DNAJC6

Summary

DNAJC6 (DnaJ heat shock protein family (Hsp40) member C6, HGNC:15469) is a protein-coding gene on chromosome 1p31.3, encoding Auxilin (O75061). May act as a protein phosphatase and/or a lipid phosphatase.

DNAJC6 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus, a glycine/phenylalanine (G/F)-rich region, and a cysteine-rich domain containing 4 motifs resembling a zinc finger domain (Ohtsuka and Hata, 2000 [PubMed 11147971]).

Source: NCBI Gene 9829 — RefSeq curated summary.

At a glance

• Gene–disease (curated): juvenile onset Parkinson disease 19A (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 407 total — 8 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 68
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001256864

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15469
Approved symbol	DNAJC6
Name	DnaJ heat shock protein family (Hsp40) member C6
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0473, PARK19
Ensembl gene	ENSG00000116675
Ensembl biotype	protein_coding
OMIM	608375
Entrez	9829

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000263441, ENST00000371069, ENST00000395325, ENST00000463018, ENST00000472787, ENST00000483402, ENST00000494710, ENST00000498720

RefSeq mRNA: 3 — MANE Select: NM_001256864 NM_001256864, NM_001256865, NM_014787

CCDS: CCDS30739, CCDS58004, CCDS58005

Canonical transcript exons

ENST00000371069 — 19 exons

Exon	Start	End
ENSE00001173706	65392431	65392865
ENSE00001656797	65309543	65309938
ENSE00003473624	65365885	65365934
ENSE00003477123	65388336	65388415
ENSE00003486206	65405870	65406133
ENSE00003495997	65408641	65408783
ENSE00003496020	65384193	65384326
ENSE00003545270	65379402	65379524
ENSE00003549119	65366048	65366196
ENSE00003577568	65398813	65398881
ENSE00003580468	65389256	65389449
ENSE00003587295	65394898	65395032
ENSE00003589322	65401761	65401880
ENSE00003596146	65385712	65385906
ENSE00003597531	65411250	65411426
ENSE00003605688	65412924	65415871
ENSE00003623737	65386812	65386929
ENSE00003639930	65364635	65364785
ENSE00003665399	65389547	65389627

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 99.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.2733 / max 818.1560, expressed in 1433 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3263	14.0935	1359
3267	5.4378	339
3271	0.8636	148
3262	0.8149	234
3270	0.3459	109
3273	0.2430	113
3272	0.1437	76
3264	0.1435	66
3265	0.1145	53
3266	0.0403	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.62	gold quality
substantia nigra pars compacta	UBERON:0001965	99.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.47	gold quality
middle temporal gyrus	UBERON:0002771	99.39	gold quality
orbitofrontal cortex	UBERON:0004167	99.39	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.35	gold quality
pons	UBERON:0000988	99.25	gold quality
inferior olivary complex	UBERON:0002127	99.17	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.17	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.12	gold quality
superior vestibular nucleus	UBERON:0007227	98.98	gold quality
CA1 field of hippocampus	UBERON:0003881	98.97	gold quality
postcentral gyrus	UBERON:0002581	98.95	gold quality
entorhinal cortex	UBERON:0002728	98.94	gold quality
parietal lobe	UBERON:0001872	98.93	gold quality
corpus callosum	UBERON:0002336	98.85	gold quality
medulla oblongata	UBERON:0001896	98.81	gold quality
superior frontal gyrus	UBERON:0002661	98.74	gold quality
subthalamic nucleus	UBERON:0001906	98.70	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.65	gold quality
inferior vagus X ganglion	UBERON:0005363	98.54	gold quality
lateral globus pallidus	UBERON:0002476	98.42	gold quality
ventral tegmental area	UBERON:0002691	98.40	gold quality
cerebellar vermis	UBERON:0004720	98.38	gold quality
occipital lobe	UBERON:0002021	97.93	gold quality
primary visual cortex	UBERON:0002436	97.71	gold quality
prefrontal cortex	UBERON:0000451	97.45	gold quality
cranial nerve II	UBERON:0000941	97.44	gold quality
midbrain	UBERON:0001891	96.60	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-81383	yes	114.86
E-HCAD-35	yes	70.74
E-MTAB-9067	yes	11.24
E-GEOD-84465	yes	11.19
E-ANND-3	yes	5.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

179 targeting DNAJC6, 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-6867-5P	100.00	82.21	3464
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1468-3P	99.96	72.74	3797
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-MIR-545-3P	99.95	70.74	2783
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-539-5P	99.93	70.30	2855

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• there are two auxilins with overlapping functions; they not only facilitate the uncoating of clathrin-coated vesicles but also prevent the formation of nonproductive clathrin cages in the cytosol (PMID:18489706)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• study reports a homozygous mutation in DNAJC6 in two patients with autosomal-recessive juvenile Parkinsonism; the mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level (PMID:22563501)
• The DNAJC6 gene encodes auxilin-1, a protein required for clathrin-dependent recycling of synaptic vesicles in neurons that is possibly at the origin of the mental retardation and epilepsy phenotype (PMID:22647716)
• Our findings further establish DNAJC6 as a juvenile parkinsonism gene, and expand the spectrums of the parkinsonism phenotype and DNAJC6 mutation (PMID:23211418)
• Missense mutations in DNAJC6 does not play a major role in PD in the Chinese population. (PMID:24126164)
• we did not detect any heterozygous or homozygous c.801-2A>G mutation in DNAJC6 in a cohort of Parkinson disease patients from southern Spain. (PMID:24220513)
• This review presented that DNAJC6 in recessive forms of juvenile parkinsonism. (PMID:24262182)
• DNAJC6 is up-regulated in hepatocellular carcinoma tissues and up-regulation of DNAJC6 expression predicts poor outcome in patients with HCC (PMID:25446072)
• DNAJC6 mutations are associated with early-onset Parkinson’s disease. (PMID:26528954)
• DNAJC6 mutations are not common causes of early onset Parkinson’s disease in Chinese population (PMID:27687717)
• Early onset Parkinson is associated with several SNPs and haplotypes of DNAJC6 gene. (PMID:30373961)
• DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia. (PMID:32472658)
• Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson’s disease-linked DNAJC6 mutations. (PMID:33597231)
• Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene. (PMID:34948429)
• Downregulation of Protease Cathepsin D and Upregulation of Pathologic alpha-Synuclein Mediate Paucity of DNAJC6-Induced Degeneration of Dopaminergic Neurons. (PMID:38928416)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnajc6	ENSDARG00000079891
mus_musculus	Dnajc6	ENSMUSG00000028528
rattus_norvegicus	Dnajc6	ENSRNOG00000052887

Paralogs (1): GAK (ENSG00000178950)

Protein

Protein identifiers

Auxilin — O75061 (reviewed: O75061)

Alternative names: DnaJ homolog subfamily C member 6

All UniProt accessions (2): O75061, S4R305

UniProt curated annotations — full annotation on UniProt →

Function. May act as a protein phosphatase and/or a lipid phosphatase. Co-chaperone that recruits HSPA8/HSC70 to clathrin-coated vesicles (CCVs) and promotes the ATP-dependent dissociation of clathrin from CCVs and participates in clathrin-mediated endocytosis of synaptic vesicles and their recycling and also in intracellular trafficking. Firstly, binds tightly to the clathrin cages, at a ratio of one DNAJC6 per clathrin triskelion. The HSPA8:ATP complex then binds to the clathrin-auxilin cage, initially at a ratio of one HSPA8 per triskelion leading to ATP hydrolysis stimulation and causing a conformational change in the HSPA8. This cycle is repeated three times to drive to a complex containing the clathrin-auxilin cage associated to three HSPA8:ADP complex. The ATP hydrolysis of the third HSPA8:ATP complex leads to a concerted dismantling of the cage into component triskelia. Then, dissociates from the released triskelia and be recycled to initiate another cycle of HSPA8’s recruitment. Also acts during the early steps of clathrin-coated vesicle (CCV) formation through its interaction with the GTP bound form of DNM1.

Subunit / interactions. Forms a complex composed of HSPA8, CLTC and DNAJC6. Interacts with HSPA8/HSC70 in an ATP-dependent manner; this interaction stimulates the HSPA8’s ATPase activity. Interacts with CLTC; this interaction produces a local change in heavy-chain contacts, creating a detectable global distortion of the clathrin coat. Interacts with AP2A2. Interacts with DNM1(GTP-bound form); this interaction allows clathrin-coated vesicle (CCV) formation at the plasma membrane.

Subcellular location. Cytoplasmic vesicle. Clathrin-coated vesicle.

Tissue specificity. Expressed in various brain regions, including cerebellum, corpus callosum, cortex, striatum, brainstem, pons, putamen, spinal cord and substantia nigra. Very low expression in non-neural tissues such as leukocytes, liver, adipose tissue, skeletal muscle and bone marrow.

Post-translational modifications. Phosphorylation at Ser-570 modulates its ability to bind CLTC and therefore the synaptic vesicle endocytosis (SVE). The N-terminus is blocked.

Disease relevance. Parkinson disease 19A, juvenile-onset (PARK19A) [MIM:615528] A juvenile form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK19A is characterized by onset of parkinsonian symptoms in the first or second decade of life. Some patients may have additional neurologic features, including intellectual disability and seizures. The disease is caused by variants affecting the gene represented in this entry. Parkinson disease 19B, early-onset (PARK19B) [MIM:615528] An early-onset form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK19B is characterized by symptoms onset in the third-to-fifth decade, slow disease progression, and prominent. response to dopaminergic therapies. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The J domain mediates interaction with HSPA8/HSC70 and is required for basket dissociation.

Isoforms (4)

UniProt ID	Names	Canonical?
O75061-1	1	yes
O75061-2	2
O75061-3	3
O75061-4	4

RefSeq proteins (3): NP_001243793, NP_001243794, NP_055602 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000387	Tyr_Pase_dom	Domain
IPR001623	DnaJ_domain	Domain
IPR014020	Tensin_C2-dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029023	Tensin_phosphatase	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036869	J_dom_sf	Homologous_superfamily

Pfam: PF10409

UniProt features (36 total): modified residue 7, sequence variant 7, compositionally biased region 4, repeat 3, splice variant 3, domain 3, mutagenesis site 2, sequence conflict 2, region of interest 2, chain 1, active site 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75061-F1	64.29	0.30

Functional residue map

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

Catalytic / active sites (1): 164 (phosphocysteine intermediate)

Post-translational modifications (7): 112, 453, 456, 563, 570, 1, 1

Mutagenesis-validated functional residues (2):

Position	Phenotype
570	increase interaction with cltc. does not affect interaction with hspa8.
570	does not affect interaction with cltc. does not affect interaction with hspa8.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 385 (showing top): GNF2_RTN1, FISCHER_G1_S_CELL_CYCLE, TTTGTAG_MIR520D, GOBP_CLATHRIN_COAT_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, BILD_HRAS_ONCOGENIC_SIGNATURE, MODULE_205, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOCC_COATED_VESICLE, TGTGTGA_MIR377, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP

GO Biological Process (8): synaptic vesicle uncoating (GO:0016191), synaptic vesicle recycling (GO:0036465), intracellular transport (GO:0046907), clathrin coat disassembly (GO:0072318), clathrin-dependent endocytosis (GO:0072583), regulation of clathrin coat assembly (GO:1905443), regulation of clathrin-dependent endocytosis (GO:2000369), dephosphorylation (GO:0016311)

GO Molecular Function (8): phosphoprotein phosphatase activity (GO:0004721), SH3 domain binding (GO:0017124), clathrin binding (GO:0030276), heat shock protein binding (GO:0031072), clathrin heavy chain binding (GO:0032050), protein tyrosine phosphatase activity (GO:0004725), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): cytoplasm (GO:0005737), cytosol (GO:0005829), postsynaptic density (GO:0014069), clathrin-coated vesicle (GO:0030136), vesicle (GO:0031982), extrinsic component of presynaptic endocytic zone membrane (GO:0098894), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	2
Membrane Trafficking	2
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
establishment of localization in cell	2
intracellular anatomical structure	2
clathrin-dependent endocytosis	2
protein binding	2
cellular anatomical structure	2
cytoplasm	2
synaptic vesicle endocytosis	1
clathrin coat disassembly	1
synaptic vesicle cycle	1
cellular localization	1
vesicle uncoating	1
receptor-mediated endocytosis	1
regulation of protein-containing complex assembly	1
clathrin coat assembly	1
regulation of receptor-mediated endocytosis	1
phosphate-containing compound metabolic process	1
phosphatase activity	1
catalytic activity, acting on a protein	1
protein domain specific binding	1
clathrin binding	1
phosphoprotein phosphatase activity	1
binding	1
catalytic activity	1
asymmetric synapse	1
postsynaptic specialization	1
coated vesicle	1
membrane-bounded organelle	1
presynaptic endocytic zone membrane	1
extrinsic component of presynaptic membrane	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

3694 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJC6	HSPA8	P11142	996
DNAJC6	SYNJ1	O43426	907
DNAJC6	CLTCL1	P53675	886
DNAJC6	CLTC	Q00610	860
DNAJC6	DNAJC13	O75165	811
DNAJC6	DNAJB4	Q9UDY4	798
DNAJC6	VPS35	Q96QK1	796
DNAJC6	DNAJB1	P25685	780
DNAJC6	ATP13A2	Q9NQ11	764
DNAJC6	FBXO7	Q9Y3I1	761
DNAJC6	VPS13C	Q709C8	748
DNAJC6	PLA2G6	O60733	739
DNAJC6	HSPA4	P34932	723
DNAJC6	PRKN	O60260	719
DNAJC6	PINK1	Q9BXM7	719

IntAct

14 interactions, top by confidence:

A	B	Type	Score
GNAT1	DNAJC6	psi-mi:“MI:0915”(physical association)	0.400
DNAJC6	BAG2	psi-mi:“MI:0915”(physical association)	0.370
MAPT	MEX3A	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POM121C	psi-mi:“MI:0914”(association)	0.350
CLTA	CLTB	psi-mi:“MI:0914”(association)	0.350
DNAJC6	HIP1	psi-mi:“MI:0914”(association)	0.350
COX6A1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
IL1RL2	DNAJC6	psi-mi:“MI:0914”(association)	0.350
GBX1	DNAJC6	psi-mi:“MI:0914”(association)	0.350
DNAJC6	PIK3C2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (76): DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-MS), DNAJC6 (Affinity Capture-RNA), DNAJC6 (Affinity Capture-RNA), DNAJC6 (Reconstituted Complex), ACBD3 (Affinity Capture-MS), AHCYL1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2B1 (Affinity Capture-MS), AP2M1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMA8, A1XD93, A1XD94, A1XD95, A1XD97, A4UMC5, A4UMC6, B3DJT0, B5DFC8, E7EXT2, E7F187, F1M3L7, F7AEX0, O14617, O54774, O75061, P52590, P53569, P57740, P78344, P79398, Q06AK6, Q0IIX9, Q12929, Q17784, Q17CQ8, Q29RR5, Q2KI89, Q5R4H4, Q5R5K8, Q5R629, Q5R7J9, Q5TYV4, Q5U2Y6, Q5ZII9, Q62448, Q66J74, Q6DI35, Q865S1, Q8BH74

Diamond homologs: O13773, O14976, O75061, P97874, Q06677, Q0WQ57, Q27974, Q80TZ3, Q99KY4, Q9FWS1, Q9SU08, A0AUV4, A8WYE4, B0WAU8, D2I3C6, D3ZBE5, E9Q0S6, F1LP90, F1MH24, F1SPM8, G5ECQ3, O34507, O43066, O75716, P0C1X8, P0C8M8, P20911, P32562, P34331, P38080, P40494, P50613, P51952, P51954, P51956, P51957, P53974, P56180, P57059, Q03147

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DNAJC6	“up-regulates activity”	HSPA8	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	5
Uncertain significance	186
Likely benign	130
Benign	49

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1399200	NM_001256864.2(DNAJC6):c.677_678dup (p.Ala227fs)	Pathogenic
1451316	NM_001256864.2(DNAJC6):c.2456dup (p.Gln820fs)	Pathogenic
219301	NM_001256864.2(DNAJC6):c.454C>T (p.Arg152Ter)	Pathogenic
253094	NM_001256864.2(DNAJC6):c.2779A>G (p.Arg927Gly)	Pathogenic
265964	NM_001256864.2(DNAJC6):c.2536C>T (p.Gln846Ter)	Pathogenic
88854	NM_001256864.2(DNAJC6):c.801-2A>G	Pathogenic
88855	NM_001256864.2(DNAJC6):c.2410C>T (p.Gln804Ter)	Pathogenic
976692	NM_001256864.2(DNAJC6):c.988C>T (p.Arg330Ter)	Pathogenic
1676536	NM_001256864.2(DNAJC6):c.49G>T (p.Glu17Ter)	Likely pathogenic
2096560	NM_001256864.2(DNAJC6):c.666+1G>A	Likely pathogenic
2505345	NM_001256864.2(DNAJC6):c.2570del (p.Pro857fs)	Likely pathogenic
3380986	NM_001256864.2(DNAJC6):c.705del (p.Met235fs)	Likely pathogenic
3646343	NM_001256864.2(DNAJC6):c.194-1G>A	Likely pathogenic

SpliceAI

3409 predictions. Top by Δscore:

Variant	Effect	Δscore
1:65345600:T:A	acceptor_gain	1.0000
1:65364784:AGGTA:A	donor_loss	1.0000
1:65364785:GGTAC:G	donor_loss	1.0000
1:65364786:G:T	donor_loss	1.0000
1:65364787:T:A	donor_loss	1.0000
1:65366033:T:TA	acceptor_gain	1.0000
1:65366046:A:AG	acceptor_gain	1.0000
1:65366046:AGT:A	acceptor_gain	1.0000
1:65366047:G:GA	acceptor_gain	1.0000
1:65366047:GT:G	acceptor_gain	1.0000
1:65366047:GTG:G	acceptor_gain	1.0000
1:65366047:GTGA:G	acceptor_gain	1.0000
1:65366047:GTGAT:G	acceptor_gain	1.0000
1:65366192:GCCGG:G	donor_gain	1.0000
1:65366194:CGG:C	donor_loss	1.0000
1:65366195:GG:G	donor_gain	1.0000
1:65366195:GGGTA:G	donor_loss	1.0000
1:65366196:GG:G	donor_gain	1.0000
1:65366197:G:GA	donor_loss	1.0000
1:65366198:T:TT	donor_loss	1.0000
1:65384187:TGACA:T	acceptor_loss	1.0000
1:65384188:GACAG:G	acceptor_loss	1.0000
1:65384189:ACAGG:A	acceptor_loss	1.0000
1:65384190:CAG:C	acceptor_loss	1.0000
1:65384191:A:AC	acceptor_loss	1.0000
1:65384191:A:AG	acceptor_gain	1.0000
1:65384191:AG:A	acceptor_gain	1.0000
1:65384191:AGGAT:A	acceptor_gain	1.0000
1:65384192:G:GG	acceptor_gain	1.0000
1:65384192:GG:G	acceptor_gain	1.0000

