.005	ABCA1
mitophagy	1	159.0×	0.009	NIPSNAP3B
lysosome organization	1	153.2×	0.009	ABCA1
protein secretion	1	131.7×	0.010	ABCA1
endosomal transport	1	122.1×	0.010	ABCA1
cellular response to xenobiotic stimulus	1	120.4×	0.010	ABCA1

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
ABCA1	0	0
NIPSNAP3B	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

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	ABCA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NIPSNAP3B

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)
ABCA1	2	—
NIPSNAP3B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01763528	PHASE3	COMPLETED	High Protein Weight Loss Diet, High Sensitivity C-Reactive Protein and Cardiovascular Risks Among Obese Women
NCT01886482	PHASE3	COMPLETED	Effect of High Protein Diet on Cardiovascular Diseases Risk Factors Among Overweight and Obese Children
NCT01886495	PHASE3	COMPLETED	Effect of High Protein Diet on Adiponectin and Inflammation Among Overweight and Obese Children
NCT00005188	Not specified	COMPLETED	Quantitative Genetic Analysis of Lipid Research Clinic Family Data
NCT01782027	Not specified	TERMINATED	Mendelian Reverse Cholesterol Transport Study