HSF4

Summary

HSF4 (heat shock transcription factor 4, HGNC:5227) is a protein-coding gene on chromosome 16q22.1, encoding Heat shock factor protein 4 (Q9ULV5). Heat-shock transcription factor that specifically binds heat shock promoter elements (HSE).

Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. HSF4 lacks the carboxyl-terminal hydrophobic repeat which is shared among all vertebrate HSFs and has been suggested to be involved in the negative regulation of DNA binding activity. Two alternatively spliced transcripts encoding distinct isoforms and possessing different transcriptional activity have been described.

Source: NCBI Gene 3299 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 5 multiple types (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 197 total — 13 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• Transcription factor: yes — 12 downstream targets (CollecTRI)
• MANE Select transcript: NM_001374675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5227
Approved symbol	HSF4
Name	heat shock transcription factor 4
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000102878
Ensembl biotype	protein_coding
OMIM	602438
Entrez	3299

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 15 protein_coding, 14 retained_intron, 7 nonsense_mediated_decay

ENST00000434833, ENST00000517680, ENST00000517685, ENST00000517729, ENST00000517750, ENST00000517867, ENST00000519105, ENST00000519224, ENST00000519601, ENST00000520247, ENST00000520304, ENST00000520528, ENST00000520833, ENST00000521314, ENST00000521374, ENST00000521624, ENST00000521916, ENST00000522023, ENST00000522027, ENST00000522295, ENST00000522459, ENST00000522870, ENST00000523077, ENST00000523562, ENST00000584272, ENST00000682526, ENST00000682677, ENST00000683295, ENST00000684701, ENST00000873724, ENST00000873725, ENST00000873726, ENST00000963185, ENST00000963186, ENST00000963187, ENST00000963188

RefSeq mRNA: 4 — MANE Select: NM_001374675 NM_001040667, NM_001374674, NM_001374675, NM_001538

CCDS: CCDS42175, CCDS45510

Canonical transcript exons

ENST00000521374 — 13 exons

Exon	Start	End
ENSE00000000261	67164745	67164934
ENSE00002092938	67169631	67169941
ENSE00003506407	67167120	67167222
ENSE00003518914	67165522	67165630
ENSE00003540244	67169036	67169101
ENSE00003578850	67169279	67169348
ENSE00003585369	67166558	67166622
ENSE00003586472	67166320	67166395
ENSE00003613300	67168831	67168936
ENSE00003644147	67167475	67167599
ENSE00003645153	67165719	67165846
ENSE00003675859	67165946	67166070
ENSE00003676115	67167720	67167947

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 98.86.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8140 / max 98.8042, expressed in 182 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154586	1.5614	495
154587	1.2184	388
154583	0.8140	182

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.86	gold quality
cerebellar hemisphere	UBERON:0002245	98.64	gold quality
cerebellar cortex	UBERON:0002129	98.57	gold quality
adenohypophysis	UBERON:0002196	98.55	gold quality
mucosa of stomach	UBERON:0001199	98.36	gold quality
right uterine tube	UBERON:0001302	98.22	gold quality
lower esophagus mucosa	UBERON:0035834	98.19	gold quality
body of pancreas	UBERON:0001150	97.86	gold quality
apex of heart	UBERON:0002098	97.67	gold quality
endocervix	UBERON:0000458	97.65	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.64	gold quality
right ovary	UBERON:0002118	97.46	gold quality
left uterine tube	UBERON:0001303	97.40	gold quality
right frontal lobe	UBERON:0002810	97.32	gold quality
lower esophagus	UBERON:0013473	97.32	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.32	gold quality
pituitary gland	UBERON:0000007	96.97	gold quality
left ovary	UBERON:0002119	96.94	gold quality
cerebellum	UBERON:0002037	96.77	gold quality
right adrenal gland cortex	UBERON:0035827	96.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.65	gold quality
right adrenal gland	UBERON:0001233	96.60	gold quality
left adrenal gland cortex	UBERON:0035825	96.45	gold quality
skin of abdomen	UBERON:0001416	96.41	gold quality
minor salivary gland	UBERON:0001830	96.34	gold quality
gastrocnemius	UBERON:0001388	96.28	gold quality
right lobe of thyroid gland	UBERON:0001119	96.25	gold quality
right coronary artery	UBERON:0001625	96.21	gold quality
ectocervix	UBERON:0012249	96.21	gold quality
left adrenal gland	UBERON:0001234	96.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

12 targets.

Target	Regulation
ABCC3	Repression
CRYAB
CRYGC	Unknown
DNASE2B	Activation
HIF1A	Unknown
HSF2	Activation
HSP90AA1	Unknown
HSPB1	Activation
LIF	Repression
RAD51	Unknown
TPM1
VIM	Repression

JASPAR motifs

Motif	Name	Family
MA0771.1	HSF4	HSF factors

JASPAR matrix evidence (PMIDs): PMID:25850300

miRNA regulators (miRDB)

7 targeting HSF4, 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-671-5P	99.52	67.11	1277
HSA-MIR-3960	99.41	66.11	96
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-8072	98.27	66.24	83
HSA-MIR-15A-3P	97.47	65.08	527
HSA-MIR-1237-5P	95.38	62.21	451
HSA-MIR-12115	94.19	66.37	738

Literature-anchored findings (GeneRIF, showing 34)

• Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. . We suggest that HSF4 is critical to lens development. (PMID:12089525)
• This is the first report describing association of an autosomal recessive cataract with the HSF4 locus on 16q21-q22.1 and the first description of HSF4 splice variants (PMID:15277496)
• HSF4 binds to alphaB-crystallin, Hsp70, and Hsp82 promoters and has a role in interacting with the canonical heat shock element of the alphaB-crystallin gene (PMID:15308659)
• Findings confirm that mutations in HSF4 may result in both autosomal dominant and autosomal recessive congenital cataract, and highlight the locus heterogeneity in autosomal recessive congenital cataract. (PMID:15959809)
• The results indicate that in the absence of Hsf1 and Hsf2, Hsf4b expression in cells leads to increased ability of Hsf4b to bind HSE during G1, leading to enhanced synthesis of inducible Hsp70. (PMID:16552721)
• These results identified a novel missense mutation R74H in the transcription factor gene HSF4 in a Chinese cataract family and expand the spectrum of HSF4 mutations causing cataract. (PMID:16876512)
• This result indicates that HSF4 mutations account for only a small fraction of age-related cataracts. (PMID:18941546)
• we have shown the first nonsense mutation in HSF4 causing autosomal recessive cataracts in a large consanguineous family from Pakistan (PMID:19014451)
• Hsf4b could interact with and phosphorylated by MAP kinase P38. (PMID:20564821)
• two missense mutations that have been associated with age-related cataract did not or only slightly alter HSF4 activity, implying that other genetic and environmental factors affect the functions of these mutant proteins. (PMID:20670914)
• HSF2 and HSF4 regulate transcription of HIF-1a and that a critical balance between these HSF is required to maintain HIF-a expression in a repressed state. (PMID:21258402)
• our findings suggest novel mechanisms of HSF2 regulation controlled by HSF4a. (PMID:21792930)
• we report the absence of mutations in all studied genes in four families with phenotypes associating cataract, mental retardation and microcephaly. (PMID:22103961)
• Presents the first evidence demonstrating that HSF4 plays a role in DNA damage repair and may contribute a better understanding of congenital cataract formation. (PMID:22587838)
• This comparative analysis with CRYAB and HSP70 demonstrates that differential heat shock response is controlled by cell-type-dependent access of HSF1 and HSF4 to specific promoters, independent of the promoter architecture. (PMID:23264262)
• HSF4 and WRN CNVs might be involved in ARC pathogenesis in the Han Chinese. (PMID:23329665)
• HSF4 exerts its function on lens differentiation via positive regulation of DLAD expression. (PMID:23507146)
• the transcriptional activation of HSF4 is mediated by interactions between activator and repressor domains within the C-terminal end. (PMID:24045990)
• This is the first report of the novel missense mutation, c.69 G–>T (p. K23N), in exon 3 of the HSF4 locus on 16q21-q22 associated with bilateral congenital cataracts in a Chinese family. (PMID:24637349)
• HSF4 p.Arg116His recreates the childhood lamellar cataract in mice suggesting that incomplete penetrance associated with early cataracts may not be an absence but a limitation of the detection of the phenotype (PMID:24975927)
• We found that HSF4 downregulation led to decrease of HIF1alpha mRNA expression (PMID:25088997)
• concluded that the new mutation of c.331C>T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family (PMID:25877371)
• HSF4 may work as a switch between lens epithelial cell proliferation and secondary fiber cell differentiation, a process which mainly depends on p53. (PMID:25940838)
• Nuclear HSF2 and HSF4 bound to HSF1 only after heat shock. (PMID:26003728)
• BCAS2 interacts with HSF4 and negatively regulates its protein stability via ubiquitination. (PMID:26319152)
• report on a novel homozygous HSF4 mutation (c.521T>C, p.Leu174Pro) in two sibs with congenital cataracts (PMID:26490182)
• In the cultured human lens epithelial cells, HSF4 could stabilize and retain p53 in the nucleus to activate its target genes such as fas cell surface death receptor (Fas) and Bcl-2-associated X apoptosis regulator (Bax). (PMID:28981088)
• High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer. (PMID:29131521)
• Ectopic UAP56 upregulated HSF4-controlled HSP25 and alpha B-crystallin proteins expression, while knocking down UAP56 by shRNA reversed it. (PMID:29164525)
• We have identified a novel mutation in HSF4 in a large British pedigree causing dominant congenital lamellar cataract (PMID:29243736)
• HMOX-1, an anti-oxidase, is a bona fide transcriptional target gene of HSF4 in HLECs (human lens epithelial cells). HSF4 directly binds to the HSE element in HMOX-1 promoter to mediate its mRNA transcription and protein accumulation. (PMID:29454088)
• The results expand the spectrum of HSF4 mutations causing congenital cataracts. (PMID:30143024)
• Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts. (PMID:34345029)
• miR-330-5p Suppress Cell Growth and Invasion via Disrupting HSF4-mediated MACC1/STAT3 Pathway in Colorectal Cancer. (PMID:38420805)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hsf4	ENSDARG00000013251
mus_musculus	Hsf4	ENSMUSG00000033249
rattus_norvegicus	Hsf4	ENSRNOG00000015253
drosophila_melanogaster	Hsf	FBGN0001222
caenorhabditis_elegans	hsf-1	WBGENE00002004

Paralogs (9): HSF2 (ENSG00000025156), HSFY2 (ENSG00000169953), HSFX1 (ENSG00000171116), HSFY1 (ENSG00000172468), HSF5 (ENSG00000176160), HSF1 (ENSG00000185122), HSFX2 (ENSG00000268738), HSFX4 (ENSG00000283463), HSFX3 (ENSG00000283697)

Protein

Protein identifiers

Heat shock factor protein 4 — Q9ULV5 (reviewed: Q9ULV5)

Alternative names: Heat shock transcription factor 4

All UniProt accessions (13): Q9ULV5, E5RG51, E5RHY0, E5RJV4, E5RK26, E7EWW4, H0YAR7, H0YAU2, H0YBG9, H0YBS6, H0YBT7, H0YC14, H0YC39

UniProt curated annotations — full annotation on UniProt →

Function. Heat-shock transcription factor that specifically binds heat shock promoter elements (HSE). Required for denucleation and organelle rupture and degradation that occur during eye lens terminal differentiation, when fiber cells that compose the lens degrade all membrane-bound organelles in order to provide lens with transparency to allow the passage of light. In this process, may regulate denucleation of lens fiber cells in part by activating DNASE2B transcription. May be involved in DNA repair through the transcriptional regulation of RAD51. May up-regulate p53/TP53 protein in eye lens fiber cells, possibly through protein stabilization. In the eye lens, controls the expression of alpha-crystallin B chain/CRYAB and consequently may be involved in the regulation of lysosomal acidification. Transcriptional repressor. Transcriptional activator.

Subunit / interactions. Homotrimer. Exhibits constitutive DNA binding and forms trimers even in the absence of stress. Interacts with ALKBH4, DUSP26, MAPK1, MAPK2, MAPK8 and MAP kinase p38.

Subcellular location. Nucleus.

Tissue specificity. Expressed in heart, skeletal muscle, eye and brain, and at much lower levels in some other tissues.

Post-translational modifications. Phosphorylated mainly on serine residues. Phosphorylation on Ser-298 promotes sumoylation on Lys-293. Isoform HSF4B is constitutively sumoylated. Sumoylation represses the transcriptional activity and is promoted by phosphorylation on Ser-298. HSFA is not sumoylated.

Disease relevance. Cataract 5, multiple types (CTRCT5) [MIM:116800] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT5 includes infantile, lamellar, zonular, nuclear, anterior polar, stellate, and Marner-type cataracts, among others. Finger malformation is observed in some kindreds. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the HSF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9ULV5-1	HSF4B	yes
Q9ULV5-2	HSF4A

RefSeq proteins (4): NP_001035757, NP_001361603, NP_001361604, NP_001529 (=MANE)

Domains & families (InterPro)

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

Pfam: PF00447

UniProt features (30 total): helix 6, sequence variant 5, region of interest 5, strand 4, mutagenesis site 2, chain 1, DNA-binding region 1, splice variant 1, sequence conflict 1, turn 1, compositionally biased region 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6J6V	X-RAY DIFFRACTION	1.2
6J6W	X-RAY DIFFRACTION	1.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULV5-F1	61.04	0.30

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 (2): 298, 293

Mutagenesis-validated functional residues (2):

Position	Phenotype
293	abolishes sumoylation. 10-fold increased in transactivational activity.
298	abolishes phosphorylation. greatly reduced sumoylation. greatly increased transactivational activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): MORF_RAGE, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, chr16q22, MODULE_16, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, MORF_FANCG, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, MODULE_157, MORF_PML, GOBP_SENSORY_PERCEPTION, GCM_ATM, MORF_PDPK1, MORF_IKBKG

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), lens fiber cell differentiation (GO:0070306), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein phosphatase binding (GO:0019903), 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 (3): chromatin (GO:0000785), nuclear speck (GO:0016607), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
negative regulation of DNA-templated transcription	1
lens development in camera-type eye	1
epithelial cell differentiation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
negative regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
phosphatase binding	1
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
nuclear ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

888 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSF4	NTM	Q9P121	866
HSF4	BFSP2	Q13515	846
HSF4	GPA33	Q99795	810
HSF4	VSIG2	Q96IQ7	770
HSF4	CRYBB1	P53674	726
HSF4	GJA8	P48165	722
HSF4	LIM2	P55344	721
HSF4	CRYGD	P07320	716
HSF4	CRYGS	P22914	703
HSF4	BFSP1	Q12934	700
HSF4	CRYBB3	P26998	699
HSF4	CRYBB2	P43320	697
HSF4	CRYAA	P02489	696
HSF4	MIP	P30301	686
HSF4	CYP27A1	Q02318	685

IntAct

9 interactions, top by confidence:

A	B	Type	Score
HSF4	HSF1	psi-mi:“MI:0914”(association)	0.530
HSF4	ALKBH4	psi-mi:“MI:0915”(physical association)	0.370
HSF4	CDK2AP2	psi-mi:“MI:0915”(physical association)	0.370
FAM200C	HSF4	psi-mi:“MI:0915”(physical association)	0.370
NUDT21	HSF4	psi-mi:“MI:0915”(physical association)	0.370
BCL6	CACNA1A	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): DAXX (Affinity Capture-Western), DAXX (Reconstituted Complex), HSF4 (Two-hybrid), HSF2 (Co-localization), HSF4 (Negative Genetic), HSF4 (Two-hybrid), HSF4 (Two-hybrid), HSF4 (Two-hybrid), HSF4 (Two-hybrid), HSF4 (Two-hybrid), HSF4 (Two-hybrid), OIP5 (Two-hybrid), KRT37 (Two-hybrid), CPSF3L (Two-hybrid), TPM3 (Two-hybrid)

ESM2 similar proteins: A1A5D9, A1L3T7, A4FV37, A6NC98, A6NJZ7, A6NNM3, O15049, P0C7N4, P0CW27, P58660, Q0P5D1, Q1HGE8, Q2NL23, Q3LUD3, Q3UPH7, Q494R4, Q4QRL3, Q5JYT7, Q5ND29, Q5XIS1, Q64697, Q6QZQ4, Q6UXH0, Q6ZS72, Q7Z6P3, Q8BLS7, Q8C2K5, Q8C7U1, Q8CB62, Q8CB87, Q8CHW5, Q8N137, Q8R1L8, Q8TE77, Q8TER5, Q91VJ2, Q969G5, Q96EN9, Q96FF7, Q96LX7

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

2 interactions.

A	Effect	B	Mechanism
HSF4	“up-regulates quantity by expression”	DNASE2B	“transcriptional regulation”
MAP2K6	“up-regulates activity”	HSF4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	8
Uncertain significance	111
Likely benign	30
Benign	12

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1333484	NM_001374675.1(HSF4):c.392G>A (p.Trp131Ter)	Pathogenic
1995440	NM_001374675.1(HSF4):c.568C>T (p.Gln190Ter)	Pathogenic
2137837	NM_001374675.1(HSF4):c.69G>T (p.Lys23Asn)	Pathogenic
2431622	NM_001374675.1(HSF4):c.627-2A>G	Pathogenic
3376746	NM_001374675.1(HSF4):c.1213C>T (p.Arg405Ter)	Pathogenic
3544405	NM_001374675.1(HSF4):c.1273dup (p.Glu425fs)	Pathogenic
3696447	NM_001374675.1(HSF4):c.536dup (p.Gln180fs)	Pathogenic
459609	NM_001374675.1(HSF4):c.89del (p.Asp30fs)	Pathogenic
567423	NM_001374675.1(HSF4):c.965dup (p.Pro323fs)	Pathogenic
7092	NM_001374675.1(HSF4):c.341T>C (p.Leu114Pro)	Pathogenic
7093	NM_001374675.1(HSF4):c.355C>T (p.Arg119Cys)	Pathogenic
7094	NM_001374675.1(HSF4):c.56C>A (p.Ala19Asp)	Pathogenic
7095	NM_001374675.1(HSF4):c.256A>G (p.Ile86Val)	Pathogenic
1065585	NM_001374675.1(HSF4):c.190A>G (p.Lys64Glu)	Likely pathogenic
1697123	NM_001374675.1(HSF4):c.1254+1G>T	Likely pathogenic
2634990	NM_001374675.1(HSF4):c.904del (p.Asp302fs)	Likely pathogenic
2636293	NM_001374675.1(HSF4):c.7G>T (p.Glu3Ter)	Likely pathogenic
3727898	NM_001374675.1(HSF4):c.117_123+3del	Likely pathogenic
4538472	NM_001374675.1(HSF4):c.897del (p.Asp302fs)	Likely pathogenic
459607	NM_001374675.1(HSF4):c.1255-2A>G	Likely pathogenic
582457	NM_001374675.1(HSF4):c.352C>T (p.Arg118Trp)	Likely pathogenic

SpliceAI

2529 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67165495:AC:A	acceptor_gain	1.0000
16:67165495:ACGGT:A	acceptor_gain	1.0000
16:67165626:CATGT:C	donor_gain	1.0000
16:67165627:ATGT:A	donor_gain	1.0000
16:67165629:GT:G	donor_gain	1.0000
16:67165631:G:GG	donor_gain	1.0000
16:67165717:AGAC:A	acceptor_gain	1.0000
16:67165718:GACG:G	acceptor_gain	1.0000
16:67166027:G:GT	donor_gain	1.0000
16:67166027:G:T	donor_gain	1.0000
16:67166037:A:T	donor_gain	1.0000
16:67166059:G:GT	donor_gain	1.0000
16:67167105:T:TA	acceptor_gain	1.0000
16:67167109:C:A	acceptor_gain	1.0000
16:67167117:CAGGT:C	acceptor_loss	1.0000
16:67167118:A:AT	acceptor_loss	1.0000
16:67167119:G:A	acceptor_loss	1.0000
16:67168829:AG:A	acceptor_gain	1.0000
16:67168829:AGG:A	acceptor_gain	1.0000
16:67168829:AGGG:A	acceptor_gain	1.0000
16:67168830:GG:G	acceptor_gain	1.0000
16:67168830:GGG:G	acceptor_gain	1.0000
16:67168830:GGGG:G	acceptor_gain	1.0000
16:67168933:AGATG:A	donor_loss	1.0000
16:67168935:ATGTG:A	donor_loss	1.0000
16:67168936:TG:T	donor_loss	1.0000
16:67168937:G:GA	donor_loss	1.0000
16:67168938:TGAG:T	donor_loss	1.0000
16:67169032:TCA:T	acceptor_loss	1.0000
16:67169033:CAG:C	acceptor_loss	1.0000

AlphaMissense

3176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67164869:T:C	F20L	1.000
16:67164870:T:G	F20C	1.000
16:67164871:C:A	F20L	1.000
16:67164871:C:G	F20L	1.000
16:67164926:T:A	W39R	1.000
16:67164926:T:C	W39R	1.000
16:67164928:G:C	W39C	1.000
16:67164928:G:T	W39C	1.000
16:67165535:T:C	F46S	1.000
16:67165559:T:C	F54S	1.000
16:67165574:T:A	L59Q	1.000
16:67165585:T:A	F63I	1.000
16:67165585:T:C	F63L	1.000
16:67165586:T:C	F63S	1.000
16:67165586:T:G	F63C	1.000
16:67165587:C:A	F63L	1.000
16:67165587:C:G	F63L	1.000
16:67165588:A:G	K64E	1.000
16:67165590:G:C	K64N	1.000
16:67165590:G:T	K64N	1.000
16:67165591:C:G	H65D	1.000
16:67165593:T:A	H65Q	1.000
16:67165593:T:G	H65Q	1.000
16:67165606:A:C	S70R	1.000
16:67165608:C:A	S70R	1.000
16:67165608:C:G	S70R	1.000
16:67165610:T:C	F71S	1.000
16:67165615:C:A	R73S	1.000
16:67165620:A:C	Q74H	1.000
16:67165620:A:T	Q74H	1.000

dbSNP variants (sampled 300 via entrez): RS1000740498 (16:67164070 C>G,T), RS1000775480 (16:67169222 C>T), RS1000812796 (16:67165957 GCGCGGCGACGACGGC>G), RS1000931461 (16:67167668 G>A), RS1001112422 (16:67163042 T>A), RS1001624778 (16:67170059 A>T), RS1001913020 (16:67163634 G>A,T), RS1002012001 (16:67168480 AAAAG>A), RS1002182057 (16:67162226 G>A), RS1002335325 (16:67168343 G>A), RS1002389252 (16:67161889 G>A,C), RS1002846574 (16:67164949 C>T), RS1003341902 (16:67170201 G>C), RS1003393091 (16:67164683 G>A,C,T), RS1004361548 (16:67161959 C>G,T)

Disease associations

OMIM: gene MIM:602438 | disease phenotypes: MIM:116800

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 5 multiple types	Definitive	Autosomal dominant
early-onset lamellar cataract	Supportive	Autosomal dominant
total early-onset cataract	Supportive	Autosomal dominant

Mondo (3): cataract 5 multiple types (MONDO:0007290), early-onset lamellar cataract (MONDO:0018611), total early-onset cataract (MONDO:0021548)

Orphanet (1): Early onset non-syndromic cataract (Orphanet:91492)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001134	Anterior polar cataract
HP:0007971	Lamellar cataract
HP:0010693	Pulverulent cataract
HP:0010920	Zonular cataract
HP:0100018	Nuclear cataract

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535342	Cataract, zonular (supp.)

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

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	2
FR900359	decreases phosphorylation	1
bisphenol F	decreases expression	1
triphenyl phosphate	affects expression	1
jinfukang	increases expression, affects cotreatment	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Oxygen	increases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Okadaic Acid	decreases expression	1
Acrylamide	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

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3C0	SEES3-1V human HSF4, clone1	Embryonic stem cell	Male
CVCL_A3C1	SEES3-1V human HSF4, clone2	Embryonic stem cell	Male
CVCL_A3C2	SEES3-1V human HSF4, clone3	Embryonic stem cell	Male
CVCL_D7RH	Ubigene A-549 HSF4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06068348	Not specified	ACTIVE_NOT_RECRUITING	Liquid Biopsy Collection Study