DNAJC3

Chr 13AR

DnaJ heat shock protein family (Hsp40) member C3

Also known as: ACPHD, ERdj6, HP58, P58, P58IPK, PRKRI, p58(IPK)

NCBI Gene: 5611 ENSG00000102580 UniProt: Q13217 OMIM: 601184

The protein regulates the unfolded protein response during endoplasmic reticulum stress and acts as a co-chaperone that stimulates HSPA8/HSC70 ATPase activity. Biallelic mutations cause autosomal recessive ataxia with combined cerebellar and peripheral involvement, hearing loss, and diabetes mellitus. The gene is not highly constrained against loss-of-function variation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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). [provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitusMIM #616192

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.52

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.017

Z-score 3.60

OE 0.30 (0.18–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.71Z-score

OE missense 0.70 (0.62–0.79)

186 obs / 264.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.18–0.52)

0≤0.351.4

Missense OE?0.70 (0.62–0.79)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 9 / 30.5Missense obs/exp: 186 / 264.4Syn Z: 0.84

Background carrier burden — how many people carry a rare variant somewhere in DNAJC3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

556 rare PASS variants

Rare truncating (LoF)

1 in 3,300

75 rare PASS variants

Rare synonymous (reference)

1 in 250

221 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DNAJC3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 3,400
South Asian	~43k	1 in 100	1 in 8,500
Remaining (unassigned)	~30k	1 in 130	1 in 4,900
European (Finnish)	~27k	1 in 910	≈ 1 in 8,900
Admixed American	~22k	1 in 110	1 in 1,700
African / African American	~21k	1 in 110	≈ 1 in 5,700
East Asian	~20k	1 in 170	1 in 1,700
Ashkenazi Jewish	~13k	1 in 900	1 in 1,400
Middle Eastern	~2,884	1 in 150	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 12 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 12.? see exons ↓