CREB3L3

Summary

CREB3L3 (cAMP responsive element binding protein 3 like 3, HGNC:18855) is a protein-coding gene on chromosome 19p13.3, encoding Cyclic AMP-responsive element-binding protein 3-like protein 3 (Q68CJ9). Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes.

This gene encodes a member of the basic-leucine zipper family and the AMP-dependent transcription factor family. The encoded protein is localized to the endoplasmic reticulum and acts as a transcription factor activated by cyclic AMP stimulation. The encoded protein binds the cyclic AMP response element (CRE) and the box-B element and has been linked to acute inflammatory response, hepatocellular carcinoma, triglyceride metabolism, and hepcidin expression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 84699 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertriglyceridemia (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 338 total — 16 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_032607

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18855
Approved symbol	CREB3L3
Name	cAMP responsive element binding protein 3 like 3
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	CREB-H, CREBH
Ensembl gene	ENSG00000060566
Ensembl biotype	protein_coding
OMIM	611998
Entrez	84699

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000078445, ENST00000595923, ENST00000598894, ENST00000602147, ENST00000602257, ENST00000909762, ENST00000909763, ENST00000909764, ENST00000909765, ENST00000909766, ENST00000909767, ENST00000961095, ENST00000961096

RefSeq mRNA: 4 — MANE Select: NM_032607 NM_001271995, NM_001271996, NM_001271997, NM_032607

CCDS: CCDS12121, CCDS62498, CCDS62499, CCDS62500

Canonical transcript exons

ENST00000078445 — 10 exons

Exon	Start	End
ENSE00001146947	4164503	4164640
ENSE00001146956	4159664	4159782
ENSE00001146965	4156995	4157295
ENSE00003138033	4171656	4173054
ENSE00003222636	4153631	4153774
ENSE00003579081	4168351	4168457
ENSE00003625213	4171383	4171479
ENSE00003627215	4170140	4170208
ENSE00003632068	4154899	4155027
ENSE00003659868	4171091	4171175

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 98.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.4853 / max 807.9121, expressed in 130 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173276	2.3619	124
173277	0.0754	8
173283	0.0282	9
173282	0.0175	7
173281	0.0023	1

Top tissues by expression

235 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.33	gold quality
jejunal mucosa	UBERON:0000399	97.48	gold quality
duodenum	UBERON:0002114	93.63	gold quality
liver	UBERON:0002107	89.23	gold quality
small intestine	UBERON:0002108	86.91	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.86	gold quality
ileal mucosa	UBERON:0000331	86.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.33	gold quality
jejunum	UBERON:0002115	78.82	gold quality
mucosa of transverse colon	UBERON:0004991	70.94	gold quality
right adrenal gland	UBERON:0001233	70.18	gold quality
left adrenal gland cortex	UBERON:0035825	69.58	gold quality
left adrenal gland	UBERON:0001234	69.35	gold quality
secondary oocyte	CL:0000655	66.22	gold quality
adrenal cortex	UBERON:0001235	66.04	gold quality
cardiac muscle of right atrium	UBERON:0003379	65.33	gold quality
left ventricle myocardium	UBERON:0006566	65.09	gold quality
myocardium	UBERON:0002349	63.47	gold quality
adrenal gland	UBERON:0002369	62.85	gold quality
right adrenal gland cortex	UBERON:0035827	61.89	gold quality
oocyte	CL:0000023	60.78	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	59.11	gold quality
intestine	UBERON:0000160	59.03	gold quality
rectum	UBERON:0001052	57.95	gold quality
hypothalamus	UBERON:0001898	57.31	gold quality
prefrontal cortex	UBERON:0000451	57.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.23	gold quality
parotid gland	UBERON:0001831	56.15	gold quality
gingival epithelium	UBERON:0001949	55.50	gold quality
vastus lateralis	UBERON:0001379	55.42	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	63.72
E-ANND-3	yes	5.74
E-CURD-135	no	611.93

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
APOA5
CREB3
CRP
FGF21	Unknown
G6PC1	Activation
HAMP
LPIN1
PCK1	Activation
PCK2	Activation

JASPAR motifs

Motif	Name	Family
MA2541.1	CREB3L3	CREB-related

JASPAR matrix evidence (PMIDs): PMID:39605320

Upstream regulators (CollecTRI, top): ESRRG, PPARA

miRNA regulators (miRDB)

26 targeting CREB3L3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-346	97.01	66.97	662
HSA-MIR-6861-5P	96.23	67.19	800
HSA-MIR-632	96.08	67.17	798
HSA-MIR-644A	96.02	66.52	786
HSA-MIR-193A-5P	95.70	65.33	613
HSA-MIR-1231	95.10	65.63	663

Literature-anchored findings (GeneRIF, showing 13)

• Levels of CREB transcripts did NOT significantly differ in the thyroid adenomas and surrounding normal tissues. (PMID:12039695)
• analysis of CREB-H trafficking into alternate pathways of ERAD and stress-regulated intramembrane proteolysis (PMID:17875199)
• findings show that CREBH an endoplasmic reticulum stress-activated transcription factor, binds to and transactivates the hepcidin promoter (PMID:19679815)
• a novel mechanism of action of activated CB1R signaling to induce hepatic gluconeogenesis via direct activation of CREBH (PMID:21693703)
• Studies indicate that mutations in CREB3L3 in individuals with extreme hypertriglyceridemia. (PMID:22262056)
• Taken together, our results demonstrated that human APOA5 is directly regulated by CREBH via CREBHRE and provided a new insight into the role of this liver-specific bZIP transcription factor in lipoprotein metabolism and triglyceride homeostasis (PMID:23957007)
• CREBH activated by HBx interacted with HBx protein, leading to a synergistic effect on the expression of AP-1 target genes and the proliferation of hepatocellular carcinoma cells and mouse primary hepatocytes. (PMID:25428452)
• Identify a novel pathogenic mutation in CREB3L3 gene in a family with dominant hypertriglyceridemia with a variable pattern of penetrance. (PMID:26427795)
• Beta-TrCP controls ubiquitination and degradation of liver-enriched transcription factor CREB-H. (PMID:27029215)
• CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine. (PMID:29738435)
• Loss-of-Function CREB3L3 Variants in Patients With Severe Hypertriglyceridemia. (PMID:32580631)
• CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins. (PMID:34491909)
• A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity. (PMID:36649378)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	creb3l3a	ENSDARG00000056226
danio_rerio	creb3l3b	ENSDARG00000090903
mus_musculus	Creb3l3	ENSMUSG00000035041
rattus_norvegicus	Creb3l3	ENSRNOG00000032202
drosophila_melanogaster	CrebA	FBGN0004396
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793
caenorhabditis_elegans		WBGENE00016162

Paralogs (9): CREM (ENSG00000095794), CREB3 (ENSG00000107175), ATF6 (ENSG00000118217), CREB1 (ENSG00000118260), ATF1 (ENSG00000123268), CREB3L4 (ENSG00000143578), CREB3L1 (ENSG00000157613), CREB3L2 (ENSG00000182158), ATF6B (ENSG00000213676)

Protein

Protein identifiers

Cyclic AMP-responsive element-binding protein 3-like protein 3 — Q68CJ9 (reviewed: Q68CJ9)

Alternative names: Transcription factor CREB-H

All UniProt accessions (1): Q68CJ9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes. Activated in response to cAMP stimulation. In vitro, binds to the cAMP response element (CRE) and box-B element. Activates transcription through box-B element. Activates transcription through CRE. May function synergistically with ATF6. In acute inflammatory response, may activate expression of acute phase response (APR) genes. May be involved in growth suppression. Regulates FGF21 transcription. Plays a crucial role in the regulation of triglyceride metabolism and is required for the maintenance of normal plasma triglyceride concentrations.

Subunit / interactions. Binds DNA as a dimer. May form homodimers. Interacts with ATF6. Interacts with SYNV1/HRD1; this interaction leads to CREB3L3 ubiquitination and proteasomal degradation.

Subcellular location. Endoplasmic reticulum membrane Nucleus.

Tissue specificity. Exclusively expressed in liver. Underexpressed in hepatocellular carcinoma tissues.

Post-translational modifications. Controlled by regulated intramembrane proteolysis (RIP). Following ER stress a fragment containing the cytoplasmic transcription factor domain is released by proteolysis. The cleavage seems to be performed sequentially by site-1 and site-2 proteases (PS1 and PS2). N- and O-glycosylated. N-glycosylation is required for optimal proteolytic activation. O-glycosylated with core 1 or possibly core 8 glycans. Ubiquitinated at Lys-294 by SYNV1/HRD1 via ‘Lys-27’-linked ubiquitin.

Disease relevance. Hypertriglyceridemia 2 (HYTG2) [MIM:619324] An autosomal dominant form of hypertriglyceridemia, a disorder characterized by elevated plasma triglyceride levels. HYTG2 patients also have increased total cholesterol levels and low levels of high density lipoprotein (HDL) cholesterol. Reduced penetrance has been observed. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the bZIP family. ATF subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q68CJ9-1	1	yes
Q68CJ9-2	2
Q68CJ9-4	3
Q68CJ9-5	4

RefSeq proteins (4): NP_001258924, NP_001258925, NP_001258926, NP_115996* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily
IPR051381	CREB_ATF_subfamily	Family

Pfam: PF00170

UniProt features (34 total): sequence variant 6, region of interest 5, glycosylation site 5, splice variant 4, chain 2, compositionally biased region 2, topological domain 2, mutagenesis site 2, site 1, modified residue 1, cross-link 1, transmembrane region 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68CJ9-F1	60.26	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 363–364 (cleavage; by ps1)

Post-translational modifications (2): 173, 294

Glycosylation sites (5): 379, 410, 413, 420, 427

Mutagenesis-validated functional residues (2):

Position	Phenotype
294	loss of ubiquitination by synv1/hrd1.
361	decreases proteolytic cleavage upon er stress.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8874211	CREB3 factors activate genes
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes

MSigDB gene sets: 134 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, TGACCTY_ERR1_Q2, GOBP_POSITIVE_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, COUP_01, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, KEGG_PROSTATE_CANCER, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, KEGG_HUNTINGTONS_DISEASE, PPAR_DR1_Q2, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE

GO Biological Process (6): positive regulation of acute inflammatory response (GO:0002675), regulation of transcription by RNA polymerase II (GO:0006357), response to unfolded protein (GO:0006986), response to endoplasmic reticulum stress (GO:0034976), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (11): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (8): Golgi membrane (GO:0000139), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Unfolded Protein Response (UPR)	1
Plasma lipoprotein remodeling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
protein dimerization activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
acute inflammatory response	1
regulation of acute inflammatory response	1
positive regulation of inflammatory response	1
response to topologically incorrect protein	1
cellular response to stress	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
identical protein binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
chromosome	1
nuclear lumen	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREB3L3	PPARA	Q07869	833
CREB3L3	MBTPS2	O43462	823
CREB3L3	MBTPS1	Q14703	790
CREB3L3	HAMP	P81172	704
CREB3L3	TMPRSS6	Q8IU80	694
CREB3L3	APCS	P02743	689
CREB3L3	ATF6	P18850	656
CREB3L3	CREB1	P16220	651
CREB3L3	HJV	Q6ZVN8	627
CREB3L3	XBP1	P17861	576
CREB3L3	LMF1	Q96S06	553
CREB3L3	GDF15	P78360	543
CREB3L3	FGF21	Q9NSA1	530
CREB3L3	ERN1	O75460	528
CREB3L3	APOA5	Q6Q788	526
CREB3L3	ERN2	Q76MJ5	526

IntAct

75 interactions, top by confidence:

A	B	Type	Score
CREB3L3	CREB3L3	psi-mi:“MI:0407”(direct interaction)	0.620
CREB3	CREB3L3	psi-mi:“MI:0407”(direct interaction)	0.620
CREB3L3	CREB3	psi-mi:“MI:0407”(direct interaction)	0.620
CREB3L3	CEP19	psi-mi:“MI:0915”(physical association)	0.560
STX5	CREB3L3	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	SGTB	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	TRAF3IP3	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	TMEM239	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	TCEANC	psi-mi:“MI:0915”(physical association)	0.560
SGTA	CREB3L3	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	RUSF1	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	FATE1	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	MCRS1	psi-mi:“MI:0915”(physical association)	0.560
GPR25	CREB3L3	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	DPY30	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	YIPF6	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
MS4A13	CREB3L3	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	SLC39A9	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	SLC38A7	psi-mi:“MI:0915”(physical association)	0.560
RHAG	CREB3L3	psi-mi:“MI:0915”(physical association)	0.560
ATF6	CREB3L3	psi-mi:“MI:0915”(physical association)	0.520
CREB3L3	NFIL3	psi-mi:“MI:0407”(direct interaction)	0.440
CREB1	CREB3L3	psi-mi:“MI:0407”(direct interaction)	0.440
CREB3L1	CREB3L3	psi-mi:“MI:0407”(direct interaction)	0.440
CREB3L3	CREB3L1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (64): PPARGC1A (Reconstituted Complex), PPARGC1A (Affinity Capture-Western), CREB3L3 (Biochemical Activity), CREB3L3 (Biochemical Activity), BTRC (Reconstituted Complex), BTRC (Affinity Capture-Western), CUL1 (Affinity Capture-Western), RBX1 (Affinity Capture-Western), CREB3L3 (Two-hybrid), CREB3L3 (Two-hybrid), SLC38A7 (Two-hybrid), SGTA (Two-hybrid), RHAG (Two-hybrid), C16orf58 (Two-hybrid), FATE1 (Two-hybrid)

ESM2 similar proteins: A1L224, A2VD01, D3ZLB7, F6VAN0, G3V909, O02761, O35451, O43889, O77628, O88479, O94983, O97930, P01100, P01101, P01102, P0C0N8, P0C0N9, P11939, P12841, P18850, P20389, P38532, Q00613, Q08CW8, Q08DJ8, Q1LYG4, Q3SYZ3, Q502F0, Q56TN0, Q56TT7, Q5FVM5, Q5RCM9, Q5UEM7, Q5UEM8, Q61817, Q64210, Q66HA2, Q68CJ9, Q6QDP7, Q6ZPJ0

Diamond homologs: A1L224, A2VD01, O43889, O44743, P29747, Q08CW8, Q1LYG4, Q3SYZ3, Q4JFH9, Q502F0, Q5FVM5, Q5RCM9, Q5UEM7, Q5UEM8, Q61817, Q66HA2, Q68CJ9, Q6QDP7, Q70SY1, Q8BH52, Q8SQ19, Q8TEY5, Q91XE9, Q96BA8, Q9D2A5, Q9Z125, F6VAN0, G3V909, O35451, P18850, Q99941, Q54Y73, O22208, O24646, P14233, Q54WN7, Q554P0, Q55E93, Q6AU90, Q8LIB3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GSK3B	“down-regulates activity”	CREB3L3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

338 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	5
Uncertain significance	160
Likely benign	93
Benign	41

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1120265	NM_032607.3(CREB3L3):c.363del (p.Cys123fs)	Pathogenic
1459713	NC_000019.9:g.(?4153745)(4170205_?)del	Pathogenic
1921534	NM_032607.3(CREB3L3):c.603C>A (p.Tyr201Ter)	Pathogenic
1943961	NM_032607.3(CREB3L3):c.130G>T (p.Glu44Ter)	Pathogenic
2110424	NM_032607.3(CREB3L3):c.241del (p.Ser81fs)	Pathogenic
2427047	NC_000019.9:g.(?4156972)(4157312_?)del	Pathogenic
2697680	NM_032607.3(CREB3L3):c.739del (p.Ile247fs)	Pathogenic
2967187	NM_032607.3(CREB3L3):c.306dup (p.Arg103fs)	Pathogenic
3242720	NC_000019.9:g.(?4153745)(4155044_?)del	Pathogenic
3608978	NM_032607.3(CREB3L3):c.724C>T (p.Arg242Ter)	Pathogenic
3671283	NM_032607.3(CREB3L3):c.577C>T (p.Gln193Ter)	Pathogenic
4698081	NM_032607.3(CREB3L3):c.717C>G (p.Tyr239Ter)	Pathogenic
4727044	NM_032607.3(CREB3L3):c.632_633del (p.Gln211fs)	Pathogenic
4772573	NM_032607.3(CREB3L3):c.457G>T (p.Glu153Ter)	Pathogenic
4777182	NM_032607.3(CREB3L3):c.478_481del (p.Arg160fs)	Pathogenic
830655	NC_000019.10:g.(?4153748)(4164640_?)del	Pathogenic
1345155	NC_000019.9:g.(?4159641)(4159799_?)dup	Likely pathogenic
1678115	NM_032607.3(CREB3L3):c.891-2A>G	Likely pathogenic
1930683	NM_032607.3(CREB3L3):c.577-2A>G	Likely pathogenic
2427048	NC_000019.9:g.(?4159641)(4164657_?)dup	Likely pathogenic
852932	NM_032607.3(CREB3L3):c.577-1G>A	Likely pathogenic

SpliceAI

1172 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4154889:C:CA	acceptor_gain	1.0000
19:4154891:C:CA	acceptor_gain	1.0000
19:4154894:CCCAG:C	acceptor_loss	1.0000
19:4154896:CA:C	acceptor_loss	1.0000
19:4154897:A:AG	acceptor_gain	1.0000
19:4154897:A:T	acceptor_loss	1.0000
19:4154897:AGAT:A	acceptor_gain	1.0000
19:4154897:AGATG:A	acceptor_gain	1.0000
19:4154898:G:GG	acceptor_gain	1.0000
19:4154898:GA:G	acceptor_gain	1.0000
19:4154898:GAT:G	acceptor_gain	1.0000
19:4154898:GATG:G	acceptor_gain	1.0000
19:4154898:GATGG:G	acceptor_gain	1.0000
19:4155025:CAGGT:C	donor_loss	1.0000
19:4155028:G:GA	donor_loss	1.0000
19:4155029:T:A	donor_loss	1.0000
19:4159649:A:AG	acceptor_gain	1.0000
19:4159649:ACCT:A	acceptor_gain	1.0000
19:4159650:C:G	acceptor_gain	1.0000
19:4159652:T:A	acceptor_gain	1.0000
19:4159657:T:TA	acceptor_gain	1.0000
19:4159661:CA:C	acceptor_loss	1.0000
19:4159662:A:AC	acceptor_loss	1.0000
19:4159663:G:GT	acceptor_loss	1.0000
19:4159663:GA:G	acceptor_gain	1.0000
19:4159663:GAA:G	acceptor_gain	1.0000
19:4159663:GAAAT:G	acceptor_gain	1.0000
19:4164637:TAAGG:T	donor_loss	1.0000
19:4164639:AGGTG:A	donor_loss	1.0000
19:4164640:GGT:G	donor_loss	1.0000

AlphaMissense

2962 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4168398:G:C	K254N	1.000
19:4168398:G:T	K254N	1.000
19:4168370:A:T	K245I	0.999
19:4168371:A:C	K245N	0.999
19:4168371:A:T	K245N	0.999
19:4168382:G:C	R249P	0.999
19:4168391:G:C	R252P	0.999
19:4168393:A:G	N253D	0.999
19:4168395:C:A	N253K	0.999
19:4168395:C:G	N253K	0.999
19:4168396:A:G	K254E	0.999
19:4168414:A:C	S260R	0.999
19:4168416:C:A	S260R	0.999
19:4168416:C:G	S260R	0.999
19:4168418:G:C	R261T	0.999
19:4168418:G:T	R261M	0.999
19:4168419:G:C	R261S	0.999
19:4168419:G:T	R261S	0.999
19:4168457:G:C	R274P	0.999
19:4171108:T:C	L303P	0.999
19:4168369:A:G	K245E	0.998
19:4168378:C:A	R248S	0.998
19:4168379:G:C	R248P	0.998
19:4168384:A:G	K250E	0.998
19:4168386:A:C	K250N	0.998
19:4168386:A:T	K250N	0.998
19:4168388:T:C	I251T	0.998
19:4168394:A:C	N253T	0.998
19:4168394:A:T	N253I	0.998
19:4168397:A:T	K254M	0.998

dbSNP variants (sampled 300 via entrez): RS1000061108 (19:4172722 C>G,T), RS1000233955 (19:4153637 G>A), RS1000310191 (19:4156802 C>G), RS1000394031 (19:4170978 C>G), RS1000468498 (19:4161826 T>C), RS1000480840 (19:4157687 A>G,T), RS1000537218 (19:4154884 T>C), RS1000610942 (19:4154602 G>A), RS1000733146 (19:4168655 C>A,G,T), RS1001030291 (19:4170825 G>C), RS1001046436 (19:4161114 T>A), RS1001235004 (19:4152298 A>T), RS1002360348 (19:4164055 C>T), RS1002384965 (19:4158308 G>A), RS1002442579 (19:4163666 C>T)

Disease associations

OMIM: gene MIM:611998 | disease phenotypes: MIM:619324, MIM:145750, MIM:128200

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertriglyceridemia 2	Strong	Autosomal dominant
hypertriglyceridemia	Strong	Autosomal dominant
hypertriglyceridemia 1	Limited	Autosomal dominant

Mondo (5): hypertriglyceridemia 2 (MONDO:0859149), RASopathy (MONDO:0021060), hypertriglyceridemia 1 (MONDO:0007788), episodic kinesigenic dyskinesia 1 (MONDO:0100352), hypertriglyceridemia (MONDO:0005347)

Orphanet (2): RASopathy (Orphanet:536391), Paroxysmal kinesigenic dyskinesia (Orphanet:98809)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002155	Hypertriglyceridemia
HP:0003124	Hypercholesterolemia
HP:0003233	Decreased HDL cholesterol concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010241_236	Apolipoprotein A1 levels	2.000000e-09
GCST010244_291	Triglyceride levels	2.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015228	Hypertriglyceridemia	C18.452.584.500.500.851
C537180	Familial paroxysmal dystonia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	3
perfluorooctanoic acid	increases expression	2
perfluorooctane sulfonic acid	affects expression, increases expression	2
Acetaminophen	decreases expression	2
Valproic Acid	increases expression	2
Cyclosporine	decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
pentanal	increases expression	1
glyceryl 2-arachidonate	affects binding, increases reaction, increases expression, decreases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
obeticholic acid	increases expression	1
trans-10,cis-12-conjugated linoleic acid	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Leflunomide	decreases expression	1
Aldehydes	increases expression	1
Ampicillin	decreases expression	1
Dust	decreases expression	1
Estradiol	decreases expression	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

242 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00246636	PHASE4	COMPLETED	Evaluation of Efficacy and Safety of Omacor (Omega-3-acid Ethyl Esters) as Add-on Therapy in Hypertriglyceridemic Subjects Treated With Antara (Fenofibrate) Followed by an 8-week Extension
NCT00286234	PHASE4	COMPLETED	Niacin, N-3 Fatty Acids and Insulin Resistance
NCT00346697	PHASE4	COMPLETED	Omega-3 Fatty Acids for High Triglycerides in HIV-infected Patients
NCT00397358	PHASE4	WITHDRAWN	Effect of Extraneal (Icodextrin)on Triglyceride Levels in PD Patients
NCT00473655	PHASE4	COMPLETED	Effect of Rosuvastatin on Triglyceride Levels in Mexican Hypertriglyceridemic Patients
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00745407	PHASE4	COMPLETED	Effects of Fenofibrate on Adipocytokine Levels In Hypertriglyceridemic Patients
NCT00758927	PHASE4	UNKNOWN	The Effects of Omega-3 Fatty Acid (OMACOR) on the Low-density Lipoprotein (LDL) Sub-fraction in Type 2 Diabetic Patients
NCT00891293	PHASE4	COMPLETED	A Second Open-Label Extension of a Double-Blind, Parallel, Phase IV Study to Assess the Efficacy and Safety of Adjunctive Lovaza® (Formerly Known as Omacor®) Therapy in Hypertriglyceridemic Subjects Treated With Antara™
NCT00931879	PHASE4	COMPLETED	Lovaza® and Microvascular Function in Type 2 Diabetes
NCT00934219	PHASE4	UNKNOWN	Triglyceride Lowering Study
NCT01003847	PHASE4	COMPLETED	Differential Metabolic Effects of Fenofibrate and Fatty Acid
NCT01010399	PHASE4	COMPLETED	Boosted Lexiva With Lovaza Adjunctive Therapy in Hypertriglyceridemic, HIV-Infected Subjects
NCT01180764	PHASE4	WITHDRAWN	Effects of Lovaza on High Density Lipoprotein (HDL) Composition and Function in Hypertriglyceridemia
NCT01462877	PHASE4	COMPLETED	A Study to Evaluate Fenofibrate Combination With Statin in Chinese Patients With Dyslipidemic
NCT01480687	PHASE4	UNKNOWN	Fish Oil Supplementation and Vascular Function in Hypertensive Patients With Hypertriglyceridemia
NCT01527747	PHASE4	SUSPENDED	Effects of DPP-4 Inhibition on Triglycerides
NCT01569724	PHASE4	COMPLETED	Carbohydrate Metabolism Disorder Frequency in Hypertriglyceridemia Induced by Bexarotene of Cutaneous T Cell Lymphoma
NCT01625442	PHASE4	COMPLETED	Crocus Sativus (Saffron) and Berberis Vulgaris (Barberry Fruit) in Metabolic Syndrome
NCT01660932	PHASE4	COMPLETED	Vascular and Metabolic Effects of Omega-3 Fatty Acids
NCT01666041	PHASE4	COMPLETED	Vascular and Metabolic Effects of Fenofibrate/Omega vs Fenofibrate
NCT02015988	PHASE4	UNKNOWN	Simvastatin and Fenofibrate vs Simvastatin Alone in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome
NCT02926027	PHASE4	COMPLETED	Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy
NCT03120299	PHASE4	COMPLETED	The Effect of Omega-3 FA on Hypertriglyceridemia in Patients With T2DM(OCEAN)
NCT03342807	PHASE4	UNKNOWN	Intravenous Administration of Insulin and Plasma Exchange on Triglyceride Levels in Early Stage of Hypertriglyceridemia-induced Pancreatitis
NCT03501680	PHASE4	UNKNOWN	Intensive Insulin for Severe/Moderate Hypertriglyceridemia Pancreatitis.
NCT05487833	PHASE4	UNKNOWN	Insulin and Standard Management in Hypertriglyceridemic Acute Pancreatitis
NCT06129526	PHASE4	UNKNOWN	Study of the Efficacy and Safety of EPA in Patients With Type-2 Diabetes
NCT00092560	PHASE3	COMPLETED	Two Investigational Drugs in Patients With Mixed Hyperlipidemia (0653-036)
NCT00092573	PHASE3	COMPLETED	Study of Ezetimibe and Fenofibrate in Patients With Mixed Hyperlipidemia (0653-036)(COMPLETED)
NCT00093899	PHASE3	COMPLETED	A Study to Evaluate an Investigational Drug in Patients With Mixed Hyperlipidemia (0653A-071)(COMPLETED)
NCT00134498	PHASE3	COMPLETED	A Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
NCT00231621	PHASE3	TERMINATED	A Study on Efficacy and Safety of Topiramate in Treatment of Obese Subjects With Dyslipidemia
NCT00246701	PHASE3	COMPLETED	Evaluation of Efficacy and Safety of Combined Omacor (Omega-3-acid Ethyl Esters) and Simvastatin Therapy in Hypertriglyceridemic Subjects
NCT00435045	PHASE3	COMPLETED	Evaluation of Efficacy and Safety of Omacor, Co-Administered With Atorvastatin, in Subjects With Hypertriglyceridemia
NCT00560430	PHASE3	COMPLETED	Regulation of Inflammatory Parameters by Telmisartan in Hypertensive Patients
NCT00887653	PHASE3	COMPLETED	Changes in Lipids and Safety of Raltegravir in HIV+ Patients With Hyperlipidemia While on Current Standard Therapy
NCT00903409	PHASE3	COMPLETED	Open-Label Extension of a Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Lovaza® and Simvastatin Therapy in Hypertriglyceridemic Subjects
NCT00973271	PHASE3	WITHDRAWN	Diazoxide Choline Controlled-Release Tablet (DCCR) for Very High Triglycerides
NCT01047501	PHASE3	COMPLETED	Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in Patients on Statins With High Tg Levels (≥ 200 and < 500 mg/dL)