Is DNAJC19 p.Leu109Ser (c.326T>C) pathogenic?

DNAJC19 p.Leu109Ser (c.326T>C) is classified Uncertain significance in DNAJC19 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-17). AlphaMissense: likely pathogenic (0.7665); Very rare (popmax 0.00331%, sas); Associated with 3-methylglutaconic aciduria type 5.

What condition is associated with DNAJC19 p.Leu109Ser (c.326T>C)?

DNAJC19 p.Leu109Ser (c.326T>C) is associated with 3-methylglutaconic aciduria type 5 (ClinVar).

How common is DNAJC19 p.Leu109Ser (c.326T>C) in the general population?

DNAJC19 p.Leu109Ser (c.326T>C) is very rare (popmax 0.00331%, sas) (gnomAD).

How is Dilated cardiomyopathy with ataxia inherited?

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

What do computational predictors say about DNAJC19 p.Leu109Ser (c.326T>C)?

AlphaMissense predicts likely pathogenic (score 0.7665) — an in-silico prediction, not a clinical call.

DNAJC19 p.Leu109Ser

c.326T>C · rs200732155 · VCV1502917

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

3-methylglutaconic aciduria type 5

Computational evidence

Protein change
AlphaMissense	0.7665	likely pathogenic
REVEL	0.341	indeterminate
SaProt	LLR -12.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 4,959 bp · p 0.0025 · regional, not allelic
Overall
CADD	27.5	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% South Asian · 3/90,586 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000343% 5/1,456,200 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,195
European (non-Finnish)	0.00017%	588,159

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: DNAJC19
Protein: p.Leu109Ser
Coding: c.326T>C
MANE Select: NM_145261
dbSNP: rs200732155
Type: single nucleotide variant
Location: chr3:180984665 (GRCh38)
Gene constraint: LOEUF 1.547 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.50
Residue 109: the j domain

Full DNAJC19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-methylglutaconic aciduria type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dilated cardiomyopathy with ataxia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DNAJC19 p.Leu109Val Uncertain significance ★ ⚠ same residue
DNAJC19 c.130-1G>C Pathogenic ★★ same condition
DNAJC19 c.4-1G>A Likely pathogenic ★★ same condition
DNAJC19 c.55+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNAJC19 p.Ala25Thr Uncertain significance ★★ ⚠ same condition
DNAJC19 p.Ala73Thr Uncertain significance ★★ same condition
DNAJC19 p.Arg84Gln Uncertain significance ★★ ⚠ same condition
DNAJC19 p.Gly68Asp 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/dnajc19-p-leu109ser (accessed [today's date]).

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