Is DNAJB2 p.Ala83= (c.249A>G) pathogenic?

DNAJB2 p.Ala83= (c.249A>G) is classified Likely benign in DNAJB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-16). Very rare (popmax 0.0028%, nfe); Associated with neuronopathy, distal hereditary motor, autosomal recessive 5.

How common is DNAJB2 p.Ala83= (c.249A>G) in the general population?

DNAJB2 p.Ala83= (c.249A>G) is very rare (popmax 0.0028%, nfe) (gnomAD).

How is DNAJB2-related Charcot-Marie-Tooth disease type 2 inherited?

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

DNAJB2 p.Ala83=

Q: What condition is associated with DNAJB2 p.Ala83= (c.249A>G)?

DNAJB2 p.Ala83= (c.249A>G) is associated with neuronopathy, distal hereditary motor, autosomal recessive 5, Charcot-Marie-Tooth disease (ClinVar).

c.249A>G · rs576058376 · VCV540533

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Conditions

neuronopathy, distal hereditary motor, autosomal recessive 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -4.4
Overall
CADD	0.219	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,180,038 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00204% 33/1,614,074 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: DNAJB2
Protein: p.Ala83=
Coding: c.249A>G
MANE Select: NM_006736
dbSNP: rs576058376
Type: single nucleotide variant
Location: chr2:219281958 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.73 · 1 PDB
Residue 83: the 'disordered' region

Full DNAJB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronopathy, distal hereditary motor, autosomal recessive 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease

For DNAJB2-related Charcot-Marie-Tooth disease type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

DNAJB2 c.175+2T>A Pathogenic/Likely pathogenic ★★ same condition
DNAJB2 c.352+1G>A Pathogenic ★★ same condition
DNAJB2 c.65+1G>A Likely pathogenic ★★ same condition
DNAJB2 p.Arg104Gln Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Arg165Cys Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Arg178His Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Arg182Cys Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Arg191Gln 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/dnajb2-p-ala83 (accessed [today's date]).

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