Is DNAJB4 p.Arg25Gln (c.74G>A) pathogenic?

DNAJB4 p.Arg25Gln (c.74G>A) is classified Pathogenic in DNAJB4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-16). AlphaMissense: likely pathogenic (0.9805); Very rare (popmax 0.000339%, nfe); Associated with congenital myopathy 21 with early respiratory failure.

What condition is associated with DNAJB4 p.Arg25Gln (c.74G>A)?

DNAJB4 p.Arg25Gln (c.74G>A) is associated with congenital myopathy 21 with early respiratory failure (ClinVar).

How common is DNAJB4 p.Arg25Gln (c.74G>A) in the general population?

DNAJB4 p.Arg25Gln (c.74G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DNAJB4 p.Arg25Gln (c.74G>A)?

AlphaMissense predicts likely pathogenic (score 0.9805) — an in-silico prediction, not a clinical call.

DNAJB4 p.Arg25Gln

c.74G>A · rs1660297324 · VCV2499484

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myopathy 21 with early respiratory failure

Computational evidence

Protein change
AlphaMissense	0.9805	likely pathogenic ✓ concordant with ClinVar
REVEL	0.489	indeterminate
SaProt	LLR -13.20	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 11 kb · p 7.2e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,984 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,832 alleles · very rare

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: DNAJB4
Protein: p.Arg25Gln
Coding: c.74G>A
MANE Select: NM_007034
dbSNP: rs1660297324
Type: single nucleotide variant
Location: chr1:78005184 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.68 (gnomAD)
Structure: AlphaFold pLDDT 83.43
Residue 25: the j domain; a UniProt-annotated variant site (in cmyo21; loss of function in chaperone-mediated protein folding; in cells subjected to heat shock, it results in increased protein aggregation and cell death compared to the wild type; unable to complement growth defects in a yeast complementation assay; does not affect subcellular location at the z line)

Full DNAJB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myopathy 21 with early respiratory failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAJB4 p.Arg25Ter Likely benign same residue
DNAJB4 p.Arg61Gly Pathogenic same condition
DNAJB4 p.Leu262Ser Pathogenic same condition
DNAJB4 p.Lys286Ter Pathogenic same condition
DNAJB4 p.Ala76Pro Uncertain significance ★ ⚠ same type
DNAJB4 p.Arg146Ser Uncertain significance ★ ⚠ same type
DNAJB4 p.Arg153His Uncertain significance ★ ⚠ same type
DNAJB4 p.Arg178Gln Uncertain significance ★ ⚠ same type

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/dnajb4-p-arg25gln (accessed [today's date]).

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