Is DNAJC3 p.Ser146fs (c.435dup) pathogenic?

DNAJC3 p.Ser146fs (c.435dup) is classified Pathogenic in DNAJC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). Very rare (popmax 0.000346%, nfe); Associated with juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome.

How common is DNAJC3 p.Ser146fs (c.435dup) in the general population?

DNAJC3 p.Ser146fs (c.435dup) is very rare (popmax 0.000346%, nfe) (gnomAD).

DNAJC3 p.Ser146fs

Q: What condition is associated with DNAJC3 p.Ser146fs (c.435dup)?

DNAJC3 p.Ser146fs (c.435dup) is associated with juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (ClinVar).

Q: How is Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.435dup · VCV3768963

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000346%, nfe)

Conditions

juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.5	phastCons 0.77

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000346% European (non-Finnish) · 4/1,154,516 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.00035% 5/1,428,990 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00164%	60,798
European (non-Finnish)grpmax	0.000346%	288,629

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DNAJC3
Protein: p.Ser146fs
Coding: c.435dup
MANE Select: NM_006260
Type: Duplication
Location: chr13:95757684 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.78 · 2 PDB
Residue 146: an α-helix

Full DNAJC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

DNAJC3 p.Arg393Ter Pathogenic/Likely pathogenic ★★ same condition
DNAJC3 p.Glu436fs Likely pathogenic ★ same condition
DNAJC3 p.Lys456fs Likely pathogenic ★ same condition
DNAJC3 c.729-1G>A Uncertain significance ★ same condition
DNAJC3 p.Arg415Ter Conflicting classifications of pathogenicity ★ same condition
DNAJC3 c.393+2T>C Pathogenic same condition
DNAJC3 c.393+2T>G Pathogenic same condition
DNAJC3 p.Arg346Ter Pathogenic same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dnajc3-p-ser146fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown