HSF2

Summary

HSF2 (heat shock transcription factor 2, HGNC:5225) is a protein-coding gene on chromosome 6q22.31, encoding Heat shock factor protein 2 (Q03933). DNA-binding protein that specifically binds heat shock promoter elements (HSE) and activates transcription.

The protein encoded by this gene belongs to the HSF family of transcription factors that bind specifically to the heat-shock promoter element and activate transcription. Heat shock transcription factors activate heat-shock response genes under conditions of heat or other stresses. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3298 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 59 total
• Druggable target: yes
• Transcription factor: yes — 30 downstream targets (CollecTRI)
• MANE Select transcript: NM_004506

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5225
Approved symbol	HSF2
Name	heat shock transcription factor 2
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000025156
Ensembl biotype	protein_coding
OMIM	140581
Entrez	3298

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000368455, ENST00000452194, ENST00000465214, ENST00000924428, ENST00000924429

RefSeq mRNA: 2 — MANE Select: NM_004506 NM_001135564, NM_004506

CCDS: CCDS47470, CCDS5124

Canonical transcript exons

ENST00000368455 — 13 exons

Exon	Start	End
ENSE00000597341	122412373	122412481
ENSE00000762901	122412637	122412764
ENSE00000762902	122413525	122413649
ENSE00000762903	122416221	122416296
ENSE00000762904	122419168	122419229
ENSE00000762909	122427903	122427956
ENSE00000762910	122431430	122431514
ENSE00000798533	122422150	122422298
ENSE00000798534	122431925	122433119
ENSE00001377345	122420135	122420222
ENSE00001907343	122399652	122399830
ENSE00003707491	122422718	122422957
ENSE00003711416	122423581	122423686

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 93.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.7912 / max 370.8697, expressed in 1777 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69517	15.3120	1771
69518	0.7107	420
69515	0.5649	296
69516	0.1507	47
69519	0.0398	13
69520	0.0131	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.53	gold quality
cortical plate	UBERON:0005343	93.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.10	gold quality
muscle of leg	UBERON:0001383	92.99	gold quality
gastrocnemius	UBERON:0001388	92.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.87	gold quality
ganglionic eminence	UBERON:0004023	92.80	gold quality
biceps brachii	UBERON:0001507	92.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.31	gold quality
embryo	UBERON:0000922	92.20	gold quality
muscle organ	UBERON:0001630	92.18	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.62	gold quality
calcaneal tendon	UBERON:0003701	91.35	gold quality
bronchial epithelial cell	CL:0002328	90.98	gold quality
adrenal tissue	UBERON:0018303	90.87	gold quality
ventricular zone	UBERON:0003053	90.58	gold quality
testis	UBERON:0000473	90.41	gold quality
vastus lateralis	UBERON:0001379	90.25	gold quality
skeletal muscle tissue	UBERON:0001134	90.15	gold quality
right testis	UBERON:0004534	90.15	gold quality
quadriceps femoris	UBERON:0001377	89.88	gold quality
left testis	UBERON:0004533	89.47	gold quality
muscle tissue	UBERON:0002385	89.29	gold quality
deltoid	UBERON:0001476	89.03	gold quality
right atrium auricular region	UBERON:0006631	88.65	gold quality
cardiac atrium	UBERON:0002081	88.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.77	gold quality
tibialis anterior	UBERON:0001385	87.71	gold quality
right adrenal gland	UBERON:0001233	87.26	gold quality
heart right ventricle	UBERON:0002080	87.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	28.07
E-ANND-3	yes	4.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

30 targets.

Target	Regulation
ADAM2
ALB
CDK5R1
CLU	Unknown
CRYAB	Activation
DACH1
DLST
FOS	Unknown
HIF1A	Unknown
HSF2
HSP90AA1
HSP90B2P
HSPA1A
HSPA1B
HSPA4	Activation
HSPA6	Activation
HSPB1
IL12A
IL6
MAP2K4	Repression
MAPK8	Repression
PRKACA
ROS1
SLU7
SUMO1
TNFSF11	Activation
TPM1
TXN	Unknown
ZFAND2A	Unknown
ZNF804A	Repression

JASPAR motifs

Motif	Name	Family
MA0770.1	HSF2	HSF factors

JASPAR matrix evidence (PMIDs): PMID:12027891

Upstream regulators (CollecTRI, top): HSF1, HSF2, HSF4, TP63, USF1

miRNA regulators (miRDB)

65 targeting HSF2, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4269	99.55	69.89	1373

Literature-anchored findings (GeneRIF, showing 37)

• characterization of the hsf2 gene and its 5’-flanking region (PMID:11795475)
• elevated expression of heat shock factor (HSF) 2A stimulates HSF1-induced transcription during oxidative stress in cancer cells (PMID:12813038)
• HSF2 influences to the formation of nuclear stress granules (PMID:12865437)
• HSF1 has a role in transcriptional regulation of the human RANK ligand gene (PMID:14699143)
• results show hsp70i bookmarking is mediated by HSF2 which binds this promoter in mitotic cells, recruits protein phosphatase 2A & interacts with the CAP-G subunit of condensin to promote dephosphorylation & inactivation of condensin complexes (PMID:15662014)
• Both HSF1 and HSF2 were able to bind the hsp70 promoter not only in response to heat shock but also during hemin-induced differentiation of K562 erythroleukemia cells. (PMID:17213196)
• The results of these experiments indicate that the HSF2 region comprising amino acids 343-363 is important for A subunit interaction. (PMID:17688198)
• During mitosis, HSF2 is bound to the HSE promoter elements of other heat shock genes, including hsp90 and hsp27, and the proto-oncogene c-fos. The presence of HSF2 is important for expression of these genes. (PMID:17915561)
• MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes in the vicinity of HSF2. (PMID:18211895)
• These results provide a potential mechanistic basis for the defective cytokinesis phenotype exhibited by HSF2-/- cells, as well as suggest a potential role for PRC1 in HSF2-mediated gene bookmarking. (PMID:18570919)
• NMR study of the SUMOylated DNA binding domain of HSF2 indicates that the SUMO moiety is flexible with respect to the DNA binding domain and has neither a noncovalent interface with nor a structural effect on the domain (PMID:19017645)
• HSF1-HSF2 heterotrimerization regulates stress-induced transcription (PMID:19129477)
• Data show that the PEST sequences of a short-lived protein called HSF2 interact with Cullin3, a subunit of a Cullin-RING E3 ubiquitin ligase, and that this interaction mediates the Cul3-dependent ubiquitination and degradation of HSF2. (PMID:19768582)
• HSF2 and HSF4 regulate transcription of HIF-1alpha and that a critical balance between these HSFs is required to maintain HIF-alpha expression in a repressed state. (PMID:21258402)
• our findings suggest novel mechanisms of HSF2 regulation controlled by HSF4a. (PMID:21792930)
• These results support a role for HSF2 in the pathogenesis of IA and further implicate this transcription factor as a potential therapeutic target. (PMID:23064888)
• Results indicate the importance of the cell cycle phase in transcriptional responses and identify the specific mechanisms for HSF1 and HSF2 in transcriptional orchestration. (PMID:23959860)
• HSF2 appears to be a potential novel molecular marker for ulcerative colitis (PMID:24533153)
• Data indicate that both heat shock factors HSF1 and HSF2 are recruited to the arsenite-inducible RNA-associated protein (AIRAP) promoter and regulate bortezomib-induced AIRAP expression. (PMID:24619424)
• the condensed chromatin of HSF2-deficient cells is accessible for HSF1 and RNA polymerase II, allowing stress-inducible Hsp expression. (PMID:25202032)
• Nuclear HSF2 and HSF4 bound to HSF1 only after heat shock. (PMID:26003728)
• This study provides the first evidence for HSF2 acting as a suppressor of invasion in human malignancies. (PMID:26119944)
• the findings of our studys suggest that HSF2 contributes to its own expression by forming a negative autoregulatory loop. (PMID:26260034)
• HSF2 can induce histone activation.Set1/MLL complex is indispensable for the transcriptional ability of HSF2. (PMID:26478434)
• Presented are the crystal structures of the human HSF2 DNA-binding domain (DBD) bound to DNA. (PMID:26727490)
• MD simulation of high-resolution X-ray structures reveals post-translational modification dependent conformational changes in HSF-DNA interaction. (PMID:27882499)
• Silencing ALG3 or HSF2 inhibited the proliferation, migration, and invasion abilities of MCF-7 cells. (PMID:29799832)
• Heat-shock transcription factor 2 promotes sodium butyrate-induced autophagy by inhibiting mTOR in ulcerative colitis. (PMID:31923427)
• Heat shock transcription factor 2 inhibits intestinal epithelial cell apoptosis through the mitochondrial pathway in ulcerative colitis. (PMID:32446363)
• Heat shock transcription factor 2 predicts mucosal healing and promotes mucosal repair of ulcerative colitis. (PMID:32538201)
• The proteostasis guardian HSF1 directs the transcription of its paralog and interactor HSF2 during proteasome dysfunction. (PMID:32607595)
• Heat shock transcription factor 2 reduces the secretion of IL-1beta by inhibiting NLRP3 inflammasome activation in ulcerative colitis. (PMID:33181254)
• Polymorphisms in the HSF2, LRRC6, MEIG1 and PTIP genes correlate with sperm motility in idiopathic infertility. (PMID:35768906)
• CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder. (PMID:36385105)
• Heat Shock Transcription Factor 2 Is Significantly Involved in Neurodegenerative Diseases, Inflammatory Bowel Disease, Cancer, Male Infertility, and Fetal Alcohol Spectrum Disorder: The Novel Mechanisms of Several Severe Diseases. (PMID:36430241)
• Genome-wide association study reveals HSF2, GJA1 and TRIM36 as susceptibility genes for preeclampsia: a community-based population study in Tianjin, China. (PMID:37735976)
• Comprehensive analysis of human tissues reveals unique expression and localization patterns of HSF1 and HSF2. (PMID:38458311)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hsf2	ENSDARG00000053097
mus_musculus	Hsf2	ENSMUSG00000019878
rattus_norvegicus	Hsf2	ENSRNOG00000000808
drosophila_melanogaster	Hsf	FBGN0001222
caenorhabditis_elegans	hsf-1	WBGENE00002004

Paralogs (9): HSF4 (ENSG00000102878), HSFY2 (ENSG00000169953), HSFX1 (ENSG00000171116), HSFY1 (ENSG00000172468), HSF5 (ENSG00000176160), HSF1 (ENSG00000185122), HSFX2 (ENSG00000268738), HSFX4 (ENSG00000283463), HSFX3 (ENSG00000283697)

Protein

Protein identifiers

Heat shock factor protein 2 — Q03933 (reviewed: Q03933)

Alternative names: Heat shock transcription factor 2

All UniProt accessions (2): Q03933, V9GZ44

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding protein that specifically binds heat shock promoter elements (HSE) and activates transcription. In higher eukaryotes, HSF is unable to bind to the HSE unless the cells are heat shocked.

Subunit / interactions. DNA-binding homotrimer in stressed or heat shocked cells, otherwise found as a homodimer.

Subcellular location. Cytoplasm. Nucleus.

Similarity. Belongs to the HSF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q03933-1	1	yes
Q03933-2	2

RefSeq proteins (2): NP_001129036, NP_004497* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000232	HSF_DNA-bd	Domain
IPR010542	Vert_HSTF_C	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00447, PF06546

UniProt features (36 total): cross-link 8, helix 6, strand 6, region of interest 4, compositionally biased region 3, mutagenesis site 2, turn 2, short sequence motif 2, chain 1, DNA-binding region 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5HDK	X-RAY DIFFRACTION	1.32
7DCI	X-RAY DIFFRACTION	1.7
5D8K	X-RAY DIFFRACTION	1.73
7DCU	X-RAY DIFFRACTION	1.75
5D8L	X-RAY DIFFRACTION	2.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03933-F1	60.42	0.26

Functional residue map

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

Post-translational modifications (8): 2, 82, 135, 139, 151, 210, 218, 237

Mutagenesis-validated functional residues (2):

Position	Phenotype
109	fails to translocate to nucleus.
196–198	fails to translocate to nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 157 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GCACCTT_MIR18A_MIR18B, HNF3ALPHA_Q6, GOBP_MALE_GAMETE_GENERATION, PATIL_LIVER_CANCER, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, KYNG_DNA_DAMAGE_BY_GAMMA_RADIATION, FOXJ2_01, RYTAAWNNNTGAY_UNKNOWN, MODULE_123, AFFAR_YY1_TARGETS_UP, MODULE_98, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, BIDUS_METASTASIS_UP, YIH_RESPONSE_TO_ARSENITE_C1

GO Biological Process (3): spermatogenesis (GO:0007283), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (11): 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), RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding (GO:0001162), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), identical protein binding (GO:0042802), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
developmental process involved in reproduction	1
male gamete generation	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
intronic transcription 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
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
binding	1
DNA binding	1
chromosome	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

954 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSF2	LHCGR	P22888	764
HSF2	HSF2BP	O75031	555
HSF2	FAM204A	Q9H8W3	539
HSF2	TMEM184C	Q9NVA4	505
HSF2	ZMYND15	Q9H091	478
HSF2	VASH2	Q86V25	432
HSF2	CCDC60	Q8IWA6	416
HSF2	CCHCR1	Q8TD31	395
HSF2	RAB11FIP2	Q7L804	380
HSF2	POLI	Q9UNA4	371
HSF2	MEIOB	Q8N635	362
HSF2	RBM44	Q6ZP01	340
HSF2	HSPB7	Q9UBY9	338
HSF2	HSPH1	Q92598	320
HSF2	TBC1D32	Q96NH3	316

IntAct

115 interactions, top by confidence:

A	B	Type	Score
HSF1	HSF2	psi-mi:“MI:0915”(physical association)	0.880
HSF1	HSF2	psi-mi:“MI:0407”(direct interaction)	0.880
HSF2	HSF1	psi-mi:“MI:0915”(physical association)	0.880
HSF2	TPM3	psi-mi:“MI:0915”(physical association)	0.850
TPM3	HSF2	psi-mi:“MI:0915”(physical association)	0.850
WDR5	HSF2	psi-mi:“MI:0915”(physical association)	0.780
HSF2	WDR5	psi-mi:“MI:0915”(physical association)	0.780
HSF2	NUP62	psi-mi:“MI:0915”(physical association)	0.670
NUP62	HSF2	psi-mi:“MI:0915”(physical association)	0.670
HSF2	CEP76	psi-mi:“MI:0915”(physical association)	0.670
HSF2BP	HSF2	psi-mi:“MI:0915”(physical association)	0.670
HSF2	BAG2	psi-mi:“MI:0915”(physical association)	0.670
HSPA2	HSF2	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (119): TPM3 (Two-hybrid), WDR5 (Two-hybrid), MTUS2 (Two-hybrid), NUP62 (Two-hybrid), IMPA2 (Affinity Capture-MS), GM2A (Affinity Capture-MS), SDR9C7 (Affinity Capture-MS), ASAH1 (Affinity Capture-MS), HSF1 (Affinity Capture-MS), PRMT1 (Affinity Capture-MS), HSF1 (Affinity Capture-MS), NCBP1 (Affinity Capture-MS), PRCC (Affinity Capture-MS), RBBP6 (Affinity Capture-MS), SRSF7 (Affinity Capture-MS)

ESM2 similar proteins: A0MZ66, A0MZ67, A1L260, A2AMM0, A2VDA9, A4IGC3, A5PJI6, B1PRL5, E7F7X0, O35867, O45420, O54724, O95810, P38533, P53112, P70302, P82094, P84903, P85125, Q03933, Q13586, Q2TLZ1, Q2TLZ2, Q2TLZ3, Q2TLZ4, Q2TLZ5, Q4V7D3, Q58CP9, Q5BKX8, Q5M8Y7, Q5XG48, Q5ZKG2, Q60ZR7, Q63918, Q66H98, Q69ZW3, Q69ZZ6, Q6NZI2, Q6P0R8, Q6P402

Diamond homologs: A0A1B0GTS1, A0A1B0GWH4, B7XIV9, C4V6H6, D0VYS2, G0SB31, G5EFT5, J9VHZ9, O14283, O49403, P10961, P22121, P22335, P22813, P38529, P38530, P38531, P38532, P38533, P41151, P41153, P41154, Q00613, Q02953, Q03933, Q08DJ8, Q10PR4, Q1HGE8, Q1PDN3, Q338B0, Q40152, Q4G112, Q5A4X5, Q5AQ33, Q5CZP2, Q5KMX8, Q5ND04, Q652B0, Q67TP9, Q6F388

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PCGF2	“down-regulates activity”	HSF2	sumoylation
HSF2	“up-regulates quantity by expression”	HSPA6	“transcriptional regulation”
CUL3	“down-regulates quantity by destabilization”	HSF2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cellular response to heat stress	6	52.5×	2e-07
Regulation of HSF1-mediated heat shock response	9	27.9×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	8	12.9×	1e-04
protein stabilization	8	8.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1901 predictions. Top by Δscore:

Variant	Effect	Δscore
6:122412368:T:TA	acceptor_gain	1.0000
6:122412370:CAG:C	acceptor_loss	1.0000
6:122412371:A:AC	acceptor_loss	1.0000
6:122412371:A:AG	acceptor_gain	1.0000
6:122412371:AGAAT:A	acceptor_gain	1.0000
6:122412372:G:GA	acceptor_gain	1.0000
6:122412372:GA:G	acceptor_gain	1.0000
6:122412372:GAA:G	acceptor_gain	1.0000
6:122412372:GAAT:G	acceptor_gain	1.0000
6:122412372:GAATG:G	acceptor_gain	1.0000
6:122412477:TATGT:T	donor_gain	1.0000
6:122412480:GT:G	donor_gain	1.0000
6:122412482:G:GG	donor_gain	1.0000
6:122412631:TTTCA:T	acceptor_loss	1.0000
6:122412632:TTCA:T	acceptor_loss	1.0000
6:122412633:TCAG:T	acceptor_loss	1.0000
6:122412634:CA:C	acceptor_loss	1.0000
6:122412635:A:AT	acceptor_loss	1.0000
6:122412635:AGAT:A	acceptor_gain	1.0000
6:122412636:GAT:G	acceptor_gain	1.0000
6:122412636:GATG:G	acceptor_gain	1.0000
6:122412760:GGAAG:G	donor_gain	1.0000
6:122412761:GAAG:G	donor_gain	1.0000
6:122412761:GAAGG:G	donor_gain	1.0000
6:122412762:A:T	donor_gain	1.0000
6:122412762:AAGGT:A	donor_loss	1.0000
6:122412764:GGTGA:G	donor_loss	1.0000
6:122412766:T:G	donor_loss	1.0000
6:122413645:AAAAG:A	donor_loss	1.0000
6:122413646:AAAG:A	donor_loss	1.0000

AlphaMissense

3590 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:122399765:T:A	F10I	1.000
6:122399765:T:C	F10L	1.000
6:122399765:T:G	F10V	1.000
6:122399766:T:C	F10S	1.000
6:122399766:T:G	F10C	1.000
6:122399767:C:A	F10L	1.000
6:122399767:C:G	F10L	1.000
6:122399769:T:A	L11H	1.000
6:122399769:T:C	L11P	1.000
6:122399774:A:C	K13Q	1.000
6:122399774:A:G	K13E	1.000
6:122399775:A:T	K13M	1.000
6:122399776:G:C	K13N	1.000
6:122399776:G:T	K13N	1.000
6:122399778:T:A	L14Q	1.000
6:122399778:T:C	L14P	1.000
6:122399787:T:C	L17P	1.000
6:122399817:T:A	I27N	1.000
6:122399822:T:A	W29R	1.000
6:122399822:T:C	W29R	1.000
6:122399823:G:C	W29S	1.000
6:122399824:G:C	W29C	1.000
6:122399824:G:T	W29C	1.000
6:122412377:G:T	G33V	1.000
6:122412385:T:C	F36L	1.000
6:122412386:T:C	F36S	1.000
6:122412387:T:A	F36L	1.000
6:122412387:T:G	F36L	1.000
6:122412392:T:A	V38D	1.000
6:122412409:T:C	F44L	1.000

dbSNP variants (sampled 300 via entrez): RS1000001736 (6:122401317 A>C,G), RS1000101898 (6:122408492 A>C), RS1000228563 (6:122426992 C>T), RS1000351585 (6:122401649 T>G), RS1000418500 (6:122417220 A>G), RS1000530341 (6:122429023 G>A), RS1000601863 (6:122427229 C>G), RS1000714457 (6:122428941 C>T), RS1000881273 (6:122409172 A>C,G), RS1000910749 (6:122409469 G>A), RS1000919017 (6:122415437 A>C), RS1000972209 (6:122422380 T>C), RS1001044304 (6:122421983 C>T), RS1001434319 (6:122402204 A>G), RS1001442397 (6:122403010 GT>G,GTT)

Disease associations

OMIM: gene MIM:140581 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002626_17	Vertical cup-disc ratio	1.000000e-08
GCST002764_11	Optic cup area	1.000000e-06
GCST002764_5	Optic cup area	4.000000e-09
GCST003170_3	Subcutaneous adipose tissue	2.000000e-07
GCST003807_3	Systolic blood pressure response to hydrochlorothiazide in hypertension	8.000000e-06
GCST004137_10	Optic cup area	3.000000e-08
GCST004137_3	Optic cup area	2.000000e-06
GCST004373_15	Atrial fibrillation	4.000000e-08
GCST004627_32	Lymphocyte count	2.000000e-16
GCST005359_12	Disease progression in age-related macular degeneration	9.000000e-07
GCST006061_130	Atrial fibrillation	9.000000e-21
GCST006061_194	Atrial fibrillation	2.000000e-16
GCST006414_119	Atrial fibrillation	4.000000e-19
GCST006414_59	Atrial fibrillation	3.000000e-11
GCST006629_56	Pulse pressure	7.000000e-10
GCST007096_170	Pulse pressure	1.000000e-12
GCST007466_9	Word reading	9.000000e-06
GCST009404_8	Optic cup area	3.000000e-08
GCST009412_20	Vertical cup-disc ratio	1.000000e-08
GCST009462_90	Optic disc size	3.000000e-16
GCST009723_54	Vertical cup-disc ratio (adjusted for vertical disc diameter)	1.000000e-09
GCST009724_7	Vertical cup-disc ratio (multi-trait analysis)	7.000000e-14
GCST90002388_5	Lymphocyte count	2.000000e-34
GCST90002403_172	Red blood cell count	5.000000e-14

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006944	systolic blood pressure change measurement
EFO:0004587	lymphocyte count
EFO:0008336	disease progression measurement
EFO:0005763	pulse pressure measurement
EFO:0005300	word reading
EFO:0006939	cup-to-disc ratio measurement
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3988631 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
cupric oxide	increases expression	1
lactacystin	increases activity	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases activity	1
CGP 52608	affects binding, increases reaction	1
entinostat	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Bortezomib	increases expression, decreases reaction	1
Arsenic Trioxide	increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Doxorubicin	decreases expression	1
Estradiol	increases expression, affects binding, increases reaction, affects reaction	1
Thimerosal	increases expression	1
Tretinoin	decreases expression	1
Zinc	decreases expression	1
Cyclosporine	increases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3881365	Binding	Activation of HSF in human HeLa cell clone 13B after 8 hrs by luciferase reporter gene assay	Cyclopentanone and cyclopentanone derivatives as potent activators of HSF-1

Clinical trials (associated diseases)

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