Is DNAJC6 p.Val353Met (c.1057G>A) pathogenic?

DNAJC6 p.Val353Met (c.1057G>A) is classified Uncertain significance in DNAJC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.6964); Very rare (popmax 0.00415%, nfe); Associated with juvenile onset Parkinson disease 19A.

What condition is associated with DNAJC6 p.Val353Met (c.1057G>A)?

DNAJC6 p.Val353Met (c.1057G>A) is associated with juvenile onset Parkinson disease 19A (ClinVar).

How common is DNAJC6 p.Val353Met (c.1057G>A) in the general population?

DNAJC6 p.Val353Met (c.1057G>A) is very rare (popmax 0.00415%, nfe) (gnomAD).

How is Atypical juvenile parkinsonism inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DNAJC6 p.Val353Met (c.1057G>A)?

AlphaMissense predicts likely pathogenic (score 0.6964) — an in-silico prediction, not a clinical call.

DNAJC6 p.Val353Met

c.1057G>A · VCV4741390

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile onset Parkinson disease 19A

Computational evidence

Protein change
AlphaMissense	0.6964	likely pathogenic
REVEL	0.764	pathogenic-leaning
SaProt	LLR -12.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 103 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V296M vs ClinVar V353M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00415% European (non-Finnish) · 49/1,180,010 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00483% 78/1,614,156 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0375%	2,668
European (non-Finnish)grpmax	0.00415%	24,082
Remaining individualsnot grpmax-eligible	0.0032%	31,254
South Asian	0.0022%	45,541
African / African-American	0.00133%	75,050

Finnish 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: DNAJC6
Protein: p.Val353Met
Coding: c.1057G>A
MANE Select: NM_001256864
Type: single nucleotide variant
Location: chr1:65386873 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.29
Residue 353: the c2 tensin-type domain

Full DNAJC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

juvenile onset Parkinson disease 19A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Atypical juvenile parkinsonism (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Adolescent, Adult

Similar variants

DNAJC6 p.Arg330Ter Pathogenic ★★ same condition
DNAJC6 p.Ala226Val Uncertain significance ★★ ⚠ same condition
DNAJC6 p.Ala234Thr Uncertain significance ★★ ⚠ same condition
DNAJC6 p.Ala277Thr Uncertain significance ★★ ⚠ same condition
DNAJC6 p.Ala611Val Uncertain significance ★★ ⚠ same condition
DNAJC6 p.Ala626Val Uncertain significance ★★ ⚠ same condition
DNAJC6 p.Ala770Val Uncertain significance ★★ ⚠ same condition
DNAJC6 p.Ala836Ser Uncertain significance ★★ ⚠ 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/dnajc6-p-val353met (accessed [today's date]).

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