DNAJC6

Chr 1AR

DnaJ heat shock protein family (Hsp40) member C6

Also known as: DJC6, PARK19

NCBI Gene: 9829 ENSG00000116675 UniProt: O75061 OMIM: 608375

DNAJC6 encodes auxilin, a co-chaperone protein that recruits HSC70 to promote ATP-dependent clathrin disassembly from coated vesicles and participates in clathrin-mediated endocytosis and synaptic vesicle recycling. Biallelic mutations cause juvenile-onset Parkinson disease 19a and early-onset Parkinson disease 19b with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.22), indicating that complete loss of function is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]).[supplied by OMIM, Mar 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.222 OMIM phenotypes

Clinical Summary— DNAJC6

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 183 VUS of 403 total submissions

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GeneReview available — DNAJC6

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 5.70

OE 0.11 (0.05–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.60Z-score

OE missense 0.80 (0.74–0.87)

424 obs / 527.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.22)

0≤0.351.4

Missense OE?0.80 (0.74–0.87)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 5 / 47.3Missense obs/exp: 424 / 527.4Syn Z: 0.63

This gene — mechanism propensity

0.3793th %ile

GOF

0.4085th %ile

LOF

0.64top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 93% of P/LP variants are LoF · LOEUF 0.22

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

403 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic5

VUS183

Likely Benign138

Benign48

Conflicting4

Pathogenic

Likely Pathogenic

183

VUS

138

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	1	0	0	9
Likely Pathogenic	5	0	0	0	5
VUS	0	168	12	3	183
Likely Benign	0	6	62	70	138
Benign	0	2	38	8	48
Conflicting	—				4
Total	13	177	112	81	387

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap DNAJC6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →