DNAJC5

Chr 20AD

DnaJ heat shock protein family (Hsp40) member C5

Also known as: CLN4, CLN4B, CSP, DNAJC5A, mir-941-2, mir-941-3, mir-941-4, mir-941-5

NCBI Gene: 80331 ENSG00000101152 UniProt: Q9H3Z4 OMIM: 611203

The encoded protein regulates 70 kDa heat shock protein ATPase activity and functions in membrane trafficking and protein folding. Mutations cause autosomal dominant neuronal ceroid lipofuscinosis type 4 (Kufs disease), an adult-onset neurodegenerative disorder characterized by progressive dementia and movement abnormalities. The pathogenic mechanism involves gain-of-function mutations that disrupt normal cellular protein homeostasis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the J protein family. J proteins function in many cellular processes by regulating the ATPase activity of 70 kDa heat shock proteins. The encoded protein plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties. The encoded protein is known to play a role in cystic fibrosis and Huntington's disease. A pseudogene of this gene is located on the short arm of chromosome 8. [provided by RefSeq, Nov 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.481 OMIM phenotype

Clinical Summary— DNAJC5

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Gene-Disease Validity (ClinGen)

adult neuronal ceroid lipofuscinosis · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 182 VUS of 419 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DNAJC5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.812

Z-score 2.62

OE 0.10 (0.04–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.79Z-score

OE missense 0.54 (0.44–0.67)

66 obs / 121.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.48)

0≤0.351.4

Missense OE?0.54 (0.44–0.67)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 1 / 9.9Missense obs/exp: 66 / 121.6Syn Z: -1.12

This gene — mechanism propensity

0.5772th %ile

GOF

0.77top 25%

LOF

0.4430th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

419 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS182

Likely Benign161

Benign54

Conflicting15

Pathogenic

182

VUS

161

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	0	0	0	0
VUS	5	90	86	1	182
Likely Benign	0	2	75	84	161
Benign	0	0	52	2	54
Conflicting	—				15
Total	5	96	213	87	416

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap DNAJC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →