Amyloidosis, hereditary systemic 3

Summary

Amyloidosis, hereditary systemic 3 (MONDO:0971008) 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: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyloidosis, hereditary systemic 3
Mondo ID	MONDO:0971008
OMIM	620657
UMLS	C4551500
MedGen	1635231
GARD	0027101
Is cancer (heuristic)	no

Data availability: 49 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hereditary amyloidosis › familial amyloid neuropathy › amyloidosis, hereditary systemic 3

Related subtypes (3): amyloidosis, hereditary systemic 1, amyloidosis, hereditary systemic 5, amyloidosis, hereditary systemic 6

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

49 retrieved; paginated sample, class counts are floors:

32 uncertain significance, 9 pathogenic, 6 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
17917	NM_000039.3(APOA1):c.148G>C (p.Gly50Arg)	APOA1	Pathogenic	criteria provided, multiple submitters, no conflicts
17923	NM_000039.3(APOA1):c.251T>G (p.Leu84Arg)	APOA1	Pathogenic	no assertion criteria provided
17927	NM_000039.3(APOA1):c.250_284delinsGTCAC (p.Leu84_Phe95delinsValThr)	APOA1	Pathogenic	no assertion criteria provided
17928	NM_000039.3(APOA1):c.220T>C (p.Trp74Arg)	APOA1	Pathogenic	criteria provided, single submitter
17932	NM_000039.3(APOA1):c.518G>C (p.Arg173Pro)	APOA1	Pathogenic	no assertion criteria provided
17933	NM_000039.3(APOA1):c.593T>C (p.Leu198Ser)	APOA1	Pathogenic	no assertion criteria provided
17934	NM_000039.3(APOA1):c.595G>C (p.Ala199Pro)	APOA1	Pathogenic	no assertion criteria provided
3767253	NM_000039.3(APOA1):c.130G>T (p.Asp44Tyr)	APOA1	Pathogenic	no assertion criteria provided
4812879	NM_000039.3(APOA1):c.286T>C (p.Trp96Arg)	APOA1	Pathogenic	no assertion criteria provided
1163527	NM_000039.3(APOA1):c.296T>C (p.Leu99Pro)	APOA1-AS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
636899	NM_000039.3(APOA1):c.388AAG[1] (p.Lys131del)	APOA1	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
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
17931	NM_000039.3(APOA1):c.341T>C (p.Leu114Pro)	APOA1	Uncertain significance	criteria provided, single submitter
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
2554657	NM_000039.3(APOA1):c.88A>G (p.Ser30Gly)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2702220	NM_000039.3(APOA1):c.658G>C (p.Ala220Pro)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2867498	NM_000039.3(APOA1):c.512A>T (p.Glu171Val)	APOA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3030577	NM_000039.3(APOA1):c.563C>T (p.Ala188Val)	APOA1	Uncertain significance	criteria provided, single submitter
3231950	NM_000039.3(APOA1):c.789G>T (p.Lys263Asn)	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 dominant	familial visceral amyloidosis	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.