HSPA12A

Summary

HSPA12A (heat shock protein family A (Hsp70) member 12A, HGNC:19022) is a protein-coding gene on chromosome 10q25.3, encoding Heat shock 70 kDa protein 12A (O43301). Adapter protein for SORL1, but not SORT1.

Predicted to enable ATP binding activity. Predicted to act upstream of or within several processes, including import into nucleus; liver development; and macrophage activation. Located in extracellular exosome.

Source: NCBI Gene 259217 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 105 total
• MANE Select transcript: NM_025015

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19022
Approved symbol	HSPA12A
Name	heat shock protein family A (Hsp70) member 12A
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13874, KIAA0417
Ensembl gene	ENSG00000165868
Ensembl biotype	protein_coding
OMIM	610701
Entrez	259217

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 11 protein_coding, 8 retained_intron, 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay

ENST00000369209, ENST00000434227, ENST00000453491, ENST00000468935, ENST00000480802, ENST00000481291, ENST00000635765, ENST00000674167, ENST00000674197, ENST00000674205, ENST00000674223, ENST00000674245, ENST00000674267, ENST00000674291, ENST00000674326, ENST00000674344, ENST00000674347, ENST00000674372, ENST00000674375, ENST00000674389, ENST00000674394, ENST00000674400, ENST00000674401, ENST00000674431, ENST00000674455, ENST00000674459, ENST00000674468, ENST00000674473, ENST00000674491, ENST00000674505

RefSeq mRNA: 2 — MANE Select: NM_025015 NM_001330164, NM_025015

CCDS: CCDS41569, CCDS81511

Canonical transcript exons

ENST00000369209 — 12 exons

Exon	Start	End
ENSE00001097408	116681791	116681877
ENSE00001097410	116679503	116679761
ENSE00001097411	116676399	116676502
ENSE00001097414	116671192	116675418
ENSE00001097416	116692351	116692467
ENSE00001097420	116681152	116681256
ENSE00001097421	116700943	116701129
ENSE00001097422	116683791	116683962
ENSE00001097424	116698635	116698739
ENSE00001449150	116742430	116742566
ENSE00002860024	116705151	116705278
ENSE00002901126	116707200	116707285

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.7143 / max 215.5465, expressed in 1310 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111561	4.9786	1068
111566	3.3212	716
111562	2.4145	833

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.72	gold quality
dorsal root ganglion	UBERON:0000044	98.59	gold quality
trigeminal ganglion	UBERON:0001675	98.31	gold quality
tibial nerve	UBERON:0001323	97.53	gold quality
sural nerve	UBERON:0015488	97.27	gold quality
pons	UBERON:0000988	96.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.57	gold quality
middle temporal gyrus	UBERON:0002771	96.41	gold quality
postcentral gyrus	UBERON:0002581	96.30	gold quality
parietal lobe	UBERON:0001872	96.12	gold quality
substantia nigra pars compacta	UBERON:0001965	96.11	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.04	gold quality
superior frontal gyrus	UBERON:0002661	95.52	gold quality
prefrontal cortex	UBERON:0000451	95.50	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.44	gold quality
orbitofrontal cortex	UBERON:0004167	95.38	gold quality
frontal pole	UBERON:0002795	95.15	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.13	gold quality
frontal cortex	UBERON:0001870	94.84	gold quality
primary visual cortex	UBERON:0002436	94.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.69	gold quality
superior vestibular nucleus	UBERON:0007227	94.68	gold quality
occipital lobe	UBERON:0002021	94.60	gold quality
endothelial cell	CL:0000115	94.27	gold quality
right frontal lobe	UBERON:0002810	94.27	gold quality
entorhinal cortex	UBERON:0002728	94.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.11	gold quality
neocortex	UBERON:0001950	93.90	gold quality
cerebral cortex	UBERON:0000956	93.61	gold quality
lateral globus pallidus	UBERON:0002476	93.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-111727	no	508.61
E-MTAB-7303	no	503.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

197 targeting HSPA12A, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-338-5P	99.92	72.34	2951

Literature-anchored findings (GeneRIF, showing 9)

• We found that HSPA12A is expressed in the human brain and shows a neuron- and region-specific transcript distribution, with strongest expression in the frontal and occipital cortical regions. HSPA12A Mrna was significantly reduced in schizophrenia. (PMID:15601604)
• High BCLC staging scores, advanced cirrhosis and the overexpression of HSPA12A and HSP90B1 might be associated with poor survival from HCC, whereas high levels of HSPA4, HSPA5 and HSPA6 might be associated with earlier recurrence of HCC (PMID:25798051)
• The genotype “A/G” of rs1665650 in HSPA12A gene was associated with a decreased risk of gastric cancer. (PMID:26302849)
• Heat-Shock protein A12A is a novel PCNA-binding protein and promotes hepatocellular carcinoma growth. (PMID:32128976)
• HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma. (PMID:32754264)
• Heat shock protein A12A activates migration of hepatocellular carcinoma cells in a monocarboxylate transporter 4-dependent manner. (PMID:35050463)
• Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer. (PMID:36394206)
• HSPA12A was identified as a key driver in colorectal cancer GWAS loci 10q26.12 and modulated by an enhancer-promoter interaction. (PMID:37245169)
• Heat-shock protein A12A attenuates oxygen-glucose deprivation/reoxygenation-induced human brain microvascular endothelial cell dysfunction via PGC-1alpha/SIRT3 pathway. (PMID:37942840)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hspa12a	ENSDARG00000070603
mus_musculus	Hspa12a	ENSMUSG00000025092
rattus_norvegicus	Hspa12a	ENSRNOG00000018019

Paralogs (4): ALPK1 (ENSG00000073331), EEF2K (ENSG00000103319), HSPA12B (ENSG00000132622), ALPK2 (ENSG00000198796)

Protein

Protein identifiers

Heat shock 70 kDa protein 12A — O43301 (reviewed: O43301)

Alternative names: Heat shock protein family A member 12A

All UniProt accessions (14): A0A1B0GTF3, A0A6I8PII9, A0A6I8PIT5, A0A6I8PIU5, A0A6I8PIW1, A0A6I8PIX2, O43301, A0A6I8PL32, A0A6I8PL68, A0A6I8PLA6, A0A6I8PLB1, A0A6I8PRZ9, A0A6I8PU93, K7ELE6

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein for SORL1, but not SORT1. Delays SORL1 internalization and affects SORL1 subcellular localization.

Subunit / interactions. Interacts with SORL1 (via cytosolic C-terminus); this interaction affects SORL1 internalization and subcellular localization.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed with highest levels in brain, kidney and muscle.

Similarity. Belongs to the heat shock protein 70 family.

RefSeq proteins (2): NP_001317093, NP_079291* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026685	HSPA12A_NBD	Domain
IPR043129	ATPase_NBD	Homologous_superfamily

UniProt features (7 total): compositionally biased region 3, initiator methionine 1, chain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43301-F1	84.94	0.62

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 (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 130 (showing top): GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, BROWNE_HCMV_INFECTION_8HR_UP, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_NUCLEAR_TRANSPORT, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, DELYS_THYROID_CANCER_DN, GOBP_MACROPHAGE_ACTIVATION, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, LIU_CMYB_TARGETS_UP, CUI_TCF21_TARGETS_2_DN, KIM_WT1_TARGETS_12HR_UP, LIU_VMYB_TARGETS_UP, chr10q25, GOMF_ADENYL_NUCLEOTIDE_BINDING

GO Biological Process (4): liver development (GO:0001889), inflammatory response (GO:0006954), macrophage activation (GO:0042116), import into nucleus (GO:0051170)

GO Molecular Function (3): ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), extracellular exosome (GO:0070062)

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
gland development	1
hepaticobiliary system development	1
defense response	1
myeloid leukocyte activation	1
nucleocytoplasmic transport	1
intercellular transport	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

3787 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPA12A	HSPA1A	P08107	797
HSPA12A	HSPA4	P34932	762
HSPA12A	HSPA13	P48723	744
HSPA12A	HSPA5	P11021	697
HSPA12A	HYOU1	Q9Y4L1	690
HSPA12A	HSPA8	P11142	661
HSPA12A	HSPA14	Q0VDF9	657
HSPA12A	HSPA4L	O95757	632
HSPA12A	B0YIZ1	B0YIZ1	620
HSPA12A	HSPA9	P30036	608
HSPA12A	GRPEL2	Q8TAA5	572
HSPA12A	HSPA6	P17066	557
HSPA12A	HSPA1L	P34931	555
HSPA12A	SORL1	Q92673	484
HSPA12A	SHTN1	A0MZ66	463

IntAct

102 interactions, top by confidence:

A	B	Type	Score
HSPA12A	HSPA12B	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
USP32	NME4	psi-mi:“MI:0914”(association)	0.560
SORL1	HSPA12A	psi-mi:“MI:0915”(physical association)	0.540
SORL1	HSPA12A	psi-mi:“MI:0403”(colocalization)	0.540
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
TMEM51	WWP2	psi-mi:“MI:0914”(association)	0.530
MGST3	GAPDHS	psi-mi:“MI:0914”(association)	0.530
AKAP12	HSPA12A	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
PODXL	HSPA12A	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
HSPA12B	EEF2K	psi-mi:“MI:0914”(association)	0.530
MACROD2	HSPA12A	psi-mi:“MI:0915”(physical association)	0.400
HSPA12A	M6PR	psi-mi:“MI:0915”(physical association)	0.370
HSPA12A	NRCAM	psi-mi:“MI:0915”(physical association)	0.370
MEGF10	HSPA12A	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (135): HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Proximity Label-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), HSPA12A (Proximity Label-MS), HSPA12A (Proximity Label-MS), HSPA12A (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PPP7, A8DYE2, O01382, O02002, O35552, O43301, O89094, O89110, P16259, P20807, P26285, P31944, P42573, P43368, P45436, P49048, P51186, P55211, P55865, P55866, P55867, P87141, P89116, Q16875, Q29IM7, Q504J1, Q5NVT1, Q5R9C1, Q60710, Q64691, Q6INN8, Q7KUT2, Q8C3Q9, Q8IRY7, Q8K0U4, Q8T4E1, Q920D5, Q94CE4, Q95M12, Q9FJD6

Diamond homologs: O43301, Q8K0U4, Q96MM6, Q9CZJ2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	93
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2163 predictions. Top by Δscore:

Variant	Effect	Δscore
10:116675415:TCCC:T	acceptor_gain	1.0000
10:116675416:CCCC:C	acceptor_gain	1.0000
10:116676397:A:AC	donor_gain	1.0000
10:116676398:C:CC	donor_gain	1.0000
10:116676398:CGGAG:C	donor_gain	1.0000
10:116676498:CCACA:C	acceptor_gain	1.0000
10:116676499:CACAC:C	acceptor_gain	1.0000
10:116676503:C:CC	acceptor_gain	1.0000
10:116676512:C:CT	acceptor_gain	1.0000
10:116676513:A:C	acceptor_gain	1.0000
10:116676517:C:CT	acceptor_gain	1.0000
10:116679501:A:AC	donor_gain	1.0000
10:116679502:C:CA	donor_gain	1.0000
10:116679502:CTTG:C	donor_gain	1.0000
10:116681793:T:A	donor_gain	1.0000
10:116681873:CTTAG:C	acceptor_gain	1.0000
10:116681875:TAG:T	acceptor_gain	1.0000
10:116681886:C:CT	acceptor_gain	1.0000
10:116681886:C:T	acceptor_gain	1.0000
10:116681887:G:T	acceptor_gain	1.0000
10:116681889:C:CT	acceptor_gain	1.0000
10:116683789:AC:A	donor_gain	1.0000
10:116683790:CC:C	donor_gain	1.0000
10:116683804:AGCT:A	donor_gain	1.0000
10:116683805:G:C	donor_gain	1.0000
10:116683811:A:AC	donor_gain	1.0000
10:116683812:C:CC	donor_gain	1.0000
10:116683857:G:C	donor_gain	1.0000
10:116692475:C:CT	acceptor_gain	1.0000
10:116692476:A:T	acceptor_gain	1.0000

AlphaMissense

4427 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:116674839:G:T	A657D	1.000
10:116674840:C:G	A657P	1.000
10:116674863:C:T	G649E	1.000
10:116674865:G:C	F648L	1.000
10:116674865:G:T	F648L	1.000
10:116674867:A:G	F648L	1.000
10:116675002:A:C	Y603D	1.000
10:116675037:G:T	A591D	1.000
10:116675047:A:C	Y588D	1.000
10:116675052:C:G	R586P	1.000
10:116675117:G:C	C564W	1.000
10:116675118:C:T	C564Y	1.000
10:116675119:A:G	C564R	1.000
10:116675184:A:G	L542P	1.000
10:116675196:C:T	G538E	1.000
10:116675197:C:A	G538W	1.000
10:116675197:C:G	G538R	1.000
10:116675197:C:T	G538R	1.000
10:116675218:G:T	R531S	1.000
10:116675244:C:T	G522D	1.000
10:116675253:A:T	V519D	1.000
10:116675257:C:G	A518P	1.000
10:116675259:C:A	G517V	1.000
10:116675259:C:T	G517D	1.000
10:116675260:C:A	G517C	1.000
10:116675260:C:G	G517R	1.000
10:116675265:A:G	L515P	1.000
10:116675364:C:A	G482V	1.000
10:116675364:C:T	G482D	1.000
10:116675365:C:G	G482R	1.000

dbSNP variants (sampled 300 via entrez): RS1000019915 (10:116812194 T>A), RS1000024372 (10:116735384 C>T), RS1000035860 (10:116814608 C>T), RS1000083428 (10:116742177 C>A,G), RS1000121582 (10:116821028 C>A,G), RS1000123562 (10:116702956 C>T), RS1000194101 (10:116680107 C>T), RS1000194454 (10:116827043 T>G), RS1000195345 (10:116767435 C>T), RS1000197710 (10:116785798 A>G), RS1000199411 (10:116701714 C>G), RS1000217077 (10:116837648 G>A,C), RS1000233661 (10:116815941 G>A,C), RS1000259688 (10:116691565 C>G), RS1000309951 (10:116767233 G>A)

Disease associations

OMIM: gene MIM:610701 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001113_11	Age at smoking initiation in chronic obstructive pulmonary disease	6.000000e-06
GCST001792_3	Colorectal cancer	9.000000e-07
GCST005951_66	Body mass index	4.000000e-08
GCST006091_4	Freckles	7.000000e-11
GCST006444_23	Bone mineral density (hip)	9.000000e-06
GCST006624_3	Systolic blood pressure	2.000000e-11
GCST007267_123	Systolic blood pressure	2.000000e-10
GCST008161_83	Waist circumference adjusted for body mass index	2.000000e-06
GCST009723_11	Vertical cup-disc ratio (adjusted for vertical disc diameter)	2.000000e-09
GCST009724_24	Vertical cup-disc ratio (multi-trait analysis)	3.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005670	smoking initiation
EFO:0004340	body mass index
EFO:0003963	freckles
EFO:0007702	hip bone mineral density
EFO:0006335	systolic blood pressure
EFO:0007789	BMI-adjusted waist circumference
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Benzo(a)pyrene	affects methylation, increases expression	5
Tetrachlorodibenzodioxin	increases expression	3
entinostat	increases expression, affects cotreatment	2
Arsenic	affects expression, affects methylation, affects cotreatment	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
beta-Naphthoflavone	increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects methylation	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
diallyl trisulfide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
MRK 003	decreases expression	1
bisphenol S	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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