AlphaMissense

6359 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:65365926:G:C	R72T	1.000
1:65365926:G:T	R72I	1.000
1:65366117:T:C	L98S	1.000
1:65379417:T:A	W130R	1.000
1:65379417:T:C	W130R	1.000
1:65379436:C:A	P136H	1.000
1:65379451:T:C	L141P	1.000
1:65379464:T:G	C145W	1.000
1:65379484:T:C	L152P	1.000
1:65379505:T:A	V159D	1.000
1:65379507:T:C	C160R	1.000
1:65379509:T:G	C160W	1.000
1:65379511:T:A	V161D	1.000
1:65385833:T:C	C251R	1.000
1:65389365:T:A	W378R	1.000
1:65389365:T:C	W378R	1.000
1:65411259:T:A	W825R	1.000
1:65411259:T:C	W825R	1.000
1:65411260:G:C	W825S	1.000
1:65411261:G:C	W825C	1.000
1:65411261:G:T	W825C	1.000
1:65411272:A:T	K829I	1.000
1:65411287:G:C	R834T	1.000
1:65411288:A:C	R834S	1.000
1:65411288:A:T	R834S	1.000
1:65411293:T:C	L836P	1.000
1:65411296:T:A	L837H	1.000
1:65411296:T:C	L837P	1.000
1:65411319:T:A	W845R	1.000
1:65411319:T:C	W845R	1.000

dbSNP variants (sampled 300 via entrez): RS1000007950 (1:65401149 T>C), RS1000010813 (1:65306519 G>A), RS1000052164 (1:65320984 A>G), RS1000088935 (1:65358641 T>C), RS1000091883 (1:65314258 G>A), RS1000092659 (1:65358992 C>T), RS1000121502 (1:65358365 A>G), RS1000123235 (1:65406484 T>C,G), RS1000128707 (1:65313171 G>C), RS1000130636 (1:65334832 T>A), RS1000138416 (1:65405660 A>T), RS1000158172 (1:65267422 A>G), RS1000197612 (1:65281305 T>C), RS1000207058 (1:65391777 T>A), RS1000210178 (1:65298988 C>T)

Disease associations

OMIM: gene MIM:608375 | disease phenotypes: MIM:615528, MIM:616192

GenCC curated gene-disease

Disease	Classification	Inheritance
juvenile onset Parkinson disease 19A	Strong	Autosomal recessive
young-onset Parkinson disease	Supportive	Autosomal recessive
atypical juvenile parkinsonism	Supportive	Autosomal recessive

Mondo (6): juvenile onset Parkinson disease 19A (MONDO:0014231), prostate cancer (MONDO:0008315), Parkinson disease 19B, early-onset (MONDO:0800369), juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (MONDO:0014523), young-onset Parkinson disease (MONDO:0017279), atypical juvenile parkinsonism (MONDO:0018321)

Orphanet (3): Atypical juvenile parkinsonism (Orphanet:391411), Familial prostate cancer (Orphanet:1331), Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (Orphanet:445062)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000338	Hypomimic face
HP:0000551	Color vision defect
HP:0000571	Hypometric saccades
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001621	Weak voice
HP:0001761	Pes cavus
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002066	Gait ataxia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001365_1	Anticoagulant levels	3.000000e-07
GCST003918_5	Idiopathic osteonecrosis of the femoral head	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004637	protein S measurement
EFO:1001930	idiopathic osteonecrosis of the femoral head

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	increases expression	3
(+)-JQ1 compound	increases expression	3
trichostatin A	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	affects cotreatment, increases expression, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
nefazodone	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	increases methylation	1
N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Carbamazepine	affects expression	1

Cellosaurus cell lines

7 cell lines: 4 induced pluripotent stem cell, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3BX	SHEHDNi002-A	Induced pluripotent stem cell	Female
CVCL_C7UY	WIBRe001-A-14	Embryonic stem cell	Female
CVCL_C7UZ	WIBRe001-A-15	Embryonic stem cell	Female
CVCL_C7V0	WIBRe001-A-16	Embryonic stem cell	Female
CVCL_E4QE	KOLF2.1J DNAJC6 48.8kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7P2	KOLF2.1J DNAJC6 S59G SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7P3	KOLF2.1J DNAJC6 S59G SNV/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer