DNAJA3

Summary

DNAJA3 (DnaJ heat shock protein family (Hsp40) member A3, HGNC:11808) is a protein-coding gene on chromosome 16p13.3, encoding DnaJ homolog subfamily A member 3, mitochondrial (Q96EY1). Modulates apoptotic signal transduction or effector structures within the mitochondrial matrix. It is a common-essential gene (DepMap: required in 95.4% of cancer cell lines).

This gene encodes a member of the DNAJ/Hsp40 protein family. DNAJ/Hsp40 proteins stimulate the ATPase activity of Hsp70 chaperones and play critical roles in protein folding, degradation, and multimeric complex assembly. The encoded protein is localized to mitochondria and mediates several cellular processes including proliferation, survival and apoptotic signal transduction. The encoded protein also plays a critical role in tumor suppression through interactions with oncogenic proteins including ErbB2 and the p53 tumor suppressor protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 9093 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 125 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 95.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_005147

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11808
Approved symbol	DNAJA3
Name	DnaJ heat shock protein family (Hsp40) member A3
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	hTid-1, Tid1-S, Tid1-L
Ensembl gene	ENSG00000103423
Ensembl biotype	protein_coding
OMIM	608382
Entrez	9093

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 9 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000262375, ENST00000355296, ENST00000431375, ENST00000570857, ENST00000572009, ENST00000572139, ENST00000572974, ENST00000573120, ENST00000574393, ENST00000574895, ENST00000575106, ENST00000576180, ENST00000576911, ENST00000577083, ENST00000885873, ENST00000885874, ENST00000885875, ENST00000935015, ENST00000966820

RefSeq mRNA: 3 — MANE Select: NM_005147 NM_001135110, NM_001286516, NM_005147

CCDS: CCDS10515, CCDS45400, CCDS66930

Canonical transcript exons

ENST00000262375 — 12 exons

Exon	Start	End
ENSE00001886738	4425868	4426092
ENSE00003467007	4450400	4450497
ENSE00003487505	4455546	4456775
ENSE00003501992	4444664	4444728
ENSE00003510994	4443017	4443164
ENSE00003517386	4441375	4441575
ENSE00003530266	4454811	4454927
ENSE00003581908	4442268	4442420
ENSE00003617806	4448733	4448848
ENSE00003624894	4434384	4434517
ENSE00003659897	4437402	4437485
ENSE00003671609	4446886	4447014

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 95.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.2870 / max 288.1639, expressed in 1813 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152469	40.2870	1813

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	95.71	gold quality
muscle of leg	UBERON:0001383	95.53	gold quality
skeletal muscle organ	UBERON:0014892	95.41	gold quality
skeletal muscle tissue	UBERON:0001134	95.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.73	gold quality
right adrenal gland	UBERON:0001233	94.65	gold quality
right adrenal gland cortex	UBERON:0035827	94.57	gold quality
right lobe of liver	UBERON:0001114	94.51	gold quality
liver	UBERON:0002107	94.20	gold quality
left adrenal gland	UBERON:0001234	94.16	gold quality
adrenal gland	UBERON:0002369	93.89	gold quality
heart left ventricle	UBERON:0002084	93.81	gold quality
left adrenal gland cortex	UBERON:0035825	93.79	gold quality
apex of heart	UBERON:0002098	93.71	gold quality
muscle tissue	UBERON:0002385	93.29	gold quality
adrenal tissue	UBERON:0018303	93.19	gold quality
mucosa of transverse colon	UBERON:0004991	92.92	gold quality
heart	UBERON:0000948	92.41	gold quality
adult mammalian kidney	UBERON:0000082	92.21	gold quality
duodenum	UBERON:0002114	92.00	gold quality
right atrium auricular region	UBERON:0006631	91.77	gold quality
tonsil	UBERON:0002372	91.51	gold quality
kidney	UBERON:0002113	91.32	gold quality
vastus lateralis	UBERON:0001379	91.25	gold quality
transverse colon	UBERON:0001157	91.21	gold quality
body of pancreas	UBERON:0001150	91.17	gold quality
prefrontal cortex	UBERON:0000451	91.11	gold quality
metanephros cortex	UBERON:0010533	91.04	gold quality
esophagus mucosa	UBERON:0002469	90.94	gold quality
right testis	UBERON:0004534	90.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

