Hypertriglyceridemia 2

Summary

Hypertriglyceridemia 2 (MONDO:0859149) is a disease caused by CREB3L3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CREB3L3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertriglyceridemia 2
Mondo ID	MONDO:0859149
OMIM	619324
UMLS	C5543398
MedGen	1783778
GARD	0027307
Is cancer (heuristic)	no

Data availability: 13 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › hypertriglyceridemia › hypertriglyceridemia 2

Related subtypes (1): hypertriglyceridemia 1

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

13 retrieved; paginated sample, class counts are floors:

3 benign, 3 conflicting classifications of pathogenicity, 3 uncertain significance, 1 risk factor, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120264	NM_032607.3(CREB3L3):c.138G>A (p.Trp46Ter)	CREB3L3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1120265	NM_032607.3(CREB3L3):c.363del (p.Cys123fs)	CREB3L3	Pathogenic	no assertion criteria provided
1120263	NM_032607.3(CREB3L3):c.[732dup;739A>T]		risk factor	no assertion criteria provided
1507133	NM_032607.3(CREB3L3):c.739dup (p.Ile247fs)	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
3269455	NM_032607.3(CREB3L3):c.1174C>T (p.Arg392Ter)	LOC125371455	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3647603	NM_032607.3(CREB3L3):c.457+5G>A	CREB3L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4819173	NM_032607.3(CREB3L3):c.485G>A (p.Cys162Tyr)	CREB3L3	Uncertain significance	criteria provided, single submitter
4819763	NM_032607.3(CREB3L3):c.1073-5A>G	CREB3L3	Uncertain significance	criteria provided, single submitter
1165837	NM_032607.3(CREB3L3):c.313G>A (p.Gly105Arg)	CREB3L3	Benign	criteria provided, multiple submitters, no conflicts
1600091	NM_032607.3(CREB3L3):c.544G>A (p.Asp182Asn)	CREB3L3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1653533	NM_032607.3(CREB3L3):c.891-14C>T	CREB3L3	Benign	criteria provided, multiple submitters, no conflicts
714753	NM_032607.3(CREB3L3):c.1245G>A (p.Thr415=)	CREB3L3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
CREB3L3	Strong	Autosomal dominant	hypertriglyceridemia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CREB3L3	Orphanet:300293	Transient infantile hypertriglyceridemia and hepatosteatosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CREB3L3	HGNC:18855	ENSG00000060566	Q68CJ9	Cyclic AMP-responsive element-binding protein 3-like protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CREB3L3	Other/Unknown	no		bZIP, bZIP_sf, CREB_ATF_subfamily

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
jejunal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CREB3L3	119	tissue_specific	marker	right lobe of liver, jejunal mucosa, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CREB3L3	1,421

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CREB3L3	Q68CJ9	60.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
CREB3 factors activate genes	1	1268.9×	0.002	CREB3L3
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.002	CREB3L3

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
positive regulation of acute inflammatory response	1	1404.3×	0.004	CREB3L3
response to unfolded protein	1	300.9×	0.008	CREB3L3
response to endoplasmic reticulum stress	1	166.8×	0.010	CREB3L3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.084	CREB3L3
regulation of transcription by RNA polymerase II	1	11.7×	0.086	CREB3L3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CREB3L3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	CREB3L3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CREB3L3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.