ATF6B

Summary

ATF6B (activating transcription factor 6 beta, HGNC:2349) is a protein-coding gene on chromosome 6p21.3, encoding Cyclic AMP-dependent transcription factor ATF-6 beta (Q99941). Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 beta), which is embedded in the endoplasmic reticulum membrane.

The protein encoded by this gene is a transcription factor in the unfolded protein response (UPR) pathway during ER stress. Either as a homodimer or as a heterodimer with ATF6-alpha, the encoded protein binds to the ER stress response element, interacting with nuclear transcription factor Y to activate UPR target genes. The protein is normally found in the membrane of the endoplasmic reticulum; however, under ER stress, the N-terminal cytoplasmic domain is cleaved from the rest of the protein and translocates to the nucleus. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1388 — RefSeq curated summary.

At a glance

• GWAS associations: 33 (top 4% of genes corpus-wide)
• Clinical variants (ClinVar): 123 total
• GTEx eGene: eQTL in 45 tissues, sQTL in 26 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.75 (unconstrained)
• MANE Select transcript: NM_004381
• Notable: 123 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2349
Approved symbol	ATF6B
Name	activating transcription factor 6 beta
Location	6p21.3
Locus type	gene with protein product
Status	Approved
Aliases	G13, ATF6beta
Ensembl gene	ENSG00000213676
Ensembl biotype	protein_coding
OMIM	600984
Entrez	1388

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 21 protein_coding, 7 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000375203

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 1, TSL 5: 1

ENST00000375203, ENST00000375201, ENST00000453203, ENST00000468502, ENST00000475705, ENST00000485314, ENST00000492342, ENST00000495579, ENST00000873759, ENST00000873760, ENST00000873761, ENST00000873762, ENST00000873763, ENST00000873764, ENST00000873765, ENST00000873766, ENST00000873767, ENST00000873768, ENST00000873769, ENST00000932422, ENST00000981297, ENST00000981298, ENST00000981299, ENST00000981301, ENST00000981302, ENST00001042819, ENST00001042820, ENST00001042821, ENST00001065898, ENST00001110200, ENST00001117335, ENST00001124118, ENST00001140309

RefSeq mRNA: 2 — MANE Select: NM_004381 NM_001136153, NM_004381

CCDS: CCDS4737, CCDS47408

Canonical transcript exons

ENST00000293709 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.12.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9702 / max 37.9465, expressed in 548 samples.

Highest expression (Bgee): monocyte, granulocyte, leukocyte, uterine tube, ovary.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ATF6B is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 45 tissues and its splicing (sQTL) in 26 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 71 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	2.8e-79	+0.63	6:32115398:C:T
Muscle Skeletal	eqtl	1.1e-55	+0.40	6:32133985:C:T
Heart Atrial Appendage	eqtl	2.9e-54	+0.57	6:32115398:C:T
Nerve Tibial	eqtl	9.8e-39	+0.41	6:32143109:G:A
Adipose Subcutaneous	eqtl	5.8e-34	+0.37	6:32115398:C:T
Skin Sun Exposed Lower leg	eqtl	8.0e-34	+0.24	6:32133985:C:T
Nerve Tibial	sqtl	6.9e-33	+0.86	6:32117821:C:T
Heart Left Ventricle	eqtl	4.5e-31	+0.51	6:32115398:C:T
Thyroid	sqtl	2.5e-30	+1.09	6:32117821:C:T
Skin Sun Exposed Lower leg	sqtl	7.1e-29	+0.95	6:32117821:C:T
Adipose Subcutaneous	sqtl	3.6e-28	+1.01	6:32117821:C:T
Lung	eqtl	9.2e-25	+0.29	6:32115398:C:T
Artery Tibial	eqtl	1.4e-24	+0.33	6:32115398:C:T
Pancreas	eqtl	2.5e-23	+0.48	6:32115398:C:T
Brain Spinal cord cervical c-1	eqtl	1.1e-22	+0.67	6:32121077:G:C
Stomach	eqtl	1.9e-22	+0.36	6:32115398:C:T
Adrenal Gland	eqtl	1.7e-21	+0.45	6:32115398:C:T
Adipose Visceral Omentum	eqtl	4.3e-20	+0.35	6:32115398:C:T
Skin Not Sun Exposed Suprapubic	sqtl	6.8e-20	+0.96	6:32117821:C:T
Breast Mammary Tissue	sqtl	1.3e-19	+1.21	6:32117821:C:T

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
72886	6.3761	1751
72885	0.8616	497
72884	0.1086	34

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.12	gold quality
granulocyte	CL:0000094	97.10	gold quality
leukocyte	CL:0000738	97.02	gold quality
right uterine tube	UBERON:0001302	96.78	gold quality
left ovary	UBERON:0002119	96.77	gold quality
right ovary	UBERON:0002118	96.67	gold quality
ovary	UBERON:0000992	96.62	gold quality
right lobe of thyroid gland	UBERON:0001119	96.62	gold quality
spleen	UBERON:0002106	96.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.55	gold quality
left lobe of thyroid gland	UBERON:0001120	96.40	gold quality
cerebellar hemisphere	UBERON:0002245	96.39	gold quality
thyroid gland	UBERON:0002046	96.38	gold quality
cerebellar cortex	UBERON:0002129	96.34	gold quality
fallopian tube	UBERON:0003889	96.33	gold quality
gall bladder	UBERON:0002110	96.31	gold quality
cerebellum	UBERON:0002037	96.26	gold quality
endocervix	UBERON:0000458	96.16	gold quality
pituitary gland	UBERON:0000007	96.14	gold quality
lymph node	UBERON:0000029	96.11	gold quality
body of uterus	UBERON:0009853	96.00	gold quality
vermiform appendix	UBERON:0001154	95.96	gold quality
skin of leg	UBERON:0001511	95.96	gold quality
ectocervix	UBERON:0012249	95.96	gold quality
adenohypophysis	UBERON:0002196	95.86	gold quality
zone of skin	UBERON:0000014	95.84	gold quality
fundus of stomach	UBERON:0001160	95.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.74	gold quality
body of stomach	UBERON:0001161	95.70	gold quality
vagina	UBERON:0000996	95.69	gold quality
uterine cervix	UBERON:0000002	95.67	gold quality
skin of abdomen	UBERON:0001416	95.67	gold quality
transverse colon	UBERON:0001157	95.65	gold quality
left uterine tube	UBERON:0001303	95.65	gold quality
esophagus mucosa	UBERON:0002469	95.65	gold quality
minor salivary gland	UBERON:0001830	95.59	gold quality
small intestine	UBERON:0002108	95.55	gold quality
prostate gland	UBERON:0002367	95.55	gold quality
saliva-secreting gland	UBERON:0001044	95.50	gold quality
right adrenal gland cortex	UBERON:0035827	95.50	gold quality
right adrenal gland	UBERON:0001233	95.39	gold quality
mucosa of transverse colon	UBERON:0004991	95.38	gold quality
blood	UBERON:0000178	95.33	gold quality
metanephros cortex	UBERON:0010533	95.33	gold quality
placenta	UBERON:0001987	95.18	gold quality
sural nerve	UBERON:0015488	95.18	gold quality
tibial nerve	UBERON:0001323	95.14	gold quality
stromal cell of endometrium	CL:0002255	95.09	gold quality
urinary bladder	UBERON:0001255	95.06	gold quality
myometrium	UBERON:0001296	95.02	gold quality
bone marrow	UBERON:0002371	95.02	gold quality
left adrenal gland	UBERON:0001234	94.87	gold quality
right coronary artery	UBERON:0001625	94.87	gold quality
duodenum	UBERON:0002114	94.86	gold quality
esophagus	UBERON:0001043	94.85	gold quality
left adrenal gland cortex	UBERON:0035825	94.80	gold quality
smooth muscle tissue	UBERON:0001135	94.77	gold quality
body of pancreas	UBERON:0001150	94.71	gold quality
thoracic mammary gland	UBERON:0005200	94.70	gold quality
stomach	UBERON:0000945	94.68	gold quality
colon	UBERON:0001155	94.64	gold quality
thoracic aorta	UBERON:0001515	94.64	gold quality
ascending aorta	UBERON:0001496	94.63	gold quality
intestine	UBERON:0000160	94.54	gold quality
lower esophagus mucosa	UBERON:0035834	94.54	gold quality
right lung	UBERON:0002167	94.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.45	gold quality
rectum	UBERON:0001052	94.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.40	gold quality
left coronary artery	UBERON:0001626	94.37	gold quality
descending thoracic aorta	UBERON:0002345	94.37	gold quality
bone marrow cell	CL:0002092	94.27	gold quality
upper lobe of left lung	UBERON:0008952	94.26	gold quality
popliteal artery	UBERON:0002250	94.15	gold quality
tibial artery	UBERON:0007610	94.14	gold quality
lower esophagus	UBERON:0013473	94.09	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.08	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.00	gold quality
adrenal gland	UBERON:0002369	94.00	gold quality
right frontal lobe	UBERON:0002810	93.98	gold quality
cortical plate	UBERON:0005343	93.92	gold quality
apex of heart	UBERON:0002098	93.91	gold quality
multicellular organism	UBERON:0000468	93.89	gold quality
nucleus accumbens	UBERON:0001882	93.81	gold quality
adipose tissue	UBERON:0001013	93.65	gold quality
ventricular zone	UBERON:0003053	93.65	gold quality
mucosa of stomach	UBERON:0001199	93.61	gold quality
cortex of kidney	UBERON:0001225	93.59	gold quality
caudate nucleus	UBERON:0001873	93.44	gold quality
ganglionic eminence	UBERON:0004023	93.31	gold quality
pancreas	UBERON:0001264	93.25	gold quality
putamen	UBERON:0001874	93.24	gold quality
tonsil	UBERON:0002372	93.24	gold quality
omental fat pad	UBERON:0010414	93.23	gold quality
hypothalamus	UBERON:0001898	93.21	gold quality
substantia nigra	UBERON:0002038	92.99	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.97	gold quality
anterior cingulate cortex	UBERON:0009835	92.96	gold quality
Ammon’s horn	UBERON:0001954	92.94	gold quality
brain	UBERON:0000955	92.93	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.55

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebral cortex	tissue	45.1	medium
Somatosensory cortex	tissue	45.1
Putamen	tissue	44.9
Motor cortex	tissue	44.5
Superior colliculi	tissue	44.4
Thalamus	tissue	43.4
Prefrontal cortex	tissue	43.3
Vagina	tissue	42.5	medium
Corpus callosum	tissue	42.5
Basal ganglia	tissue	42.0	medium
Occipital cortex	tissue	41.9
Midbrain	tissue	41.6
Substantia nigra	tissue	41.5
Hippocampal formation	tissue	41.1
Entorhinal cortex	tissue	41.1
Spinal cord	tissue	41.0
Olfactory bulb	tissue	40.9
Pons	tissue	40.3
Temporal cortex	tissue	40.2
Insular cortex	tissue	40.0
Ventral forebrain	tissue	39.8
Medulla oblongata	tissue	39.5
Pituitary gland	tissue	39.1
Retrosplenial and cingulate cortex	tissue	39.0
Hypothalamus	tissue	38.7
Septum	tissue	38.3
Retrosplenial cortex	tissue	38.3
Periaqueductal gray	tissue	35.6
Amygdala	tissue	35.5
Frontal cortex	tissue	34.8
Cerebellum	tissue	33.4	medium
Bone marrow	tissue	27.7	high
Caudate putamen	tissue	27.6
Fallopian tube	tissue	20.8	high
Tonsil	tissue	15.9	high
Epididymis	tissue	15.8	medium
Thymus	tissue	15.7
Endometrium 1	tissue	15.0	medium
Thyroid gland	tissue	14.9	high
Ovary	tissue	13.6	medium
Parathyroid gland	tissue	13.4	low
Lymph node	tissue	13.3	medium
Colon	tissue	13.3	high
Rectum	tissue	13.1	high
Adrenal gland	tissue	12.7	medium
Stomach 1	tissue	12.4	high
Prostate	tissue	12.3	medium
Esophagus	tissue	11.2	high
Skin 1	tissue	11.1	medium
Duodenum	tissue	11.1	high
Gallbladder	tissue	10.9	medium
Cervix	tissue	10.3	medium
Lung	tissue	9.5	medium
Postcentral gyrus	tissue	9.5
Salivary gland	tissue	9.3	medium
Heart muscle	tissue	9.2	low
Adipose tissue	tissue	8.8	not detected
Spleen	tissue	8.7	low
Smooth muscle	tissue	8.2	medium
Placenta	tissue	8.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — White matter (42.5), Dorsal spinal cord (41.0), Ventral hippocampus (40.3), Ventral spinal cord (39.9), Dorsal hippocampus (39.2).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets:

Target	Regulation
CD74
HSPA5	Activation
INS
KDR
MANF	Unknown

JASPAR motifs

Motif	Name	Family
UN0110.1	ATF6B	CREB-related factors
UN0110.2	ATF6B	CREB-related factors
UN0111.1	ATF6B	CREB-related factors
UN0111.2	ATF6B	CREB-related factors
UN0112.1	ATF6B	CREB-related factors
UN0968.1	ATF6B::ETV4	CREB-related factors,Ets-related
UN0973.1	ATF6B::FLI1	CREB-related factors,Ets-related

miRNA regulators (miRDB)

Targeting ATF6B by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 46 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6780B-3P	99.13	67.18	622
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-5187-5P	98.54	67.94	952

Functional genomics

gnomAD constraint: pLI 1.99e-09, LOEUF 0.752, missense Z 1.43 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000375203 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
6:32,115,742–32,121,052	530 / 632.6	0.84	no
6:32,121,053–32,121,105	7 / 18.1	0.39	no
6:32,121,106–32,128,207	253 / 243.1	1.04	no

Literature-anchored findings (GeneRIF, showing 5)

• unglycosylated ATF6beta may directly facilitate the expression of ERSR genes by losing its repressor function to ATF6alpha (PMID:19693772)
• ATF4 and ATF6beta act synergistically in the negative regulation of placental growth factor mRNA expression (PMID:26648175)
• Polymorphism in the 3’-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses. (PMID:32504404)
• Establishment of a reporter system for monitoring activation of the ER stress transducer ATF6beta. (PMID:33894672)
• Loss of ATF6alpha in a human carcinoma cell line is compensated not by its paralogue ATF6beta but by sustained activation of the IRE1 and PERK arms for tumor growth in nude mice. (PMID:36696173)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000101369
mus_musculus	Atf6b	ENSMUSG00000015461
rattus_norvegicus	Atf6b	ENSRNOG00000000431
drosophila_melanogaster	CrebA	FBGN0004396
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793
caenorhabditis_elegans		WBGENE00016162

Paralogs (9): CREB3L3 (ENSG00000060566), CREM (ENSG00000095794), CREB3 (ENSG00000107175), ATF6 (ENSG00000118217), CREB1 (ENSG00000118260), ATF1 (ENSG00000123268), CREB3L4 (ENSG00000143578), CREB3L1 (ENSG00000157613), CREB3L2 (ENSG00000182158)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:105121) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
scaly skin	1
abnormal skin morphology	1
increased sensitivity to induced cell death	1
preweaning lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Danio rerio	Q1LYG4	98.4%	Diamond
Macaca fascicularis	Q5UEM8	96.2%	Diamond
Bos taurus	Q3SYZ3	74.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PPT2-EGFL8	ncRNA	100532746
MIR6721	ncRNA	102466190
AGPAT1	protein-coding	10554
FKBPL	protein-coding	63943
PRRT1	protein-coding	80863
EGFL8	protein-coding	80864
PPT2	protein-coding	9374
CYP21A2	protein-coding	1589
TNXB	protein-coding	7148
C4B	protein-coding	721

Protein

Protein identifiers

Cyclic AMP-dependent transcription factor ATF-6 beta — Q99941 (reviewed: Q99941)

Alternative names: Activating transcription factor 6 beta, Protein G13, cAMP response element-binding protein-related protein, cAMP-responsive element-binding protein-like 1

All UniProt accessions (3): Q99941, A0A1U9X796, H0Y7D7

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 beta), which is embedded in the endoplasmic reticulum membrane. Endoplasmic reticulum stress promotes processing of this form, releasing the transcription factor form that translocates into the nucleus, where it activates transcription of genes involved in the unfolded protein response (UPR). Transcription factor that acts in the unfolded protein response (UPR) pathway by activating UPR target genes induced during ER stress. Binds DNA on the 5’-CCAC[GA]-3’ half of the ER stress response element (ERSE) (5’-CCAATN(9)CCAC[GA]-3’) when NF-Y is bound to ERSE.

Subunit / interactions. Homodimer and heterodimer with ATF6-alpha. The dimer interacts with the nuclear transcription factor Y (NF-Y) trimer through direct binding to NF-Y subunit C (NF-YC).

Subcellular location. Endoplasmic reticulum membrane Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. N-glycosylated. During unfolded protein response, a fragment of approximately 60 kDa containing the cytoplasmic transcription factor domain is released by proteolysis. The cleavage is probably performed sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) proteases.

Domain organisation. The basic domain functions as a nuclear localization signal. The basic leucine-zipper domain is sufficient for association with the NF-Y trimer and binding to ERSE.

Similarity. Belongs to the bZIP family. ATF subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99941-1	2	yes
Q99941-2	1

RefSeq proteins (2): NP_001129625, NP_004372* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily
IPR051882	ATF_bZIP_TF	Family

Pfam: PF00170

UniProt features (34 total): region of interest 9, glycosylation site 5, compositionally biased region 4, sequence conflict 4, site 3, chain 2, topological domain 2, initiator methionine 1, modified residue 1, splice variant 1, transmembrane region 1, domain 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99941-F1	55.31	0.14

Human Protein Atlas

Protein class: Predicted membrane proteins, Plasma proteins, Transcription factors, Basic domains

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; nucleoli

Antibody reliability (HPA): IH uncertain · IF supported

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 (3)

Position	Role
410	important for cleavage by mbtps2
413	important for cleavage by mbtps2
440–441	cleavage; by mbtps1

Post-translational modifications (1)

Type	Positions
N-acetylalanine	2

Glycosylation sites (5)

Type	Positions
N-linked (glcnac…) asparagine	476, 505, 610, 627, 676

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-8874177	ATF6B (ATF6-beta) activates chaperones	electronic
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-381119	Unfolded Protein Response (UPR)	—

MSigDB gene sets: 190 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, RNGTGGGC_UNKNOWN, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MORF_RAD51L3, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_ER_NUCLEUS_SIGNALING_PATHWAY, MORF_CTSB, MORF_IL4, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, MODULE_157

GO Biological Process (11): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), signal transduction (GO:0007165), endoplasmic reticulum unfolded protein response (GO:0030968), response to endoplasmic reticulum stress (GO:0034976), ATF6-mediated unfolded protein response (GO:0036500), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of ATF6-mediated unfolded protein response (GO:1903892), regulation of DNA-templated transcription (GO:0006355), response to unfolded protein (GO:0006986), regulation of ATF6-mediated unfolded protein response (GO:1903891)

GO Molecular Function (8): transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), protein-DNA complex (GO:0032993), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Unfolded Protein Response (UPR)	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

55 GO namespaces:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
ATF6-mediated unfolded protein response	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
gene expression	1
RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
cellular response to stress	1
ER-nucleus signaling pathway	1
endoplasmic reticulum unfolded protein response	1
positive regulation of DNA-templated transcription	1
negative regulation of endoplasmic reticulum unfolded protein response	1
regulation of ATF6-mediated unfolded protein response	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
response to topologically incorrect protein	1
regulation of endoplasmic reticulum unfolded protein response	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	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
nucleic acid binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
chromosome	1
intracellular membraneless organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endomembrane system	1
protein-containing complex	1
transcription regulator complex	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of ATF6-mediated unfolded protein response	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
response to endoplasmic reticulum stress	BP	direct assay
RNA polymerase II transcription regulator complex	CC	direct assay
endoplasmic reticulum membrane	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
protein-DNA complex	CC	direct assay
DNA-binding transcription factor activity	MF	direct assay
sequence-specific double-stranded DNA binding	MF	direct assay
transcription cis-regulatory region binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 828 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATF6B	XBP1	P17861	850
ATF6B	MBTPS2	O43462	784
ATF6B	HSPA5	P11021	770
ATF6B	MBTPS1	Q14703	770
ATF6B	ERN1	O75460	749
ATF6B	EDEM1	Q92611	738
ATF6B	HSP90B1	P14625	734
ATF6B	EIF2AK3	Q9NZJ5	708
ATF6B	ERN2	Q76MJ5	683
ATF6B	TNXB	P22105	671
ATF6B	CALR	P27797	637
ATF6B	CYP21A2	P04033	631
ATF6B	BHLHA15	Q7RTS1	627
ATF6B	ATF4	P18848	622
ATF6B	SCAP	Q12770	591

IntAct

Human interaction partners of ATF6B in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
ATF6	direct interaction	0.440	2
XBP1	direct interaction	0.440	2
CDK6	phosphorylation reaction	0.440	1
CREBZF	direct interaction	0.440	1
AK4	association	0.350	1

BioGRID (101 interactions; top human partners by supporting records): AK4 (Affinity Capture-MS; 3 records), ERLEC1 (Affinity Capture-MS; 3 records), HLA-E (Affinity Capture-MS; 3 records), LYRM7 (Affinity Capture-MS; 3 records), RWDD2B (Affinity Capture-MS; 3 records), TEX15 (Affinity Capture-MS; 3 records), MPPE1 (Affinity Capture-MS; 2 records), OS9 (Affinity Capture-MS; 2 records), OXSM (Affinity Capture-MS; 2 records), PPP1R9A (Affinity Capture-MS; 2 records), TBC1D15 (Affinity Capture-MS; 2 records), TMED6 (Affinity Capture-MS; 2 records), XBP1 (FRET; 2 records), ATF6 (Two-hybrid), BTNL2 (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
ATF6B	“up-regulates quantity by expression”	HSPA5	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for ATF6B: 123 ClinVar records (0 pathogenic / likely pathogenic); 33 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	18
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 1,390):

Position(s)	Effect	Δscore	Sites
6:32116736	donor_gain	1.0000
6:32116816–32116817	acceptor_loss	1.0000	5
6:32116822	acceptor_gain	1.0000
6:32117132	acceptor_gain	1.0000
6:32117405–32117406	acceptor_loss	1.0000	2
6:32118954–32118955	donor_loss	1.0000	6
6:32119151–32119152	acceptor_gain	1.0000	2
6:32119160	acceptor_gain	1.0000
6:32120913	acceptor_gain	1.0000
6:32126115–32126116	donor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:600984 | disease phenotypes:

GWAS associations

showing 30 of 33 associations:

Study	Trait	p-value
GCST005540_1	Sarcoidosis (Lofgren’s syndrome)	4e-66
GCST004133_55	Ulcerative colitis	5e-65
GCST005541_20	Sarcoidosis (Lofgren’s syndrome vs non-Lofgren’s syndrome)	3e-33
GCST004131_25	Inflammatory bowel disease	2e-31
GCST004521_71	Autism spectrum disorder or schizophrenia	6e-18
GCST004521_265	Autism spectrum disorder or schizophrenia	3e-17
GCST004521_214	Autism spectrum disorder or schizophrenia	2e-16
GCST004521_85	Autism spectrum disorder or schizophrenia	5e-16
GCST004521_268	Autism spectrum disorder or schizophrenia	3e-15
GCST004521_269	Autism spectrum disorder or schizophrenia	3e-15
GCST004521_87	Autism spectrum disorder or schizophrenia	5e-15
GCST004521_220	Autism spectrum disorder or schizophrenia	1e-14
GCST002100_3	Atopic dermatitis	3e-14
GCST004521_121	Autism spectrum disorder or schizophrenia	4e-14
GCST004521_124	Autism spectrum disorder or schizophrenia	4e-14
GCST004602_231	Mean corpuscular volume	3e-13
GCST004521_89	Autism spectrum disorder or schizophrenia	5e-13
GCST004521_168	Autism spectrum disorder or schizophrenia	2e-12
GCST007329_6	Automobile speeding propensity	2e-12
GCST004521_127	Autism spectrum disorder or schizophrenia	4e-12
GCST90002397_471	Mean spheric corpuscular volume	8e-12
GCST90002392_465	Mean corpuscular volume	5e-11
GCST001986_2	Age-related macular degeneration	2e-10
GCST004521_177	Autism spectrum disorder or schizophrenia	2e-10
GCST005580_153	Intraocular pressure	5e-10
GCST010479_25	Coronary artery disease	3e-9
GCST001942_21	Prostate cancer	5e-9
GCST009731_31	Blood protein levels in cardiovascular risk	6e-9
GCST004521_105	Autism spectrum disorder or schizophrenia	3e-8
GCST90020024_412	A body shape index	3e-8

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0008579	risk-taking behaviour
EFO:0008173	interleukin 16 measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases expression, decreases expression, increases abundance	3
sodium arsenite	increases abundance, increases expression, decreases expression	2
Arsenic	increases reaction, increases cleavage, increases expression, affects reaction, decreases expression (+2 more)	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
Particulate Matter	increases abundance, increases expression, affects expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
beta-N-methylamino-L-alanine	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation	1
Nonidet P-40	increases expression	1
kojic acid	decreases expression	1
fisetin	decreases reaction, increases expression	1
1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid	decreases reaction, increases expression	1
arsenic trichloride	affects binding, increases abundance, increases reaction, increases cleavage, increases expression (+1 more)	1
jinfukang	increases expression, affects cotreatment	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arbutin	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Folic Acid	affects expression	1
Methotrexate	increases expression	1
Ouabain	increases expression	1
Ozone	increases expression	1
Quercetin	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8HN	Ubigene HCT 116 ATF6B KO	Cancer cell line	Male
CVCL_D9Y2	Ubigene HeLa ATF6B KO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.