40 targeting DNAJA3, 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-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-3117-5P	99.04	67.93	618
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4421	97.99	64.89	701

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 31)

• role as a repressor of Ikappa B kinase beta subunit (PMID:11927590)
• Tid-1S in Th2 cells following activation has a role in induction of apoptosis resistance during the activation of Th2 cells (PMID:12879007)
• an important cell death regulator and could exert tumor suppressor activity (PMID:15156195)
• findings suggest that the status of hTid-1 in gliomas may contribute to their susceptibility to cell death triggers (PMID:15589840)
• hTid-1 represses the activity of NF-kappaB through physical and functional interactions with the IKK complex and IkappaB (PMID:15601829)
• the carboxyl-terminal end of TID1 (residues 224-429) bound to Trk at the activation loop (Tyr(P)(683)-Tyr(684)(P)(684) (PMID:15753086)
• Tid-1(L) may play a critical role in pVHL-mediated tumor suppression by modulating the pVHL-dependent HIF-1alpha stability. (PMID:15805242)
• Tid1 is critical for the transition of double-negative to double-positive cells in early T cell development through modulation of antiapoptotic bcl-2 expression. (PMID:15879105)
• Tid1 negatively regulates the motility and metastasis of breast cancer cells, most likely through attenuation of nuclear factor kappaB activity on the promoter of the IL8 gene. (PMID:16204048)
• hTid1 may act as a chaperone to facilitate the folding, processing and maturation of Epstein-Barr virus-encoded BARF1 protein. (PMID:16518412)
• The association of Tid1 with chaperones and/or protein substrates in the cytosol provides a mechanism for the alternate fates and functions of Tid1 in mitochondrial and nonmitochondrial pathways. (PMID:16531398)
• The association of the endogenous Tid50/Tid48 proteins with the adenomatous polyposis coli (APC) tumor suppressor is shown. (PMID:17588722)
• The expression of the genes htid-1 and APC was altered in colorectal tumors. (PMID:18097612)
• amino-terminal segment of APC promotes cell sensitivity to apoptosis modulated through its binding to 40- and 43-kilodalton hTID-1 isoforms. (PMID:19900451)
• htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2. (PMID:20565727)
• hTid1 negatively regulates the expression and transcriptional activity of STAT5b and suppresses the growth of hematopoietic cells transformed by an oncogenic form of STAT5b. (PMID:21106534)
• findings denote hTid-1(S) as an essential regulatory component of MetR signaling (PMID:21242965)
• Tid1 and CHIP play pivotal roles in affecting the levels of ErbB2 protein, and that both are significant prognostic indicators of breast cancer patient survival. (PMID:21710689)
• Data show that elevated DnaJA3 induces dynamin-related protein 1 (Drp1)-depedendent mitochondrial fragmentation and decreased cell viability. (PMID:22595283)
• loss of hTid-1(S) expression in the basal layer of skin epidermis correlates with the enhanced HSP27 phosphorylation, keratinocyte hyperproliferation, and excess actin cytoskeleton organization in lesional psoriatic skin (PMID:22692211)
• Tid1 acts as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation. (PMID:23698466)
• TID1 prevents complex I aggregation and support the existence of a TID1-mediated stress response to ATP synthase inhibition (PMID:24492964)
• Impaired stoichiometry between mtHsp40 and mtHsp70 promotes Opa1L cleavage, leading to cristae opening, decreased OXPHOS, and triggering of mitochondrial fragmentation after reduction in their chaperone function. (PMID:25904328)
• Tid1 increases autophagic flux by interacting with the Beclin 1-containing autophagy protein complex. (PMID:26055714)
• The Role of the Phylogenetically Conserved Cochaperone Protein Droj2/DNAJA3 in NF-kappaB Signaling. (PMID:26245905)
• Herein, the authors first revealed that Galectin-7 was one of the Tid1-interacting client proteins. An inverse association of protein expression profile between Tid1 and Galectin-7 was determined in head and neck squamous cell carcinoma patients. Low Tid1 and high Galectin-7 expression predicted poor overall survival in head and neck squamous cell carcinoma. (PMID:30083263)
• A novel variant of the human mitochondrial DnaJ protein, Tid1, associates with a human disease exhibiting developmental delay and polyneuropathy. (PMID:30770860)
• identified HSPA1A and HSPA8 as the HSP70 family proteins that physically interact with DNAJA3, and established their requirement for the phosphorylation of NF-kappaB p65 (PMID:31005254)
• Tid1-S attenuates LPS-induced cardiac hypertrophy and apoptosis through ER-a mediated modulation of p-PI3K/p-Akt signaling cascade. (PMID:31081962)
• Mitochondrial ““dysmorphology”” in variant classification. (PMID:34750646)
• Structural resemblance of the DNAJA-family protein, Tid1, to the DNAJB-family Hsp40. (PMID:35651334)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnaja3a	ENSDARG00000058494
danio_rerio	dnaja3b	ENSDARG00000102295
mus_musculus	Dnaja3	ENSMUSG00000004069
rattus_norvegicus	Dnaja3	ENSRNOG00000003855
drosophila_melanogaster	CG5504	FBGN0002174
caenorhabditis_elegans		WBGENE00001028

Paralogs (3): DNAJA2 (ENSG00000069345), DNAJA1 (ENSG00000086061), DNAJA4 (ENSG00000140403)

Protein

Protein identifiers

DnaJ homolog subfamily A member 3, mitochondrial — Q96EY1 (reviewed: Q96EY1)

Alternative names: DnaJ protein Tid-1, Hepatocellular carcinoma-associated antigen 57, Tumorous imaginal discs protein Tid56 homolog

All UniProt accessions (6): Q96EY1, I3L1I6, I3L1T6, I3L1T9, I3L3D3, Q53G26

UniProt curated annotations — full annotation on UniProt →

Function. Modulates apoptotic signal transduction or effector structures within the mitochondrial matrix. Affect cytochrome C release from the mitochondria and caspase 3 activation, but not caspase 8 activation. Isoform 1 increases apoptosis triggered by both TNF and the DNA-damaging agent mytomycin C; in sharp contrast, isoform 2 suppresses apoptosis. Can modulate IFN-gamma-mediated transcriptional activity. Isoform 2 may play a role in neuromuscular junction development as an effector of the MUSK signaling pathway.

Subunit / interactions. Interacts with JAK2, HSPA9B and IFN-gammaR2 chain. Interacts with Ras GTPase-activating protein 1 (RASA1). Isoform 2 interacts with MUSK (via the cytoplasmic domain).

Subcellular location. Mitochondrion matrix. Cytoplasm. Cytosol. Postsynaptic cell membrane.

Tissue specificity. Widely expressed with highest levels in heart, liver, lung and skeletal muscles. Also expressed in keratinocytes; expression level and distribution is altered in basal cell carcinomas.

Post-translational modifications. Tyrosine phosphorylated.

Domain organisation. Modulation of apoptosis, i.e. proapoptotic activity of isoform 1 and antiapoptotic activity of isoform 2, is J domain-dependent.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96EY1-1	1, Tid-1(L)	yes
Q96EY1-2	2, Tid-1(S)
Q96EY1-3	3

RefSeq proteins (3): NP_001128582, NP_001273445, NP_005138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001305	HSP_DnaJ_Cys-rich_dom	Domain
IPR001623	DnaJ_domain	Domain
IPR002939	DnaJ_C	Domain
IPR008971	HSP40/DnaJ_pept-bd	Homologous_superfamily
IPR012724	DnaJ	Family
IPR018253	DnaJ_domain_CS	Conserved_site
IPR036410	HSP_DnaJ_Cys-rich_dom_sf	Homologous_superfamily
IPR036869	J_dom_sf	Homologous_superfamily
IPR051938	Apopto_cytoskel_mod	Family

Pfam: PF00226, PF00684, PF01556

UniProt features (44 total): binding site 8, strand 8, modified residue 5, helix 5, repeat 4, splice variant 3, sequence conflict 2, transit peptide 1, chain 1, domain 1, sequence variant 1, mutagenesis site 1, turn 1, zinc finger region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2CTT	SOLUTION NMR
2DN9	SOLUTION NMR
6IWS	SOLUTION NMR
7X89	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EY1-F1	75.04	0.42

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 (8): 236; 239; 253; 256; 275; 278; 289; 292

Post-translational modifications (5): 58, 134, 238, 293, 398

Mutagenesis-validated functional residues (1):

Position	Phenotype
121	loss of modulation of apoptosis.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 298 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_97, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_PEPTIDE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GOBP_T_CELL_HOMEOSTASIS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, MODULE_182, GOBP_CELLULAR_SENESCENCE, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION

GO Biological Process (26): negative regulation of transcription by RNA polymerase II (GO:0000122), mitochondrial DNA replication (GO:0006264), protein folding (GO:0006457), activation-induced cell death of T cells (GO:0006924), mitochondrion organization (GO:0007005), small GTPase-mediated signal transduction (GO:0007264), neuromuscular junction development (GO:0007528), negative regulation of cell population proliferation (GO:0008285), response to heat (GO:0009408), positive regulation of protein ubiquitination (GO:0031398), T cell differentiation in thymus (GO:0033077), response to type II interferon (GO:0034341), positive regulation of T cell proliferation (GO:0042102), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), negative regulation of programmed cell death (GO:0043069), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), protein stabilization (GO:0050821), negative regulation of type II interferon-mediated signaling pathway (GO:0060336), skeletal muscle acetylcholine-gated channel clustering (GO:0071340), cellular senescence (GO:0090398), immune system process (GO:0002376), regulation of immune system process (GO:0002682), apoptotic process (GO:0006915), response to stress (GO:0006950), regulation of cell population proliferation (GO:0042127)

GO Molecular Function (16): signaling receptor binding (GO:0005102), type II interferon receptor binding (GO:0005133), ATP binding (GO:0005524), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), Hsp70 protein binding (GO:0030544), GTPase regulator activity (GO:0030695), protein-containing complex binding (GO:0044877), NF-kappaB binding (GO:0051059), obsolete unfolded protein binding (GO:0051082), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), IkappaB kinase complex binding (GO:0106137), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515), heat shock protein binding (GO:0031072), metal ion binding (GO:0046872)

GO Cellular Component (13): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cytoplasmic side of plasma membrane (GO:0009898), neuromuscular junction (GO:0031594), mitochondrial nucleoid (GO:0042645), postsynaptic membrane (GO:0045211), actin filament (GO:0005884), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
cellular anatomical structure	3
negative regulation of cellular process	2
apoptotic process	2
regulation of apoptotic process	2
protein binding	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
DNA-templated DNA replication	1
mitochondrial DNA metabolic process	1
cellular process	1
protein maturation	1
T cell homeostasis	1
T cell apoptotic process	1
organelle organization	1
intracellular signaling cassette	1
synapse organization	1
cell population proliferation	1
regulation of cell population proliferation	1
response to stress	1
response to temperature stimulus	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
T cell differentiation	1
response to cytokine	1
innate immune response	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
programmed cell death	1
regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1

Protein interactions and networks

STRING

3011 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJA3	HSPA9	P30036	854
DNAJA3	HSPA8	P11142	816
DNAJA3	HSPA4	P34932	713
DNAJA3	GRPEL2	Q8TAA5	707
DNAJA3	HSPA1A	P08107	697
DNAJA3	TCHP	Q9BT92	648
DNAJA3	IFNGR2	P38484	646
DNAJA3	POLG	P54098	639
DNAJA3	LONP1	P36776	620
DNAJA3	ATRX	P46100	620
DNAJA3	MUSK	O15146	604
DNAJA3	HSPA5	P11021	585
DNAJA3	RNF34	Q969K3	580
DNAJA3	DNAJC19	Q96DA6	580
DNAJA3	GRPEL1	Q9HAV7	568

IntAct

192 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
HTT	DNAJA3	psi-mi:“MI:0915”(physical association)	0.670
ATXN1	DNAJA3	psi-mi:“MI:0915”(physical association)	0.670
DNAJA3	HTT	psi-mi:“MI:0915”(physical association)	0.670
MET	DNAJA3	psi-mi:“MI:0915”(physical association)	0.640
MET	DNAJA3	psi-mi:“MI:0403”(colocalization)	0.640
IRS4	PIK3R2	psi-mi:“MI:0914”(association)	0.640
HTRA3	VIM	psi-mi:“MI:0914”(association)	0.580
AICDA	DNAJA2	psi-mi:“MI:0914”(association)	0.570
CYSRT1	DNAJA3	psi-mi:“MI:0915”(physical association)	0.560
DNAJA3	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
DNAJA3	ATOSB	psi-mi:“MI:0915”(physical association)	0.550
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
IRAK1	SEC16A	psi-mi:“MI:0914”(association)	0.530
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
P/V	IRS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (450): DNAJA3 (Affinity Capture-MS), DNAJA3 (Affinity Capture-MS), DNAJA3 (Two-hybrid), DNAJA3 (Two-hybrid), DNAJA3 (Two-hybrid), INPP5J (Two-hybrid), OSGIN1 (Two-hybrid), NOC4L (Two-hybrid), GCC1 (Two-hybrid), MYO15B (Two-hybrid), FAM214B (Two-hybrid), FRMD6 (Two-hybrid), ALS2CR11 (Two-hybrid), DNAJA3 (Affinity Capture-MS), DNAJA3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6GDY8, A0A1D6LAB7, A8JGV8, C8V213, O74752, O94625, O94657, P0DO01, P0DO02, P0DO03, P25294, P25303, P25491, P27692, P35191, P39102, P53940, P78004, P87239, Q09912, Q0CLX0, Q0DHL4, Q0JB88, Q10MW6, Q1DMX8, Q24331, Q27237, Q28I38, Q38813, Q54ED3, Q58DR2, Q5S7T7, Q626I7, Q6AYU3, Q6H6R9, Q759T6, Q7RUX3, Q8EUM4, Q8FM80, Q8GWW8

Diamond homologs: A0LJ41, A1V9Q3, A1WAR7, A1WX30, A2ALW5, A3DF24, A4IR30, A5ITA7, A5WBF8, A6QHC2, A6U251, A7GT07, A7X2Y0, A7Z6W0, A8FFD1, A8Z4B8, A9KE65, A9NDK6, A9VHU0, B0JW23, B0VQ00, B1HUD0, B1WVR2, B1Y787, B1YKT0, B2GBQ6, B2I2G6, B2J3J3, B3EE31, B7GV08, B7HPL2, B7I2B2, B7JN38, B8CXL0, B8FUN3, B9DNJ9, B9IY80, C1ESK7, C3L5R6, C3P8L9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	18.9×	6e-04
Activation of AMPK downstream of NMDARs	5	13.9×	2e-03
RHO GTPases activate IQGAPs	5	12.6×	2e-03
PI3K Cascade	6	11.9×	8e-04
Aggrephagy	6	10.9×	1e-03
Constitutive Signaling by Aberrant PI3K in Cancer	11	10.2×	3e-06
Selective autophagy	5	10.2×	4e-03
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	7	9.9×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	7	17.6×	9e-05
tumor necrosis factor-mediated signaling pathway	7	13.8×	3e-04
protein autophosphorylation	11	9.5×	3e-05
cell surface receptor protein tyrosine kinase signaling pathway	8	8.3×	1e-03
positive regulation of cell growth	7	7.6×	6e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	12	5.6×	4e-04
positive regulation of MAPK cascade	11	5.3×	2e-03
negative regulation of apoptotic process	18	3.7×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	98
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
983281	GRCh37/hg19 16p13.3-11.2(chr16:2959279-30190593)x3	Pathogenic

SpliceAI

2101 predictions. Top by Δscore:

Variant	Effect	Δscore
16:4434378:TTTTA:T	acceptor_loss	1.0000
16:4434379:TTTAG:T	acceptor_loss	1.0000
16:4434380:TTA:T	acceptor_loss	1.0000
16:4434381:TAG:T	acceptor_loss	1.0000
16:4434382:A:AG	acceptor_gain	1.0000
16:4434382:AGGAA:A	acceptor_loss	1.0000
16:4434383:G:GG	acceptor_gain	1.0000
16:4434513:ATCAG:A	donor_loss	1.0000
16:4434514:TCAG:T	donor_loss	1.0000
16:4434515:CAG:C	donor_loss	1.0000
16:4434516:AG:A	donor_loss	1.0000
16:4434517:GG:G	donor_loss	1.0000
16:4434518:GT:G	donor_loss	1.0000
16:4434519:T:G	donor_loss	1.0000
16:4437397:CTTA:C	acceptor_loss	1.0000
16:4437400:A:AG	acceptor_gain	1.0000
16:4437400:AGCTT:A	acceptor_gain	1.0000
16:4437401:G:A	acceptor_loss	1.0000
16:4437401:G:GT	acceptor_gain	1.0000
16:4437401:GC:G	acceptor_gain	1.0000
16:4437401:GCT:G	acceptor_gain	1.0000
16:4437401:GCTT:G	acceptor_gain	1.0000
16:4437401:GCTTG:G	acceptor_gain	1.0000
16:4437482:TGAGG:T	donor_loss	1.0000
16:4437485:GG:G	donor_loss	1.0000
16:4437487:T:G	donor_loss	1.0000
16:4441371:GTAGG:G	acceptor_loss	1.0000
16:4441373:A:AC	acceptor_loss	1.0000
16:4441506:G:GT	donor_gain	1.0000
16:4441571:AGGAA:A	donor_gain	1.0000

AlphaMissense

3143 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:4434502:G:C	K110N	1.000
16:4434502:G:T	K110N	1.000
16:4437406:C:A	A117D	1.000
16:4437410:G:C	K118N	1.000
16:4437410:G:T	K118N	1.000
16:4437417:C:A	H121N	1.000
16:4437417:C:G	H121D	1.000
16:4437419:C:A	H121Q	1.000
16:4437419:C:G	H121Q	1.000
16:4437459:T:C	F135L	1.000
16:4437461:C:A	F135L	1.000
16:4437461:C:G	F135L	1.000
16:4442295:G:C	A220P	1.000
16:4442394:T:C	C253R	1.000
16:4443056:T:C	C275R	1.000
16:4434500:A:G	K110E	0.999
16:4434509:T:G	Y113D	0.999
16:4434512:T:G	Y114D	0.999
16:4437418:A:G	H121R	0.999
16:4437460:T:C	F135S	0.999
16:4437460:T:G	F135C	0.999
16:4441379:T:C	L145S	0.999
16:4441513:T:C	F190L	0.999
16:4441515:T:A	F190L	0.999
16:4441515:T:G	F190L	0.999
16:4442281:T:C	L215S	0.999
16:4442296:C:A	A220D	0.999
16:4442343:T:C	C236R	0.999
16:4442344:G:A	C236Y	0.999
16:4442352:T:A	C239S	0.999

dbSNP variants (sampled 300 via entrez): RS1000158599 (16:4448145 G>C,T), RS1000396388 (16:4444974 A>G,T), RS1000508279 (16:4433592 C>G), RS1000534269 (16:4453663 C>G,T), RS1000684364 (16:4429279 C>T), RS1000762082 (16:4449021 G>A), RS1000819599 (16:4449774 C>T), RS1000827044 (16:4456986 C>G,T), RS1001003485 (16:4453506 C>T), RS1001238238 (16:4435358 C>T), RS1001261320 (16:4425715 T>A,C), RS1001275253 (16:4440329 G>A), RS1001404489 (16:4431212 T>C), RS1001494543 (16:4436787 C>A,G), RS1001640459 (16:4441948 T>C)

Disease associations

OMIM: gene MIM:608382 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (1): complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST004946_101	Schizophrenia	5.000000e-09
GCST006956_6	Erectile dysfunction	2.000000e-06
GCST007483_39	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-10
GCST007487_6	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-10
GCST007500_5	Waist-to-hip ratio adjusted for BMI (additive genetic model)	3.000000e-08
GCST007502_5	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5.000000e-08
GCST010244_334	Triglyceride levels	4.000000e-14
GCST012227_377	Hip circumference adjusted for BMI	3.000000e-13
GCST012228_505	Waist-hip index	1.000000e-08
GCST012229_178	Hip index	1.000000e-08
GCST012230_147	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST90002387_12	Immature fraction of reticulocytes	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067268 (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
9.01	Kd	0.989	nM	CHEMBL3752910
9.00	ED50	1.006	nM	CHEMBL3752910
6.72	Kd	189.8	nM	CHEMBL5653589
6.71	ED50	193.1	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148249: Binding affinity to human DNAJA3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0010	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148249: Binding affinity to human DNAJA3 incubated for 45 mins by Kinobead based pull down assay	kd	0.1898	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Estradiol	increases reaction, increases expression, affects binding	2
Valproic Acid	increases expression, affects cotreatment	2
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects expression	1
manganese chloride	decreases expression, increases abundance	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
bisphenol S	affects expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Clozapine	affects cotreatment, increases expression	1
Cuprizone	affects cotreatment, increases expression, decreases expression	1
Diclofenac	affects expression	1
Dimethyl Sulfoxide	increases expression	1
Gold	affects binding, increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Manganese	decreases expression, increases abundance	1
Ouabain	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	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
CHEMBL5651291	Binding	Binding affinity to human DNAJA3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder