DNAJC3

Summary

DNAJC3 (DnaJ heat shock protein family (Hsp40) member C3, HGNC:9439) is a protein-coding gene on chromosome 13q32.1, encoding DnaJ homolog subfamily C member 3 (Q13217). Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress.

This gene encodes a protein with multiple tetratricopeptide repeat (TPR) motifs as well as the highly conserved J domain found in DNAJ chaperone family members. It is a member of the tetratricopeptide repeat family of proteins and acts as an inhibitor of the interferon-induced, dsRNA-activated protein kinase (PKR).

Source: NCBI Gene 5611 — RefSeq curated summary.

At a glance

• Gene–disease (curated): juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 90 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 27
• MANE Select transcript: NM_006260

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9439
Approved symbol	DNAJC3
Name	DnaJ heat shock protein family (Hsp40) member C3
Location	13q32.1
Locus type	gene with protein product
Status	Approved
Aliases	P58, P58IPK, HP58, ERdj6, p58(IPK)
Ensembl gene	ENSG00000102580
Ensembl biotype	protein_coding
OMIM	601184
Entrez	5611

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000376795, ENST00000602402, ENST00000880232, ENST00000880233, ENST00000935418, ENST00000947240, ENST00000947241, ENST00000947242, ENST00000947243

RefSeq mRNA: 1 — MANE Select: NM_006260 NM_006260

CCDS: CCDS9479

Canonical transcript exons

ENST00000602402 — 12 exons

Exon	Start	End
ENSE00000853784	95763833	95763953
ENSE00000853785	95763643	95763748
ENSE00000853786	95760679	95760798
ENSE00000853787	95760040	95760221
ENSE00000853788	95757644	95757796
ENSE00000853791	95725178	95725252
ENSE00000853792	95723242	95723366
ENSE00000853793	95709227	95709337
ENSE00000940123	95785939	95786071
ENSE00000940124	95787007	95787155
ENSE00003293049	95677139	95677337
ENSE00003407254	95790873	95794988

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.2713 / max 613.2858, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135691	39.8596	1821
135690	6.1355	1648
135692	2.2761	1219

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.30	gold quality
caput epididymis	UBERON:0004358	99.00	gold quality
oocyte	CL:0000023	98.58	gold quality
epithelium of nasopharynx	UBERON:0001951	98.36	gold quality
pericardium	UBERON:0002407	98.23	gold quality
cauda epididymis	UBERON:0004360	98.19	gold quality
secondary oocyte	CL:0000655	98.09	gold quality
decidua	UBERON:0002450	98.06	gold quality
pylorus	UBERON:0001166	97.91	gold quality
palpebral conjunctiva	UBERON:0001812	97.73	gold quality
seminal vesicle	UBERON:0000998	97.66	gold quality
parotid gland	UBERON:0001831	97.27	gold quality
cardia of stomach	UBERON:0001162	96.99	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.99	gold quality
saphenous vein	UBERON:0007318	96.91	gold quality
visceral pleura	UBERON:0002401	96.70	gold quality
urethra	UBERON:0000057	96.56	gold quality
renal medulla	UBERON:0000362	96.49	gold quality
germinal epithelium of ovary	UBERON:0001304	96.43	gold quality
parietal pleura	UBERON:0002400	96.21	gold quality
mammary duct	UBERON:0001765	96.10	gold quality
tibia	UBERON:0000979	96.04	gold quality
synovial joint	UBERON:0002217	95.99	gold quality
superior surface of tongue	UBERON:0007371	95.95	gold quality
bronchial epithelial cell	CL:0002328	95.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.69	gold quality
trigeminal ganglion	UBERON:0001675	95.67	gold quality
calcaneal tendon	UBERON:0003701	95.55	gold quality
pigmented layer of retina	UBERON:0001782	95.42	gold quality
trabecular bone tissue	UBERON:0002483	95.39	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-ENAD-21	yes	3438.47
E-CURD-10	yes	1610.20
E-CURD-88	yes	91.44
E-CURD-122	yes	39.31
E-HCAD-1	yes	33.10
E-MTAB-8410	yes	23.90
E-MTAB-10553	yes	9.31
E-GEOD-81608	no	1910.20
E-HCAD-13	no	3.04
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, ERP29, WFS1

miRNA regulators (miRDB)

171 targeting DNAJC3, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-607	99.97	73.62	5593

Literature-anchored findings (GeneRIF, showing 15)

• Spleen cells from transgenic mice overexpressing (Hu)PKR were studied and compared to those from wild-type mice after drug treatment. Dact-treated spleen cells were resistant to apoptosis; ConA-treated cells had decreased cell division. (PMID:12034040)
• P58(IPK) is an important component of a negative feedback loop used by the cell to inhibit eIF2alpha signaling, and thus attenuate the unfolded protein response. (PMID:12601012)
• The study demonstrates that P58(IPK) inhibits endoplasmic reticulum (ER) stress and plays an important role in maintaining balance and stability of the ER in human retinal capillary endothelial cells. (PMID:18568130)
• Coxsackievirus B3 infection induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1. (PMID:20554776)
• the crystal structure of human P58(IPK) (PMID:21799829)
• interplay between p38 phosphorylation and p58(IPK) upregulation has key roles in modulating ERp29-induced cell-growth arrest and survival (PMID:22064321)
• p58(IPK) suppresses coxsackievirus B3-induced apoptosis through selective activation of PI3K/Akt pathway that requires activation of ATF6a and subsequently upregulates mitofusin 2. (PMID:24134518)
• p58IPK is a general inhibitor of the eIF2alpha kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2alpha phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis (PMID:25329545)
• Loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans. (PMID:25466870)
• DNAJC3 p.H238N is likely to be a variant causing diabetes. (PMID:29767246)
• DNAJC3-AS1 is up-regulated in osteosarcoma (OS) tissues and its high expression is associated with poor prognosis of OS patients. (PMID:30652414)
• Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group. (PMID:32738013)
• DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes. (PMID:33486469)
• Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation. (PMID:34654017)
• Reduced DNAJC3 Expression Affects Protein Translocation across the ER Membrane and Attenuates the Down-Modulating Effect of the Translocation Inhibitor Cyclotriazadisulfonamide. (PMID:35054769)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnajc3a	ENSDARG00000041110
mus_musculus	Dnajc3	ENSMUSG00000022136
rattus_norvegicus	Dnajc3	ENSRNOG00000010352
drosophila_melanogaster	CG10565	FBGN0037051
drosophila_melanogaster	P58IPK	FBGN0037718
drosophila_melanogaster	l(3)80Fg	FBGN0287183
caenorhabditis_elegans		WBGENE00001020
caenorhabditis_elegans		WBGENE00001025
caenorhabditis_elegans		WBGENE00001026
caenorhabditis_elegans		WBGENE00001029
caenorhabditis_elegans	dnj-28	WBGENE00001046
caenorhabditis_elegans		WBGENE00008122

Paralogs (20): DNAJC11 (ENSG00000007923), DNAJC25 (ENSG00000059769), DNAJC10 (ENSG00000077232), DNAJC5 (ENSG00000101152), DNAJC17 (ENSG00000104129), DNAJC2 (ENSG00000105821), DNAJC12 (ENSG00000108176), DNAJC4 (ENSG00000110011), DNAJC16 (ENSG00000116138), DNAJC14 (ENSG00000135392), DNAJC1 (ENSG00000136770), DNAJC13 (ENSG00000138246), DNAJC5B (ENSG00000147570), DNAJC5G (ENSG00000163793), DNAJC7 (ENSG00000168259), DNAJC21 (ENSG00000168724), DNAJC18 (ENSG00000170464), DNAJC24 (ENSG00000170946), DNAJC30 (ENSG00000176410), DNAJC9 (ENSG00000213551)

Protein

Protein identifiers

DnaJ homolog subfamily C member 3 — Q13217 (reviewed: Q13217)

Alternative names: Endoplasmic reticulum DNA J domain-containing protein 6, Interferon-induced, double-stranded RNA-activated protein kinase inhibitor, Protein kinase inhibitor of 58 kDa

All UniProt accessions (3): Q13217, A8KA82, X6R9L0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Acts as a negative regulator of the EIF2AK4/GCN2 kinase activity by preventing the phosphorylation of eIF-2-alpha at ‘Ser-52’ and hence attenuating general protein synthesis under ER stress, hypothermic and amino acid starving stress conditions. Co-chaperone of HSPA8/HSC70, it stimulates its ATPase activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity.

Subunit / interactions. Interacts with EIF2AK4/GCN2; this interaction occurs under endoplasmic reticulum (ER) stress, hypothermic and amino acid starving stress conditions and inhibits EIF2AK4/GCN2 kinase activity. Interacts with EIF2AK3. Interacts with EIF2AK2. Forms a trimeric complex with DNAJB1 and HSPA8. Interacts with THAP12.

Subcellular location. Endoplasmic reticulum.

Tissue specificity. Widely expressed with high level in the pancreas and testis. Also expressed in cell lines with different levels.

Disease relevance. Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus (ACPHD) [MIM:616192] A disease characterized by juvenile-onset diabetes and neurodegeneration, resulting in ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The J domain mediates interaction with HSPA8. Binding to misfolded proteins is mediated by a hydrophobic patch forming a large groove within the first two TPR repeats.

Induction. Up-regulated during an endoplasmic reticulum stress via ATF6. Activated in response to infection by influenza virus through the dissociation of DNAJB1. Down-regulated by DNAJB1 and THAP12.

RefSeq proteins (1): NP_006251* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR036869	J_dom_sf	Homologous_superfamily
IPR051727	DnaJ_C3_Co-chaperones	Family

Pfam: PF00226, PF00515, PF13181, PF13432, PF14559

UniProt features (45 total): helix 25, repeat 9, region of interest 2, disulfide bond 2, turn 2, signal peptide 1, chain 1, domain 1, modified residue 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2Y4T	X-RAY DIFFRACTION	3
2Y4U	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13217-F1	86.78	0.75

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): 274

Disulfide bonds (2): 248–258, 313–329

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-192823	Viral mRNA Translation
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-6798695	Neutrophil degranulation
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9833482	PKR-mediated signaling
R-HSA-9918432	Maturation of DENV proteins

MSigDB gene sets: 362 (showing top): REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, GOBP_RESPONSE_TO_COLD, GOBP_REGULATION_OF_PHOSPHORYLATION, BIOCARTA_RNA_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, FISCHER_G1_S_CELL_CYCLE, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MODULE_522, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_TRANSLATIONAL_INITIATION

GO Biological Process (11): response to unfolded protein (GO:0006986), protein folding in endoplasmic reticulum (GO:0034975), positive regulation of translation initiation in response to endoplasmic reticulum stress (GO:0036494), negative regulation of apoptotic process (GO:0043066), obsolete proteolysis involved in protein catabolic process (GO:0051603), defense response to virus (GO:0051607), cellular response to cold (GO:0070417), negative regulation of translation in response to endoplasmic reticulum stress (GO:1902010), negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation (GO:1903912), regulation of translation (GO:0006417), response to endoplasmic reticulum stress (GO:0034976)

GO Molecular Function (5): protein kinase inhibitor activity (GO:0004860), protein kinase binding (GO:0019901), protein-folding chaperone binding (GO:0051087), misfolded protein binding (GO:0051787), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), cytosol (GO:0005829), membrane (GO:0016020), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), extracellular vesicle (GO:1903561)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Influenza Viral RNA Transcription and Replication	1
IRE1alpha activates chaperones	1
Metabolism of proteins	1
Innate Immune System	1
Post-translational protein modification	1
Antimicrobial mechanism of IFN-stimulated genes	1
Dengue Virus Genome Translation and Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
response to endoplasmic reticulum stress	2
cellular response to stress	2
translation	2
protein binding	2
cytoplasm	2
response to topologically incorrect protein	1
protein folding	1
translational initiation	1
positive regulation of translational initiation in response to stress	1
regulation of translation initiation in response to endoplasmic reticulum stress	1
positive regulation of translation in response to endoplasmic reticulum stress	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
defense response	1
response to virus	1
response to cold	1
negative regulation of translation in response to stress	1
regulation of translation in response to endoplasmic reticulum stress	1
negative regulation of protein phosphorylation	1
regulation of translational initiation	1
eiF2alpha phosphorylation in response to endoplasmic reticulum stress	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
protein kinase activity	1
kinase inhibitor activity	1
protein kinase regulator activity	1
kinase binding	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

2597 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJC3	EIF2AK2	P19525	919
DNAJC3	HSPA5	P11021	880
DNAJC3	THAP12	O43422	874
DNAJC3	HYOU1	Q9Y4L1	813
DNAJC3	XBP1	P17861	793
DNAJC3	EDEM1	Q92611	766
DNAJC3	EIF2S1	P05198	757
DNAJC3	SIL1	Q9H173	751
DNAJC3	DNAJB1	P25685	748
DNAJC3	ATF6	P18850	742
DNAJC3	SEC61A1	P38378	708
DNAJC3	ERN1	O75460	693
DNAJC3	HSP90B1	P14625	664
DNAJC3	HSPA4	P34932	652
DNAJC3	HERPUD1	Q15011	628

IntAct

91 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
DNAJC3	DEDD	psi-mi:“MI:0914”(association)	0.530
WNT7A	LDLR	psi-mi:“MI:0914”(association)	0.530
B4GALT4	HSPA5	psi-mi:“MI:0914”(association)	0.530
GLB1L2	HSPA5	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
ECEL1	CLGN	psi-mi:“MI:0914”(association)	0.530
EGFL8	MPO	psi-mi:“MI:0914”(association)	0.530
GAA	CLGN	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
TMEM106A	B4GALT3	psi-mi:“MI:0914”(association)	0.530
ALK	PIK3R2	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:2364”(proximity)	0.420
CASQ2	DNAJC3	psi-mi:“MI:0915”(physical association)	0.400
SCN4A	DNAJC3	psi-mi:“MI:0915”(physical association)	0.400
RABL6	DNAJC3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
M2	IPO5	psi-mi:“MI:0914”(association)	0.350
PTPRO	PLXNB2	psi-mi:“MI:0914”(association)	0.350
LAMP1	HAX1	psi-mi:“MI:0914”(association)	0.350
MATN3	P4HB	psi-mi:“MI:0914”(association)	0.350
HTRA4	PSMD12	psi-mi:“MI:0914”(association)	0.350
HTRA4	ATOX1	psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
ERN2	SEC16A	psi-mi:“MI:0914”(association)	0.350
NUTM2F	IRF6	psi-mi:“MI:0914”(association)	0.350
DDR2	PLD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (273): DNAJC3 (Affinity Capture-MS), DNAJC3 (Co-fractionation), DNAJC3 (Co-fractionation), DNAJC3 (Co-fractionation), DNAJC3 (Co-fractionation), DNAJC3 (Co-fractionation), DNAJC3 (Co-fractionation), HSPA14 (Co-fractionation), HSPA8 (Co-fractionation), HYOU1 (Co-fractionation), DNAJC3 (Proximity Label-MS), DNAJC3 (Proximity Label-MS), HSPA5 (Reconstituted Complex), DNAJC3 (Affinity Capture-RNA), DNAJC3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0D1E2P6, A0A0D2XVZ5, A0A0P0VG31, A0A0P1AAU8, A0A287B8J2, A2WYG9, A4QP73, B9EHT4, B9F2Y7, D0NCC1, J9VKM5, O08788, O59739, P0C7L7, P0CP26, P0CP27, P14725, P28023, P39742, P82874, P92792, Q10MW6, Q13217, Q14203, Q149L6, Q27968, Q28I38, Q54M21, Q54NS3, Q58DR2, Q5JJI4, Q5JNB5, Q5R686, Q5R6H3, Q5ZI13, Q6PCJ1, Q6YUL8, Q7ZXQ8, Q8TBM8, Q91YW3

Diamond homologs: A0A0D2XVZ5, A0KMI5, A0Q1R3, A3DF24, A4XKA5, A5IIT4, A5ITA7, A5W9N6, A6LJ63, A6QHC2, A6U251, A6UEY1, A7X2Y0, A8Z4B8, B0KK26, B1J5W7, B1LCI2, B2J3J3, B3PXH2, B3WEQ6, B5ZWQ1, B7IFE0, B7KEJ8, B8CXL0, B8FUN3, B8HLD2, B9DNJ9, B9JGW2, B9JZ89, B9KAB9, B9MJZ0, C3MC05, C4L8Y4, C5B7L8, J9VKM5, O06431, O33529, O34136, P25303, P30725

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
DNAJC3	“down-regulates activity”	EIF2AK3	binding
DNAJC3	“down-regulates activity”	EIF2AK4	binding
DNAJC3	“down-regulates activity”	EIF2AK2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
WNT ligand biogenesis and trafficking	6	28.2×	3e-05
Class B/2 (Secretin family receptors)	6	12.7×	2e-03
Innate Immune System	13	3.7×	6e-03
Neutrophil degranulation	14	3.6×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell fate commitment	6	14.8×	3e-03
canonical Wnt signaling pathway	7	8.9×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	53
Likely benign	14
Benign	2

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1693484	NM_006260.5(DNAJC3):c.393+2T>G	Pathogenic
1693485	NM_006260.5(DNAJC3):c.393+2T>C	Pathogenic
1693487	NM_006260.5(DNAJC3):c.1A>G (p.Met1Val)	Pathogenic
1693488	NM_006260.5(DNAJC3):c.1036C>T (p.Arg346Ter)	Pathogenic
3768963	NM_006260.5(DNAJC3):c.435dup (p.Ser146fs)	Pathogenic
1693486	NM_006260.5(DNAJC3):c.1367_1370del (p.Lys456fs)	Likely pathogenic
1803129	NM_006260.5(DNAJC3):c.1305del (p.Glu436fs)	Likely pathogenic
985483	NM_006260.5(DNAJC3):c.1296_1300del (p.Lys433fs)	Likely pathogenic

SpliceAI

1992 predictions. Top by Δscore:

Variant	Effect	Δscore
13:95677334:GAAG:G	donor_gain	1.0000
13:95677337:GGT:G	donor_loss	1.0000
13:95677338:G:GG	donor_gain	1.0000
13:95677338:GT:G	donor_loss	1.0000
13:95677339:T:A	donor_loss	1.0000
13:95709219:A:AG	acceptor_gain	1.0000
13:95709220:T:G	acceptor_gain	1.0000
13:95709221:TTTTA:T	acceptor_loss	1.0000
13:95709222:TTTA:T	acceptor_loss	1.0000
13:95709223:TTA:T	acceptor_loss	1.0000
13:95709224:TAG:T	acceptor_loss	1.0000
13:95709225:A:AG	acceptor_gain	1.0000
13:95709226:G:GT	acceptor_gain	1.0000
13:95709226:GGT:G	acceptor_gain	1.0000
13:95709333:CGTAG:C	donor_loss	1.0000
13:95709336:AGG:A	donor_loss	1.0000
13:95709337:GGTT:G	donor_loss	1.0000
13:95709338:G:T	donor_loss	1.0000
13:95709339:T:A	donor_loss	1.0000
13:95723236:TTTCA:T	acceptor_loss	1.0000
13:95723237:TTCA:T	acceptor_loss	1.0000
13:95723238:TCAG:T	acceptor_loss	1.0000
13:95723239:CA:C	acceptor_loss	1.0000
13:95723240:A:AG	acceptor_gain	1.0000
13:95723240:AG:A	acceptor_loss	1.0000
13:95723240:AGAT:A	acceptor_gain	1.0000
13:95723241:G:C	acceptor_loss	1.0000
13:95723241:G:GG	acceptor_gain	1.0000
13:95723241:GATG:G	acceptor_gain	1.0000
13:95723362:CTGCA:C	donor_gain	1.0000

AlphaMissense

3336 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:95763915:G:C	R346P	1.000
13:95787042:G:C	R415P	1.000
13:95787062:C:G	H422D	1.000
13:95787113:T:C	F439L	1.000
13:95787115:C:A	F439L	1.000
13:95787115:C:G	F439L	1.000
13:95787132:C:A	A445D	1.000
13:95787144:T:A	L449H	1.000
13:95709275:G:A	G44D	0.999
13:95709287:T:C	L48P	0.999
13:95709310:G:C	A56P	0.999
13:95709311:C:A	A56D	0.999
13:95723280:G:C	A78P	0.999
13:95723358:T:C	F104L	0.999
13:95723360:C:A	F104L	0.999
13:95723360:C:G	F104L	0.999
13:95725194:G:A	G112D	0.999
13:95725229:G:C	A124P	0.999
13:95760076:G:C	A195P	0.999
13:95760178:A:C	S229R	0.999
13:95760180:C:A	S229R	0.999
13:95760180:C:G	S229R	0.999
13:95760692:T:C	C248R	0.999
13:95760696:T:C	L249P	0.999
13:95760722:T:C	C258R	0.999
13:95763917:G:C	A347P	0.999
13:95763953:G:C	A359P	0.999
13:95787038:T:G	Y414D	0.999
13:95787062:C:A	H422N	0.999
13:95787063:A:G	H422R	0.999

dbSNP variants (sampled 300 via entrez): RS1000000219 (13:95689463 G>A), RS1000009223 (13:95741424 A>G), RS1000012550 (13:95786213 A>G), RS1000071109 (13:95732624 G>A), RS1000073497 (13:95708644 C>T), RS1000134465 (13:95698498 A>G), RS1000150940 (13:95741539 T>A), RS1000154789 (13:95789335 T>G), RS1000307742 (13:95795189 A>T), RS1000311625 (13:95714459 A>G), RS1000354644 (13:95701857 T>C), RS1000374474 (13:95730579 C>G), RS1000386733 (13:95711921 A>C,G), RS1000408009 (13:95708535 C>A), RS1000423878 (13:95754939 A>G)

Disease associations

OMIM: gene MIM:601184 | disease phenotypes: MIM:616192

GenCC curated gene-disease

Disease	Classification	Inheritance
juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome	Strong	Autosomal recessive
type 2 diabetes mellitus	Limited	Autosomal dominant

Mondo (3): prostate cancer (MONDO:0008315), juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (MONDO:0014523), type 2 diabetes mellitus (MONDO:0005148)

Orphanet (2): Familial prostate cancer (Orphanet:1331), Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (Orphanet:445062)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000819	Diabetes mellitus
HP:0001256	Mild intellectual disability
HP:0001272	Cerebellar atrophy
HP:0002059	Cerebral atrophy
HP:0002066	Gait ataxia
HP:0002522	Areflexia of lower limbs
HP:0003431	Decreased motor nerve conduction velocity
HP:0003448	Decreased sensory nerve conduction velocity
HP:0003487	Babinski sign
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0006827	Atrophy of the spinal cord
HP:0007108	Demyelinating peripheral neuropathy
HP:0007141	Sensorimotor neuropathy
HP:0007366	Atrophy/Degeneration affecting the brainstem
HP:0008619	Bilateral sensorineural hearing impairment
HP:0009830	Peripheral neuropathy
HP:0010871	Sensory ataxia
HP:0011463	Childhood onset
HP:0025708	Early young adult onset
HP:0034063	Anti-islet antigen-2 antibody positivity
HP:0040217	Elevated hemoglobin A1c
HP:0100543	Cognitive impairment
HP:0100651	Type I diabetes mellitus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008158_90	Body mass index	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Cyclosporine	affects cotreatment, increases expression	6
sodium arsenite	decreases expression, increases abundance, increases expression	5
Cadmium Chloride	increases expression, decreases reaction	3
Thapsigargin	increases expression, decreases transport, increases response to substance	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, increases expression, affects cotreatment	2
Calcitriol	increases expression, affects cotreatment	2
Copper	affects binding, decreases expression, increases expression	2
Estradiol	affects expression, affects cotreatment, increases expression	2
Testosterone	increases expression, decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	increases expression	2
Tunicamycin	increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
beta-N-methylamino-L-alanine	increases expression	1
lasiocarpine	decreases expression	1
bisphenol A	decreases methylation	1
Nonidet P-40	increases expression	1
methylparaben	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	increases expression, affects cotreatment	1
nefazodone	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
motexafin gadolinium	decreases reaction, increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus