HSPA1L

Summary

HSPA1L (heat shock protein family A (Hsp70) member 1 like, HGNC:5234) is a protein-coding gene on chromosome 6p21.33, encoding Heat shock 70 kDa protein 1-like (P34931). Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein comple….

This gene encodes a 70kDa heat shock protein. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein.

Source: NCBI Gene 3305 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inflammatory bowel disease (Moderate, GenCC)
• GWAS associations: 26
• Clinical variants (ClinVar): 123 total
• Druggable target: yes
• MANE Select transcript: NM_005527

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5234
Approved symbol	HSPA1L
Name	heat shock protein family A (Hsp70) member 1 like
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	HSP70-HOM, hum70t
Ensembl gene	ENSG00000204390
Ensembl biotype	protein_coding
OMIM	140559
Entrez	3305

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000375654, ENST00000879288, ENST00000879289, ENST00000879290, ENST00000879291, ENST00000879292, ENST00000954474

RefSeq mRNA: 1 — MANE Select: NM_005527 NM_005527

CCDS: CCDS34413

Canonical transcript exons

ENST00000375654 — 2 exons

Exon	Start	End
ENSE00001853823	31814889	31815283
ENSE00001943225	31809619	31811985

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 93.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2256 / max 22.6930, expressed in 86 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72837	0.2076	82
72836	0.0180	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	93.24	gold quality
right testis	UBERON:0004534	93.24	gold quality
testis	UBERON:0000473	92.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.43	gold quality
skeletal muscle tissue	UBERON:0001134	76.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.41	gold quality
blood	UBERON:0000178	74.76	gold quality
muscle tissue	UBERON:0002385	73.62	gold quality
granulocyte	CL:0000094	73.23	gold quality
muscle of leg	UBERON:0001383	72.72	gold quality
gastrocnemius	UBERON:0001388	72.29	gold quality
ganglionic eminence	UBERON:0004023	71.93	gold quality
ventricular zone	UBERON:0003053	71.67	gold quality
cortical plate	UBERON:0005343	71.46	gold quality
right uterine tube	UBERON:0001302	71.14	gold quality
stromal cell of endometrium	CL:0002255	70.86	gold quality
leukocyte	CL:0000738	70.06	gold quality
monocyte	CL:0000576	69.60	gold quality
superior frontal gyrus	UBERON:0002661	69.14	gold quality
putamen	UBERON:0001874	69.10	gold quality
islet of Langerhans	UBERON:0000006	68.72	gold quality
caudate nucleus	UBERON:0001873	68.67	gold quality
fallopian tube	UBERON:0003889	68.43	gold quality
anterior cingulate cortex	UBERON:0009835	68.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.27	gold quality
primary visual cortex	UBERON:0002436	68.10	gold quality
nucleus accumbens	UBERON:0001882	68.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	67.80	gold quality
lymph node	UBERON:0000029	67.56	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting HSPA1L, 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-574-5P	100.00	66.01	989
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-320A-5P	98.88	66.75	1248
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-1265	98.36	66.46	598
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-5571-3P	97.80	66.07	640
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813

Literature-anchored findings (GeneRIF, showing 35)

• Heat shock protein 70 genotypes HSPA1B and HSPA1L influence cytokine concentrations, clinical outcome after severe injury (PMID:12544996)
• HSP70-hom gene polymorphism may have a role in graft-versus-host disease after hematopoietic stem cell transplantation (PMID:17060867)
• examined the relationship between the HSP70-hom polymorphism and the clinical characteristics of the malignancy at the time of diagnosis (PMID:17578680)
• A strong association was found between HSP-70/Hom rs2075800 G and uveitis in patients with sarcoidosis. (PMID:17591867)
• polymorphisms in HSP70-HOM genes associated with noise-induced hearing loss (PMID:18813331)
• significant individual and interactive influences of five polymorphisms in three genes of Hsp70 family on essential hypertension. (PMID:19085089)
• The aim of this paper is to investigate a set of mutations in three genes, HSPA1A, HSPA1B and HSPA1L, in schizophrenia; findings further support a role of heat shock proteins in the pathophysiology of schizophrenia (PMID:19439993)
• HSPA1B genotyping showed that AG genotype was significantly associated with the severity of foot ulceration, need for amputation and median length of hospital stay but HSPA1L genotypes did not show any significant association with these parameters. (PMID:19731315)
• Results are likely to indicate a primary association between HSPA1B gene polymorphisms with childhood acute lymphoblastic leukemia. (PMID:20012387)
• These results suggest that HSP70 gene polymorphisms (HSPA1A, B, and L) influence susceptibility to development of sudden sensorineural hearing loss in the Taiwanese population. (PMID:22922572)
• studied the relationship between blood levels of HSP70 and HSP90 and genotypes of HSP70, GSTT1, and GSTM1 polymorphic variants in individuals chronically exposed to mercury (PMID:23330093)
• The risk for the development of chronic hepatitis and hepatocellular carcinoma compared to healthy controls irrespective of the aetiology was significant in terms of the HSPA1B marker than HSPA1L in the Indian population. (PMID:23490384)
• In HSPA1L T2437C polymorphisms, there was no significant differences in frequencies of the variant homozygous in patients compared to controls. (PMID:23666708)
• The potential implication of HSPA1A +190G/C, HSPA1B +1267A/G, and HSPA1L +2437T/C polymorphisms in the susceptibility to paranoid schizophrenia in a homogenous Caucasian Polish population, was analyzed. (PMID:23893339)
• findings show polymorphisms of HSP70 genes are associated with the development of gastric cancer and duodenal ulcers in a population at high risk for gastric cancer in Costa Rica (PMID:24051039)
• HSP70-hom polymorphisms modify the association of diethylhexyl phthalates exposure with insulin resistance. (PMID:25044062)
• may be a predictive biomarker for chronic graft-versus-host disease following allogeneic stem cell transplantation (PMID:25680846)
• Infertility in males with normal sperm parameters was not significantly associated with HSPA1L:c.1478C>T gene polymorphism. (PMID:26160076)
• HSPA1L (rs2227956) is associated with a decreased risk of idiopathic pulmonary fibrosis in a Mexican population. (PMID:26496868)
• Polymorphism of HSPA1L gene is associated with the development of esophageal Carcinoma. (PMID:26745065)
• A heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L in ulcerative colitis patient. Five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) were found in six other patients. All six rare HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity. (PMID:28126021)
• The rs2763979 locus of the HSP70 genes may be associated with susceptibility to noise-induced hearing loss (NIHL) in Chinese individuals, and other HSP70 genes may also be susceptibility genes for NIHL, but the results must be further replicated in additional independent sample sets. (PMID:28182740)
• In a cohort of youth at risk for bipolar disorder, pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for bipolar disorder in vulnerable populations. (PMID:28291257)
• This is the first study to show that HSPA1L mediated HIF-1alpha stabilization. In addition, this is the first study to show that GP78 inactivation promotes cancer cell proliferation, migration and eventual tumor growth both in vivo and in vitro by increasing cellular prion protein. (PMID:28759037)
• HSP70-HOM gene polymorphism associated with susceptibility to noise-induced hearing loss. (PMID:29072670)
• Whole exome sequencing identified multiple rare, likely damaging HSPA1L variants in several families of northern Finnish origin affected by recurrent spontaneous preterm births, and this gene was associated with the glucocorticoid receptor signaling pathway. (PMID:30001343)
• Support for previously reported associations between HSPA1A and HSPA1B SNPs and schizophrenia symptomatology. (PMID:30342847)
• HSPA1L rs2227956 and HSPA1B rs1061581 gene polymorphisms are associated with susceptibility to idiopathic male infertility in Iranian population. (PMID:31228677)
• Association of polymorphism in heat shock protein 70 genes with type 2 diabetes in Bangladeshi population. (PMID:31816668)
• HSPA1L rs1061581 polymorphism is associated with the risk of preeclampsia in Han Chinese women. (PMID:32039449)
• HSPA1L Enhances Cancer Stem Cell-Like Properties by Activating IGF1Rbeta and Regulating beta-Catenin Transcription. (PMID:32971893)
• A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease. (PMID:33742129)
• Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth. (PMID:34429451)
• Expressions of HSPA1L and HSPA9 are associated with poor sperm quality of low-motility spermatozoa in fertile men. (PMID:34796524)
• Analysis of the heat shock protein 70 (HSP70) genetic variants in nonsegmental vitiligo patients. (PMID:36345598)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hspa1l	ENSMUSG00000007033
rattus_norvegicus	Hspa1l	ENSRNOG00000047966
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), HSPA4 (ENSG00000170606), HSPA6 (ENSG00000173110), HSPA14 (ENSG00000187522), HSPA1B (ENSG00000204388), HSPA1A (ENSG00000204389)

Protein

Protein identifiers

Heat shock 70 kDa protein 1-like — P34931 (reviewed: P34931)

Alternative names: Heat shock 70 kDa protein 1-Hom, Heat shock protein family A member 1L

All UniProt accessions (2): P34931, A0A1U9X7W7

UniProt curated annotations — full annotation on UniProt →

Function. Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The affinity for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. Positive regulator of PRKN translocation to damaged mitochondria.

Subunit / interactions. Interacts with PRKN.

Tissue specificity. Expressed in spermatids.

Domain organisation. The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. The C-terminal substrate-binding domain (SBD) (also known as peptide-binding domain) binds to the client/substrate proteins. The two domains are allosterically coupled so that, when ATP is bound to the NBD, the SBD binds relatively weakly to clients. When ADP is bound in the NBD, a conformational change enhances the affinity of the SBD for client proteins.

Induction. Not induced by heat shock.

Similarity. Belongs to the heat shock protein 70 family.

RefSeq proteins (1): NP_005518* (*=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
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00012

UniProt features (62 total): helix 18, strand 17, sequence variant 7, sequence conflict 5, binding site 5, turn 4, mutagenesis site 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3GDQ	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34931-F1	89.28	0.67

Functional residue map

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

Ligand- & substrate-binding residues (5): 14–17; 73; 204–206; 270–277; 341–344

Mutagenesis-validated functional residues (3):

Position	Phenotype
73	no rescue of prkn translocation deficit in knockout cells.
396	no rescue of prkn translocation deficit in knockout cells.
638–641	no rescue of prkn translocation deficit in knockout cells.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation
R-HSA-9833482	PKR-mediated signaling

MSigDB gene sets: 176 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_SINGLE_FERTILIZATION, BENPORATH_ES_WITH_H3K27ME3, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, KEGG_MAPK_SIGNALING_PATHWAY, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MORF_RAD51L3, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_DN, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN, GOBP_PROTEIN_MATURATION, FISCHER_G2_M_CELL_CYCLE, GOBP_SPERM_EGG_RECOGNITION, GOBP_REGULATION_OF_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MITOCHONDRION

GO Biological Process (5): response to unfolded protein (GO:0006986), binding of sperm to zona pellucida (GO:0007339), protein refolding (GO:0042026), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), response to stress (GO:0006950)

GO Molecular Function (9): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), heat shock protein binding (GO:0031072), ubiquitin protein ligase binding (GO:0031625), protein folding chaperone (GO:0044183), obsolete unfolded protein binding (GO:0051082), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (9): zona pellucida receptor complex (GO:0002199), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell body (GO:0044297), blood microparticle (GO:0072562), COP9 signalosome (GO:0008180)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cellular response to heat stress	2
Cellular responses to stress	1
HSF1-dependent transactivation	1
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein folding	2
ATP-dependent activity	2
response to topologically incorrect protein	1
sperm-egg recognition	1
response to stimulus	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
ubiquitin-like protein ligase binding	1
molecular_function	1
protein folding chaperone	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
chaperonin-containing T-complex	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular region	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

3783 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPA1L	HSP90AB1	P08238	722
HSPA1L	HSP90AA1	P07900	685
HSPA1L	ANXA11	P50995	635
HSPA1L	HSP90B1	P14625	619
HSPA1L	STIP1	P31948	617
HSPA1L	BTNL2	Q9UIR0	610
HSPA1L	HSPE1	P61604	602
HSPA1L	HSPB1	P04792	600
HSPA1L	HLA-B	P01889	583
HSPA1L	SIAH3	Q8IW03	571
HSPA1L	HLA-DRB1	P01911	567
HSPA1L	HSPB2	Q16082	558
HSPA1L	ST6GAL1	P15907	556
HSPA1L	HSPA12A	O43301	555
HSPA1L	HSPB3	Q12988	534

IntAct

208 interactions, top by confidence:

A	B	Type	Score
	TOMM70	psi-mi:“MI:0914”(association)	0.980
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
BAG4	HSPA1L	psi-mi:“MI:0915”(physical association)	0.670
HSF1	KPNA3	psi-mi:“MI:0914”(association)	0.640
DNAJC8	SF3B1	psi-mi:“MI:0914”(association)	0.640
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
TRIM38	HSPA1L	psi-mi:“MI:0915”(physical association)	0.560
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.560
MAP3K1	HSPA1L	psi-mi:“MI:2364”(proximity)	0.540
HSPA1L	TP53	psi-mi:“MI:2364”(proximity)	0.540
HSPA1L	TRAF2	psi-mi:“MI:2364”(proximity)	0.540
HSPA1L	TAB1	psi-mi:“MI:2364”(proximity)	0.540
HSPA1L	TP53	psi-mi:“MI:0915”(physical association)	0.540
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
KLHL34	BAG3	psi-mi:“MI:0914”(association)	0.530
ANKK1	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
ILK	HSPA8	psi-mi:“MI:0914”(association)	0.530
CCT8L2	ACSL4	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
HSPA2	DNAJC13	psi-mi:“MI:0914”(association)	0.530
P/V	HSPA4L	psi-mi:“MI:0914”(association)	0.530
CCDC28B	HSPA1L	psi-mi:“MI:0914”(association)	0.510
MAPRE2	PSMB1	psi-mi:“MI:0914”(association)	0.510

BioGRID (406): HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA1L (Affinity Capture-MS)

ESM2 similar proteins: A5A8V7, O65719, O97125, P02827, P08106, P08418, P09189, P0CB32, P0DMV8, P0DMV9, P0DMW0, P0DMW1, P11143, P14659, P16627, P17156, P17879, P22953, P22954, P24629, P25840, P26413, P27322, P34930, P34931, P34933, P41825, P54652, P55063, Q06248, Q24789, Q27965, Q27975, Q28222, Q4R888, Q4U0F3, Q5R7D3, Q61696, Q6S4N2, Q7YQC6

Diamond homologs: A0A509AJG0, A2Q0Z1, A5A8V7, G3I8R9, O24581, O59855, O73885, P02827, P06761, P07823, P08106, P08108, P08418, P09189, P0CB32, P0DMV8, P0DMV9, P0DMW0, P0DMW1, P10591, P10592, P11021, P11142, P11147, P14659, P16474, P16627, P17066, P17156, P17879, P19120, P19208, P19378, P20029, P20163, P22202, P22954, P24067, P26413, P27420

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MAPKAPK2	“up-regulates activity”	HSPA1L	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 239 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
RIP-mediated NFkB activation via ZBP1	9	34.4×	7e-10
TRAF6 mediated NF-kB activation	10	25.9×	7e-10
MAP3K8 (TPL2)-dependent MAPK1/3 activation	5	20.3×	1e-04
TNF signaling	8	19.2×	5e-07
TAK1-dependent IKK and NF-kappa-B activation	11	18.8×	2e-09
Regulation of NF-kappa B signaling	5	18.0×	2e-04
TNFR1-induced NF-kappa-B signaling pathway	9	17.2×	2e-07
TICAM1, RIP1-mediated IKK complex recruitment	5	17.1×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	11	44.6×	9e-14
regulation of cellular response to heat	6	30.4×	5e-06
canonical NF-kappaB signal transduction	16	28.2×	2e-16
tumor necrosis factor-mediated signaling pathway	13	20.6×	2e-11
interleukin-1-mediated signaling pathway	5	19.3×	4e-04
potassium ion homeostasis	5	18.4×	5e-04
protein refolding	6	18.0×	9e-05
cell volume homeostasis	6	17.4×	1e-04

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	96
Likely benign	9
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

127 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31811981:GAGGC:G	acceptor_gain	1.0000
6:31811983:GGC:G	acceptor_gain	1.0000
6:31811984:GC:G	acceptor_gain	1.0000
6:31811985:CCTA:C	acceptor_gain	1.0000
6:31811986:C:CC	acceptor_gain	1.0000
6:31811986:CT:C	acceptor_loss	1.0000
6:31811987:T:G	acceptor_loss	1.0000
6:31811988:A:C	acceptor_gain	1.0000
6:31811982:AGGC:A	acceptor_gain	0.9900
6:31811982:AGGCC:A	acceptor_gain	0.9900
6:31811983:GGCCT:G	acceptor_gain	0.9900
6:31811984:GCCTA:G	acceptor_gain	0.9900
6:31811985:CCTAT:C	acceptor_gain	0.9900
6:31811986:C:T	acceptor_gain	0.9900
6:31811988:A:AC	acceptor_gain	0.9900
6:31814884:CTCA:C	donor_loss	0.9900
6:31814885:TCA:T	donor_loss	0.9900
6:31814886:CA:C	donor_loss	0.9900
6:31814888:C:CA	donor_loss	0.9900
6:31811986:CTATG:C	acceptor_gain	0.9800
6:31814879:A:AC	donor_gain	0.9700
6:31814880:C:CC	donor_gain	0.9700
6:31811987:T:A	acceptor_gain	0.9600
6:31814891:AGTCT:A	donor_gain	0.9600
6:31815014:C:A	donor_gain	0.9600
6:31814883:GCTCA:G	donor_loss	0.9500
6:31814880:CTGG:C	donor_gain	0.9100
6:31814887:A:AC	donor_gain	0.8900
6:31814888:C:CC	donor_gain	0.8900
6:31814925:T:TA	donor_gain	0.7800

AlphaMissense

4226 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:31810954:C:T	G340E	1.000
6:31811154:C:A	K273N	1.000
6:31811154:C:G	K273N	1.000
6:31811296:C:T	G226E	1.000
6:31811434:G:T	A180D	1.000
6:31811443:T:A	E177V	1.000
6:31811527:G:T	P149Q	1.000
6:31811754:T:A	K73N	1.000
6:31811754:T:G	K73N	1.000
6:31811755:T:A	K73I	1.000
6:31811847:G:C	S42R	1.000
6:31811847:G:T	S42R	1.000
6:31811849:T:G	S42R	1.000
6:31810498:G:T	A492D	0.999
6:31810504:A:T	V490D	0.999
6:31810633:C:A	G447V	0.999
6:31810634:C:G	G447R	0.999
6:31810683:G:C	F430L	0.999
6:31810683:G:T	F430L	0.999
6:31810685:A:G	F430L	0.999
6:31810762:C:T	G404E	0.999
6:31810763:C:A	G404W	0.999
6:31810771:A:G	L401P	0.999
6:31810852:C:T	G374E	0.999
6:31810853:C:A	G374W	0.999
6:31810853:C:G	G374R	0.999
6:31810853:C:T	G374R	0.999
6:31810954:C:A	G340V	0.999
6:31810955:C:A	G340W	0.999
6:31810955:C:G	G340R	0.999

dbSNP variants (sampled 300 via entrez): RS1000060402 (6:31809311 G>A), RS1000603059 (6:31811825 C>T), RS1001162238 (6:31814530 A>C), RS1002163083 (6:31813018 C>G), RS1002283867 (6:31813338 C>T), RS1002327850 (6:31814201 G>A), RS1002613873 (6:31812927 T>C), RS1003074670 (6:31812621 CTATTTTT>C), RS1003364419 (6:31809407 A>C,G), RS1003803445 (6:31809596 A>C,G), RS1003842291 (6:31815399 A>C), RS1004168726 (6:31809349 G>A), RS1005023338 (6:31814394 T>A,C), RS1005521886 (6:31814175 G>A), RS1005572569 (6:31813964 G>A)

Disease associations

OMIM: gene MIM:140559 | disease phenotypes: MIM:266600, MIM:606963

GenCC curated gene-disease

Disease	Classification	Inheritance
inflammatory bowel disease	Moderate	Autosomal dominant

Mondo (3): inflammatory bowel disease 1 (MONDO:0009960), chronic obstructive pulmonary disease (MONDO:0005002), inflammatory bowel disease (MONDO:0005265)

Orphanet (0):

HPO phenotypes

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

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST002453_3	Ulcerative colitis	5.000000e-14
GCST002876_5	Type 1 diabetes and autoimmune thyroid diseases	5.000000e-25
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_224	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_281	Autism spectrum disorder or schizophrenia	5.000000e-09
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST008916_30	Asthma	1.000000e-09
GCST008917_2	Asthma (childhood onset)	4.000000e-07
GCST008921_1	Asthma and major depressive disorder	2.000000e-16
GCST90002388_78	Lymphocyte count	2.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432
D029424	Pulmonary Disease, Chronic Obstructive	C08.381.495.389; C23.550.291.500.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465288 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1043620	Toxicity	3	carbamazepine
rs2227956	Toxicity	3	carbamazepine	Epilepsy

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs506770	HSPA1A, HSPA1L		0.00	0
rs1043620	HSPA1A, HSPA1L	3	2.00	1	carbamazepine
rs2227956	HSPA1A, HSPA1L, LSM2	3	2.25	1	carbamazepine

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Heat shock proteins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	5
Cadmium	increases abundance, increases expression	3
Copper	affects binding, decreases expression, increases expression	3
pyrithione zinc	increases expression	2
sodium arsenite	increases expression	2
Troglitazone	affects cotreatment, increases expression, decreases reaction, decreases expression	2
Arsenic	affects methylation, increases expression	2
Formaldehyde	increases expression	2
Dronabinol	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
GSK-J4	decreases expression	1
Glupearl 19S	increases expression	1
beta-N-methylamino-L-alanine	increases expression	1
bismuth tripotassium dicitrate	increases expression	1
tungsten carbide	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases methylation	1
deoxynivalenol	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
diisononyl phthalate	increases methylation	1
quercitrin	affects expression	1
trichostatin A	decreases reaction, affects expression	1
2-butenal	increases expression	1
ferric ammonium citrate	increases expression, increases abundance	1
diethyl maleate	increases expression	1
arsenite	increases expression	1
bromoacetate	decreases expression	1
sulforaphane	affects binding	1
aurin	increases 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
CHEMBL5321346	Binding	Binding affinity to HspA1L (unknown origin) assessed as dissociation constant by FP assay	Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78. — J Med Chem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1NA	Abcam K-562 HSPA1L KO	Cancer cell line	Female
CVCL_D2JV	Abcam Raji HSPA1L KO	Cancer cell line	Male
CVCL_D7RJ	Ubigene A-549 HSPA1L KO	Cancer cell line	Male
CVCL_SR75	HAP1 HSPA1L (-) 1	Cancer cell line	Male
CVCL_SR76	HAP1 HSPA1L (-) 2	Cancer cell line	Male
CVCL_UQ76	Abcam Jurkat HSPA1L KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	PHASE4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	PHASE4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	PHASE4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study