HSPA4

Summary

HSPA4 (heat shock protein family A (Hsp70) member 4, HGNC:5237) is a protein-coding gene on chromosome 5q31.1, encoding Heat shock 70 kDa protein 4 (P34932).

Predicted to enable adenyl-nucleotide exchange factor activity. Involved in chaperone-mediated protein complex assembly and protein insertion into mitochondrial outer membrane. Located in cytosol and extracellular exosome. Implicated in Chagas disease. Biomarker of chronic obstructive pulmonary disease; rheumatoid arthritis; type 2 diabetes mellitus; and ulcerative colitis.

Source: NCBI Gene 3308 — RefSeq curated summary.

At a glance

• GWAS associations: 43
• Clinical variants (ClinVar): 123 total
• Druggable target: yes
• MANE Select transcript: NM_002154

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5237
Approved symbol	HSPA4
Name	heat shock protein family A (Hsp70) member 4
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	HS24/P52, HSPH2
Ensembl gene	ENSG00000170606
Ensembl biotype	protein_coding
OMIM	601113
Entrez	3308

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 19 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000304858, ENST00000504328, ENST00000514825, ENST00000870715, ENST00000870716, ENST00000870717, ENST00000870718, ENST00000870719, ENST00000870720, ENST00000870721, ENST00000936299, ENST00000936300, ENST00000936301, ENST00000936302, ENST00000936303, ENST00000936304, ENST00000936305, ENST00000968144, ENST00000968145, ENST00000968146, ENST00000968147

RefSeq mRNA: 1 — MANE Select: NM_002154 NM_002154

CCDS: CCDS4166

Canonical transcript exons

ENST00000304858 — 19 exons

Exon	Start	End
ENSE00001131336	133099545	133099652
ENSE00001131343	133097161	133097286
ENSE00001131349	133096098	133096250
ENSE00001131358	133092700	133092789
ENSE00001131367	133091193	133091374
ENSE00001131374	133089562	133089695
ENSE00001131379	133089055	133089161
ENSE00001131386	133088404	133088555
ENSE00001131428	133073230	133073329
ENSE00001131437	133070374	133070496
ENSE00001131455	133067417	133067557
ENSE00001131465	133064980	133065037
ENSE00001282385	133101759	133101878
ENSE00001282523	133104233	133106449
ENSE00001897299	133052013	133052357
ENSE00002520232	133073993	133074126
ENSE00003480446	133076654	133076898
ENSE00003561818	133086782	133086858
ENSE00003568059	133103865	133104026

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 104.7227 / max 862.2353, expressed in 1828 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58512	84.7479	1828
58511	16.0866	1790
58521	2.4341	993
58520	0.8696	490
58517	0.4272	198
58522	0.1573	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.48	gold quality
cervix squamous epithelium	UBERON:0006922	98.46	gold quality
adrenal tissue	UBERON:0018303	97.89	gold quality
gingival epithelium	UBERON:0001949	97.88	gold quality
lower esophagus mucosa	UBERON:0035834	97.85	gold quality
islet of Langerhans	UBERON:0000006	97.67	gold quality
squamous epithelium	UBERON:0006914	97.53	gold quality
right testis	UBERON:0004534	97.51	gold quality
left testis	UBERON:0004533	97.45	gold quality
esophagus mucosa	UBERON:0002469	97.35	gold quality
gingiva	UBERON:0001828	97.34	gold quality
esophagus squamous epithelium	UBERON:0006920	97.24	gold quality
stromal cell of endometrium	CL:0002255	97.16	gold quality
pharyngeal mucosa	UBERON:0000355	97.16	gold quality
cortical plate	UBERON:0005343	97.10	gold quality
amniotic fluid	UBERON:0000173	97.08	gold quality
tendon of biceps brachii	UBERON:0008188	97.07	gold quality
testis	UBERON:0000473	97.05	gold quality
tonsil	UBERON:0002372	97.05	gold quality
oral cavity	UBERON:0000167	97.00	gold quality
epithelium of nasopharynx	UBERON:0001951	96.91	gold quality
nasopharynx	UBERON:0001728	96.89	gold quality
cartilage tissue	UBERON:0002418	96.62	gold quality
parotid gland	UBERON:0001831	96.55	gold quality
ventricular zone	UBERON:0003053	96.50	gold quality
epithelium of esophagus	UBERON:0001976	96.48	gold quality
tongue squamous epithelium	UBERON:0006919	96.28	gold quality
tendon	UBERON:0000043	96.18	gold quality
mucosa of transverse colon	UBERON:0004991	96.18	gold quality
ganglionic eminence	UBERON:0004023	95.98	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10137	yes	1232.98
E-GEOD-134144	yes	26.64
E-GEOD-124858	no	581.69
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPG, CEBPZ, CREG1, DDIT3, EGR1, ENO1, FOXO3, GLI2, GTF3A, HIF1A, HSF1, HSF2, IRF1, JUN, KAT5, MTF1, MXD1, MYB, MYC, NFAT5, NFIA, NR3C1, NR5A1, RCOR2, SIRT1, SMARCA1, SNAI1, SP1, STAT1, STAT3, TBP, TCF23, TCF3, TEF, TFAM, TP53, TP63, WT1

miRNA regulators (miRDB)

56 targeting HSPA4, 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-4803	99.98	71.99	3117
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-4325	99.49	72.20	1342

Literature-anchored findings (GeneRIF, showing 40)

• induction and expression analysis after heat and physical exercise, transcriptional, protein expression, and subcellular localization (PMID:12485826)
• we show that in mammals, the cytosolic chaperones Hsp90 and Hsp70 dock onto a specialized TPR domain in the import receptor Tom70 at the outer mitochondrial membrane. (PMID:12526792)
• APG-2 has a chaperone-like activity similar to Hsp110 and is overexpressed in human hepatocellular carcinoma. (PMID:14987991)
• stress proteins in subcellular structures of cancer cells exposed to heat shock (PMID:15378924)
• T cell immunity to Hsp70 and Hsp90, like Hsp60-specific immunity, can modulate arthritogenic response in adjuvant arthritis. Regulatory mechanisms induced by Hsp60, Hsp70, and Hsp90 are reinforced by an immune network that connects their reactivities. (PMID:15529360)
• Polymorphism of the HSP70-hom gene is associated with the development of posttransplant complications. Recipient HSP-AA homozygous genotype is a risk factor for acute graft-versus-host disease (PMID:15818324)
• This study suggests that Hsp70 and Hsp90 are closely related to cytoprotection of RPE cells in response to protein phosphatase inhibition. (PMID:15950770)
• The overexpression of HSP70 and HSP90beta are probably correlated with the occurrence, development and prognosis of nasopharyngeal carcinoma. (PMID:16248461)
• specific down-regulation of HSP70 in KATO III cells occurred only in the presence of live Helicobacter pylori; a novel regulatory mechanism for H. pylori-induced HSP70-dependent apoptosis in the human gastric epithelial cell line is proposed (PMID:16579839)
• Human keratinocyte-derived cells release Hsp70 in the extracellular medium through a pathway involving secretory-like granules. (PMID:16584808)
• Both heat and BPDE can induce the expressions of Hsp27 and Hsp70 in A549 cells. (PMID:16598923)
• Acidic pH exposure protects HEMEC through induction of Hsps and activation of MAPK and PI3 kinase pathway. (PMID:16790501)
• Results showed HSP70 expression was inhibited in Helicobacter pylori infected MKN7 cells. (PMID:16845230)
• The binding of Hsp70 with PreAS only requires the substrate-binding subdomain, and the binding with AS nuclei requires the C-terminal lid subdomain as well. (PMID:17010992)
• Coexpression of the chaperone protein Hsp70, causes alpha-synuclein to adopt a different, open conformation, but Hsp70 does not alter alpha-synuclein-alpha-synuclein interactions. (PMID:17012257)
• our results imply that CPm, Hsp70h and p64 act cooperatively to encapsidate a defined region of the closterovirus genome. (PMID:17027895)
• Plasminogen bound to hsps 27, 60, and 70 and Angiostatin predominantly bound to hsp 27 and to hsp 70 in a concentration- and kringle-dependent manner. (PMID:17206383)
• The basal levels of Hsp32, Hsp70 and Hsp90 increased significantly with age in controls. Higher levels of Hsp32, Hsp70 and Hsp90 were noticed in patients with inflammation. (PMID:17211576)
• Our results suggest that the widespread accumulation of Hsc70 and Hsp70 may occur in brains with MSA, and that Hsc70 and Hsp70 may be associated with the pathogenesis of MSA. (PMID:17240362)
• All of the breast cell lines examined showed Hsp70 surface expression. These results also confirm previous studies, demonstrating that Hsp70 is on the plasma membrane of tumor cell lines. (PMID:17278882)
• These findings suggest that in tumors retaining functional p53 and expressing high levels of Hsp70, TRAIL may be an effective therapy. (PMID:17278883)
• data suggest that blood cardioplegia can induce an increment in the expression of hsp70-1, confirming its protective role in ischemia/reperfusion injury. (PMID:17311516)
• HSP60 and HSP70 released upon tissue damage might play a role in the regulation of bacteria-induced inflammation (PMID:17553457)
• Authors hypothesized that differing relations between surface expression of Hsp70 on tumor cells and clinical outcomes may reflect differences in the route of metastases. (PMID:17580361)
• HSP70-mediated inhibition of apoptosis seems to be of minor importance for carcinogenesis and tumor progression in renal cell carcinomas. (PMID:17616937)
• The expression of HSP70 was elevated in carcinoma tissues compared with para-carcinoma tissues. (PMID:17802821)
• Results suggest that the individuals with the homozygous HSP70-1 C/C genotype among the coke-oven workers may be susceptible to DNA damage. (PMID:17988935)
• Heat shock and ADM chemotherapy both induce over expression of HSP70 and MDR1. (PMID:18088459)
• HSP70 gene expression tended to be induced in the group administered Healing and Wound Emulsion following gamma-ray irradiation. (PMID:18162458)
• The degradation of Hsp70 was significantly reduced in TAT-Hsp40-containing cells as a consequence of reduced ubiquitin-proteasome activity after oxidative injury. (PMID:18258197)
• Hsp70 cell surface and mRNA expression was studied in K562, Jurkat and CCRF-CEM human leukemia cell lines (PMID:18297536)
• Hsp70 interaction with membranes acts as a platform for its release into the extracellular environment during its recovery from stress. (PMID:18322243)
• Sequential measurement intraoperatively of the levels of the heat shock proteins HSP70 and HSP27 in the cerebrospinal fluid can predict those patients who are at greatest risk for paralysis during thoracic aneurysm surgery. (PMID:18418731)
• The over-expressions of HSP70 and pim-1 protein/mRNA are related to tumor burden in leukemia patients. (PMID:18426646)
• PHAPI, CAS, and Hsp70 function together to accelerate nucleotide exchange on Apaf-1 and prevent inactive Apaf-1/cytochrome c aggregation. (PMID:18439902)
• these data suggest that the IkappaB-alpha/NF-kappaB pathway has a critical role in the partial maturation of dendritic cells induced by recombinant HSP70. (PMID:18456818)
• These results suggest that aging-related changes in basal Hsp70 levels in peripheral blood lymphocyte are linked to the altered frequency of lymphocyte subsets and not to increases in aged lymphocytes per se. (PMID:18489731)
• Hsp70 was isolated as a putative Rictor interacting protein. (PMID:18505677)
• The structure of an Hsp110:Hsc70 nucleotide exchange complex, is reported. (PMID:18550409)
• The newly discovered interaction between HBP21 and Hsp70 suggests that HBP21 may be involved in the inhibition of progression and metastasis of tumor cells. (PMID:18587674)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	hspa4a	ENSDARG00000004754
danio_rerio	hspa4b	ENSDARG00000018989
mus_musculus	Hspa4	ENSMUSG00000020361
rattus_norvegicus	Hspa4	ENSRNOG00000016596
drosophila_melanogaster	Hsp110	FBGN0026418
caenorhabditis_elegans	hsp-70	WBGENE00002026
caenorhabditis_elegans		WBGENE00009691
caenorhabditis_elegans		WBGENE00009692
caenorhabditis_elegans		WBGENE00016250

Paralogs (13): HSPA5 (ENSG00000044574), HSPA8 (ENSG00000109971), HSPA9 (ENSG00000113013), HSPH1 (ENSG00000120694), HSPA2 (ENSG00000126803), HYOU1 (ENSG00000149428), HSPA13 (ENSG00000155304), HSPA4L (ENSG00000164070), HSPA6 (ENSG00000173110), HSPA14 (ENSG00000187522), HSPA1B (ENSG00000204388), HSPA1A (ENSG00000204389), HSPA1L (ENSG00000204390)

Protein

Protein identifiers

Heat shock 70 kDa protein 4 — P34932 (reviewed: P34932)

Alternative names: HSP70RY, Heat shock 70-related protein APG-2, Heat shock protein family H member 2

All UniProt accessions (1): P34932

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with TJP1/ZO-1.

Subcellular location. Cytoplasm.

Similarity. Belongs to the heat shock protein 70 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P34932-1	1	yes
P34932-2	2

RefSeq proteins (1): NP_002145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013126	Hsp_70_fam	Family
IPR018181	Heat_shock_70_CS	Conserved_site
IPR029047	HSP70_peptide-bd_sf	Homologous_superfamily
IPR029048	HSP70_C_sf	Homologous_superfamily
IPR042052	HSPA4_NBD	Domain
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00012

UniProt features (27 total): modified residue 14, sequence conflict 6, compositionally biased region 3, region of interest 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34932-F1	86.27	0.77

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 (14): 393, 415, 430, 538, 546, 647, 660, 679, 756, 773, 53, 76, 89, 336

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3371453	Regulation of HSF1-mediated heat shock response

MSigDB gene sets: 219 (showing top): ELVIDGE_HYPOXIA_DN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, TSENG_IRS1_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, PAL_PRMT5_TARGETS_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, TATTATA_MIR374, GOBP_CHAPERONE_MEDIATED_PROTEIN_COMPLEX_ASSEMBLY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, USF_C, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP

GO Biological Process (4): protein folding (GO:0006457), response to unfolded protein (GO:0006986), protein import into mitochondrial matrix (GO:0030150), chaperone-mediated protein complex assembly (GO:0051131)

GO Molecular Function (5): adenyl-nucleotide exchange factor activity (GO:0000774), ATP binding (GO:0005524), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to heat stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular process	1
protein maturation	1
response to topologically incorrect protein	1
protein transmembrane import into intracellular organelle	1
protein localization to mitochondrion	1
import into the mitochondrion	1
mitochondrial protein import pathway	1
protein-containing complex assembly	1
ATP binding	1
ADP binding	1
ATPase regulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein folding chaperone	1
ATP-dependent activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

9808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPA4	DNAJB1	P25685	999
HSPA4	HSP90AA1	P07900	999
HSPA4	HSP90AB1	P08238	999
HSPA4	STUB1	Q9UNE7	998
HSPA4	STIP1	P31948	998
HSPA4	HSPBP1	Q9NZL4	997
HSPA4	BAG3	O95817	997
HSPA4	BAG1	Q99933	997
HSPA4	FKBP4	Q02790	996
HSPA4	TLR4	O00206	995
HSPA4	CDC37	Q16543	994
HSPA4	HSPB8	Q9UJY1	994
HSPA4	ST13	P50502	993
HSPA4	APAF1	O14727	993
HSPA4	TLR2	O60603	992

IntAct

229 interactions, top by confidence:

A	B	Type	Score
HSPA8	BAG2	psi-mi:“MI:2364”(proximity)	0.860
HSPA8	HSPA4	psi-mi:“MI:0915”(physical association)	0.830
CCDC117	HSP90AA1	psi-mi:“MI:0914”(association)	0.740
APPBP2	HSPA4	psi-mi:“MI:0915”(physical association)	0.720
HSPA4	APPBP2	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EGFR	HSPA4	psi-mi:“MI:0915”(physical association)	0.670
TCAP	HSPA8	psi-mi:“MI:0914”(association)	0.660
HSPA4	CREB1	psi-mi:“MI:2364”(proximity)	0.570
HSPA4	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
HSPA4	POU6F2	psi-mi:“MI:0915”(physical association)	0.560
VDAC1	HK1	psi-mi:“MI:0914”(association)	0.560
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
DLD	PDHB	psi-mi:“MI:0914”(association)	0.530
METTL21A	BAG3	psi-mi:“MI:0914”(association)	0.530
TRMT12	HSPA8	psi-mi:“MI:0914”(association)	0.530
MAP2K2	BAG2	psi-mi:“MI:0914”(association)	0.530
N	HNRNPDL	psi-mi:“MI:0914”(association)	0.530

BioGRID (1204): HSPA4 (Affinity Capture-Western), HSPA4 (Reconstituted Complex), HSPA4 (Affinity Capture-Western), HSPA4 (Affinity Capture-Western), HSPA4 (Affinity Capture-Western), TP53 (Affinity Capture-Western), HSPA4 (Affinity Capture-MS), TRAF6 (Affinity Capture-Western), HSPA4 (Affinity Capture-MS), HSPA4 (Affinity Capture-Western), Slc12a3 (Affinity Capture-Western), APPBP2 (Two-hybrid), AGTRAP (Two-hybrid), HSPA4 (Affinity Capture-RNA), HSPA4 (Affinity Capture-RNA)

ESM2 similar proteins: A2X6S3, A2YR10, A4FUX8, O88600, O94805, O95757, O96019, P30172, P32390, P34932, P42528, P47117, P48722, P53458, P53490, P78712, P81228, P81229, P86173, P93372, P93374, P93375, Q0IEG8, Q0IIM3, Q2TFN9, Q4R333, Q5R606, Q5R8R4, Q5RDM4, Q60446, Q61316, Q61699, Q61WW9, Q66HA8, Q69YN2, Q6K908, Q6ZJW9, Q84M92, Q92598, Q96482

Diamond homologs: A2Q0Z1, A5A8V7, F4HQD4, O59838, O59855, O65719, O73885, O74225, O88600, O93866, O95757, O97125, P02827, P08108, P09435, P09446, P0CB32, P0DMV8, P0DMV9, P0DMW0, P0DMW1, P10591, P10592, P11142, P16019, P17879, P18694, P19120, P19378, P22202, P22953, P24629, P26413, P27322, P27541, P29357, P32589, P32590, P34930, P34931

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 221 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
Attenuation phase	6	15.2×	5e-04
Dengue Virus Genome Translation and Replication	6	11.8×	2e-03
PINK1-PRKN Mediated Mitophagy	5	11.1×	5e-03
Signaling by ERBB2	5	10.8×	5e-03
Lysosome Vesicle Biogenesis	5	10.1×	6e-03
HSF1-dependent transactivation	5	9.8×	7e-03
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	8	9.6×	5e-04
Regulation of HSF1-mediated heat shock response	9	7.8×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
potassium ion homeostasis	6	24.2×	5e-05
protein refolding	6	19.7×	1e-04
cell volume homeostasis	5	15.8×	2e-03
mitophagy	8	13.4×	5e-05
autophagosome maturation	7	12.9×	2e-04
response to unfolded protein	8	12.7×	5e-05
T cell costimulation	6	11.8×	2e-03
potassium ion import across plasma membrane	6	11.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	76
Likely benign	4
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

2928 predictions. Top by Δscore:

Variant	Effect	Δscore
5:133052333:A:AG	donor_gain	1.0000
5:133052354:CGCC:C	donor_gain	1.0000
5:133052355:GCC:G	donor_gain	1.0000
5:133052355:GCCG:G	donor_gain	1.0000
5:133052358:G:GG	donor_gain	1.0000
5:133064975:TCTA:T	acceptor_loss	1.0000
5:133064976:CTA:C	acceptor_loss	1.0000
5:133064977:TA:T	acceptor_loss	1.0000
5:133064978:A:AG	acceptor_gain	1.0000
5:133064978:AG:A	acceptor_gain	1.0000
5:133064978:AGG:A	acceptor_gain	1.0000
5:133064978:AGGG:A	acceptor_loss	1.0000
5:133064979:G:GT	acceptor_gain	1.0000
5:133064979:GG:G	acceptor_gain	1.0000
5:133064979:GGG:G	acceptor_gain	1.0000
5:133064979:GGGCT:G	acceptor_gain	1.0000
5:133065033:GCCAG:G	donor_gain	1.0000
5:133065035:CAGGT:C	donor_loss	1.0000
5:133065036:AGG:A	donor_loss	1.0000
5:133065038:GTAAA:G	donor_loss	1.0000
5:133065039:T:A	donor_loss	1.0000
5:133067413:TTA:T	acceptor_loss	1.0000
5:133067414:TAG:T	acceptor_loss	1.0000
5:133067416:GGTA:G	acceptor_gain	1.0000
5:133067555:AAG:A	donor_loss	1.0000
5:133067556:AG:A	donor_loss	1.0000
5:133067557:GG:G	donor_loss	1.0000
5:133067558:G:T	donor_loss	1.0000
5:133070369:T:A	acceptor_gain	1.0000
5:133070371:CA:C	acceptor_loss	1.0000

AlphaMissense

5588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:133052303:C:A	A18D	1.000
5:133073261:G:C	R154P	1.000
5:133089057:T:G	C380W	1.000
5:133089059:C:A	A381D	1.000
5:133091253:T:A	V480D	1.000
5:133091298:C:A	A495E	1.000
5:133052263:G:C	G5R	0.999
5:133052264:G:A	G5D	0.999
5:133052296:G:C	A16P	0.999
5:133052297:C:A	A16D	0.999
5:133052318:T:A	I23N	0.999
5:133052334:T:A	N28K	0.999
5:133052334:T:G	N28K	0.999
5:133052347:C:A	R33S	0.999
5:133065008:C:A	R46S	0.999
5:133065018:G:A	G49E	0.999
5:133065027:C:A	A52D	0.999
5:133070441:T:C	L125P	0.999
5:133070489:T:A	V141D	0.999
5:133073258:G:C	R153T	0.999
5:133073259:A:C	R153S	0.999
5:133073259:A:T	R153S	0.999
5:133073275:G:C	A159P	0.999
5:133073306:G:C	R169P	0.999
5:133073999:T:C	L179P	0.999
5:133074007:G:A	G182R	0.999
5:133074007:G:C	G182R	0.999
5:133074008:G:A	G182E	0.999
5:133074122:T:C	L220P	0.999
5:133076784:G:C	R265P	0.999

dbSNP variants (sampled 300 via entrez): RS1000004298 (5:133089719 A>G), RS1000120054 (5:133089881 T>C), RS1000130387 (5:133050225 G>C), RS1000175691 (5:133085591 T>TGGA), RS1000207425 (5:133076401 A>G), RS1000390852 (5:133103382 T>C), RS1000401687 (5:133079265 A>G), RS1000418705 (5:133050575 T>C), RS1000468165 (5:133095666 T>A), RS1000491528 (5:133073850 T>C), RS1000521684 (5:133057381 C>A), RS1000550144 (5:133066957 G>A), RS1000632196 (5:133073505 G>A), RS1000648729 (5:133078450 C>G,T), RS1000685155 (5:133072062 C>T)

Disease associations

OMIM: gene MIM:601113 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST003476_5	Eyebrow thickness	3.000000e-06
GCST004619_82	Reticulocyte fraction of red cells	6.000000e-09
GCST004988_666	Breast cancer	8.000000e-09
GCST006630_3	Diastolic blood pressure	6.000000e-14
GCST006979_121	Heel bone mineral density	2.000000e-19
GCST007692_116	Chronic obstructive pulmonary disease	2.000000e-08
GCST008074_151	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-11
GCST008074_53	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-07
GCST008075_78	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-08
GCST008076_48	Triglyceride levels	1.000000e-06
GCST008083_118	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-11
GCST008083_24	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-07
GCST008084_53	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-07
GCST008087_112	Triglyceride levels in current drinkers	9.000000e-06
GCST008087_20	Triglyceride levels in current drinkers	7.000000e-09
GCST009391_686	Metabolite levels	5.000000e-06
GCST010242_359	HDL cholesterol levels	1.000000e-10
GCST010244_225	Triglyceride levels	5.000000e-19
GCST010658_9	High density lipoprotein cholesterol levels	1.000000e-06
GCST010660_18	Triglyceride levels	1.000000e-06
GCST010796_5190	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_5191	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-11
GCST010796_5192	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-11
GCST010796_5193	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_5194	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_5195	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-11
GCST012228_110	Waist-hip index	5.000000e-09
GCST012230_9	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST90002385_346	High light scatter reticulocyte count	1.000000e-18
GCST90002386_40	High light scatter reticulocyte percentage of red cells	2.000000e-18

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0006336	diastolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0008529	kynurenine measurement
EFO:0004327	electrocardiography
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0010701	mean reticulocyte volume
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169130 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.11	Kd	77.68	nM	CHEMBL5653589
7.11	ED50	77.68	nM	CHEMBL5653589
5.50	Kd	3182	nM	CHEMBL3752910
5.50	ED50	3182	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148551: Binding affinity to human HSPA4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0777	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148551: Binding affinity to human HSPA4 incubated for 45 mins by Kinobead based pull down assay	kd	3.1820	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, decreases reaction, increases expression, increases reaction, decreases expression	7
Arsenic Trioxide	increases expression, decreases reaction	5
methylmercuric chloride	increases expression, affects cotreatment	4
Atrazine	decreases expression, decreases reaction, increases expression	3
Tobacco Smoke Pollution	increases expression, affects expression	3
geldanamycin	increases expression, decreases response to substance	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	decreases methylation, affects cotreatment, increases expression	2
Caffeine	increases expression, increases phosphorylation	2
Cannabidiol	affects cotreatment, increases expression	2
Copper	affects binding, decreases expression	2
Doxorubicin	increases expression, decreases response to substance	2
Estradiol	increases expression	2
Ivermectin	affects cotreatment, increases expression, decreases expression	2
Silicon Dioxide	affects secretion, increases expression	2
Smoke	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
moringin	affects cotreatment, increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
pyrithione zinc	increases expression	1
Nonidet P-40	increases expression	1
methylparaben	decreases expression	1
afimoxifene	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5145383	Binding	Binding affinity to HSPA4 in human DOHH-2 cells by MS analysis	PES derivative PESA is a potent tool to globally profile cellular targets of PES. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1NC	Abcam K-562 HSPA4 KO	Cancer cell line	Female
CVCL_D2JX	Abcam Raji HSPA4 KO	Cancer cell line	Male
CVCL_D6B7	HyCyte HCCLM3 KO-hHSPA4	Cancer cell line	Male
CVCL_D9GG	Ubigene HEK293 HSPA4 KO	Transformed cell line	Female
CVCL_UQ78	Abcam Jurkat HSPA4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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