Hypertriglyceridemia 1

Summary

Hypertriglyceridemia 1 (MONDO:0007788) is a disease caused by APOA5 (GenCC Definitive), with 5 cohort genes and 1 clinical trial.

At a glance

• Causal gene: APOA5 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 16
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertriglyceridemia 1
Mondo ID	MONDO:0007788
OMIM	145750
SNOMED CT	34528009
UMLS	C5444012
MedGen	1787149
GARD	0024577
Is cancer (heuristic)	no

Also known as: hypertriglyceridemia, familial

Data availability: 16 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › hypertriglyceridemia › hypertriglyceridemia 1

Related subtypes (1): hypertriglyceridemia 2

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

16 retrieved; paginated sample, class counts are floors:

5 conflicting classifications of pathogenicity, 3 uncertain significance, 2 benign, 2 likely pathogenic, 2 benign/likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
381733	NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)	APOA5	Pathogenic	criteria provided, multiple submitters, no conflicts
978324	NM_001371904.1(APOA5):c.990_993del (p.Asp332fs)	APOA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066069	NM_001371904.1(APOA5):c.681C>A (p.Cys227Ter)	APOA5	Likely pathogenic	criteria provided, single submitter
4075749	NM_001371904.1(APOA5):c.667C>T (p.Arg223Cys)	APOA5	Likely pathogenic	criteria provided, single submitter
1204530	NM_001371904.1(APOA5):c.823C>T (p.Gln275Ter)	APOA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2137252	NM_001371904.1(APOA5):c.644C>T (p.Pro215Leu)	APOA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4402	NM_001371904.1(APOA5):c.553G>T (p.Gly185Cys)	APOA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
917849	NM_032607.3(CREB3L3):c.718G>A (p.Glu240Lys)	CREB3L3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
979022	NM_032607.3(CREB3L3):c.732dup (p.Lys245fs)	CREB3L3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803845	NM_001371904.1(APOA5):c.1081A>C (p.Ser361Arg)	APOA5	Uncertain significance	criteria provided, single submitter
4077046	NM_001371904.1(APOA5):c.1027C>T (p.Arg343Cys)	APOA5	Uncertain significance	criteria provided, single submitter
2627073	NM_001371904.1(APOA5):c.16_39del (p.Ala6_Ala13del)	LOC108491825	Uncertain significance	criteria provided, multiple submitters, no conflicts
127141	NM_001371904.1(APOA5):c.*158C>T	APOA5	Benign	criteria provided, multiple submitters, no conflicts
4403	NM_001371904.1(APOA5):c.56C>G (p.Ser19Trp)	APOA5	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1822	NM_001302998.2(LIPI):c.164G>A (p.Cys55Tyr)	LIPI	Benign	criteria provided, multiple submitters, no conflicts
5969	NM_006269.2(RP1):c.2953A>T (p.Asn985Tyr)	RP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
APOA5	Definitive	Autosomal dominant	hypertriglyceridemia 1	5
CREB3L3	Strong	Autosomal dominant	hypertriglyceridemia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOA5	Orphanet:530849	Familial apolipoprotein A5 deficiency
CREB3L3	Orphanet:300293	Transient infantile hypertriglyceridemia and hepatosteatosis
RP1	Orphanet:791	Retinitis pigmentosa
MAPRE2	Orphanet:2505	Multiple benign circumferential skin creases on limbs

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOA5	HGNC:17288	ENSG00000110243	Q6Q788	Apolipoprotein A-V	gencc,clinvar
CREB3L3	HGNC:18855	ENSG00000060566	Q68CJ9	Cyclic AMP-responsive element-binding protein 3-like protein 3	gencc,clinvar
RP1	HGNC:10263	ENSG00000104237	P56715	Oxygen-regulated protein 1	clinvar
LIPI	HGNC:18821	ENSG00000188992	Q6XZB0	Lipase member I	clinvar
MAPRE2	HGNC:6891	ENSG00000166974	Q15555	Microtubule-associated protein RP/EB family member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOA5	Apolipoprotein A-V	Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL.
CREB3L3	Cyclic AMP-responsive element-binding protein 3-like protein 3	Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes.
RP1	Oxygen-regulated protein 1	Microtubule-associated protein regulating the stability and length of the microtubule-based axoneme of photoreceptors.
LIPI	Lipase member I	Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid.
MAPRE2	Microtubule-associated protein RP/EB family member 2	Adapter protein that is involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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	2.4×	0.353
Other/Unknown	4	1.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOA5	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
CREB3L3	Other/Unknown	no		bZIP, bZIP_sf, CREB_ATF_subfamily
RP1	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
LIPI	Enzyme (other)	yes	3.1.1.111	TAG_lipase, Lipase, Lipase_LIPH
MAPRE2	Other/Unknown	no		CH_dom, EB1_C, MAPRE

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
male germ line stem cell (sensu Vertebrata) in testis	2
liver	1
skeletal muscle tissue of rectus abdominis	1
duodenum	1
jejunal mucosa	1
olfactory segment of nasal mucosa	1
right uterine tube	1
cauda epididymis	1
corpus epididymis	1
corpus callosum	1
cortical plate	1
dorsal root ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOA5	45	tissue_specific	yes	right lobe of liver, liver, skeletal muscle tissue of rectus abdominis
CREB3L3	119	tissue_specific	marker	right lobe of liver, jejunal mucosa, duodenum
RP1	103	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis
LIPI	102	tissue_specific	marker	corpus epididymis, male germ line stem cell (sensu Vertebrata) in testis, cauda epididymis
MAPRE2	300	ubiquitous	marker	cortical plate, dorsal root ganglion, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAPRE2	2,195
APOA5	1,919
CREB3L3	1,421
RP1	797
LIPI	424

Intra-cohort edges

A	B	Sources
APOA5	CREB3L3	string_interaction
APOA5	LIPI	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 5 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPI	Q6XZB0	89.19
MAPRE2	Q15555	75.12
APOA5	Q6Q788	72.38
CREB3L3	Q68CJ9	60.26
RP1	P56715	37.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 5 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
Assembly of active LPL and LIPC lipase complexes	2	400.7×	1e-04	APOA5, CREB3L3
CREB3 factors activate genes	1	423.0×	0.013	CREB3L3
Chylomicron remodeling	1	380.7×	0.013	APOA5
Metabolism of lipids	2	21.0×	0.013	APOA5, LIPI
Plasma lipoprotein remodeling	1	158.6×	0.021	APOA5
Glycerophospholipid biosynthesis	1	112.0×	0.025	LIPI
Synthesis of PA	1	97.6×	0.025	LIPI
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.028	APOA5
Phospholipid metabolism	1	66.8×	0.028	LIPI
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.033	APOA5
Metabolism	2	7.7×	0.033	APOA5, LIPI
Post-translational protein phosphorylation	1	33.4×	0.041	APOA5
PPARA activates gene expression	1	31.5×	0.041	APOA5
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.042	APOA5
Transport of small molecules	1	8.4×	0.130	APOA5
Post-translational protein modification	1	6.4×	0.158	APOA5
Metabolism of proteins	1	4.1×	0.223	APOA5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of very-low-density lipoprotein particle remodeling	1	1685.2×	0.010	APOA5
positive regulation of ARF protein signal transduction	1	1123.5×	0.010	MAPRE2
triglyceride-rich lipoprotein particle remodeling	1	1123.5×	0.010	APOA5
photoreceptor cell development	1	842.6×	0.010	RP1
very-low-density lipoprotein particle clearance	1	674.1×	0.010	APOA5
acylglycerol homeostasis	1	674.1×	0.010	APOA5
positive regulation of triglyceride catabolic process	1	421.3×	0.010	APOA5
positive regulation of lipid catabolic process	1	374.5×	0.010	APOA5
positive regulation of focal adhesion disassembly	1	374.5×	0.010	MAPRE2
positive regulation of non-motile cilium assembly	1	374.5×	0.010	RP1
retinal rod cell development	1	337.0×	0.010	RP1
positive regulation of acute inflammatory response	1	280.9×	0.010	CREB3L3
retinal cone cell development	1	280.9×	0.010	RP1
phototransduction, visible light	1	259.3×	0.010	RP1
protein localization to microtubule	1	259.3×	0.010	MAPRE2
positive regulation of fatty acid biosynthetic process	1	259.3×	0.010	APOA5
positive regulation of keratinocyte migration	1	259.3×	0.010	MAPRE2
phospholipid efflux	1	224.7×	0.010	APOA5
regulation of microtubule polymerization or depolymerization	1	210.7×	0.010	MAPRE2
photoreceptor cell outer segment organization	1	210.7×	0.010	RP1
cellular response to light stimulus	1	210.7×	0.010	RP1
lipoprotein metabolic process	1	187.2×	0.011	APOA5
triglyceride catabolic process	1	160.5×	0.011	APOA5
positive regulation of receptor-mediated endocytosis	1	160.5×	0.011	APOA5
tissue regeneration	1	153.2×	0.011	APOA5
axoneme assembly	1	108.7×	0.015	RP1
cholesterol efflux	1	105.3×	0.015	APOA5
phosphatidic acid biosynthetic process	1	102.1×	0.015	LIPI
triglyceride homeostasis	1	96.3×	0.016	APOA5
triglyceride metabolic process	1	88.7×	0.016	APOA5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APOA5	0	0
CREB3L3	0	0
RP1	0	0
LIPI	0	0
MAPRE2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RP1	1	Binding:1
MAPRE2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIPI	3.1.1.111, 3.1.1.32	phosphatidylserine sn-1 acylhydrolase, phospholipase A1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	LIPI
E	Difficult family or no structure, no drug	4	APOA5, CREB3L3, RP1, MAPRE2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APOA5	0	—
CREB3L3	0	—
RP1	1	—
LIPI	0	—
MAPRE2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05860569	PHASE1	RECRUITING	Safety Evaluation of Gene Therapy Drug in the Treatment of Primary Hypertriglyceridemic Patients With Recurrent Pancreatitis