Is DNAJB2 p.Asp33Glu (c.99C>G) pathogenic?

DNAJB2 p.Asp33Glu (c.99C>G) is classified Uncertain significance in DNAJB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely pathogenic (0.9964); Very rare (popmax 0.00134%, afr); Associated with neuronopathy, distal hereditary motor, autosomal recessive 5.

What condition is associated with DNAJB2 p.Asp33Glu (c.99C>G)?

DNAJB2 p.Asp33Glu (c.99C>G) is associated with neuronopathy, distal hereditary motor, autosomal recessive 5 (ClinVar).

How common is DNAJB2 p.Asp33Glu (c.99C>G) in the general population?

DNAJB2 p.Asp33Glu (c.99C>G) is very rare (popmax 0.00134%, afr) (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.

What do computational predictors say about DNAJB2 p.Asp33Glu (c.99C>G)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

DNAJB2 p.Asp33Glu

c.99C>G · rs1352880084 · VCV2445616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronopathy, distal hereditary motor, autosomal recessive 5

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic · top 3% in DNAJB2
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -11.58	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 4	GERP 0.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,150 bp · p 0.0024 · regional, not allelic
Overall
CADD	25.7	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 0.00134% African / African-American · 1/74,898 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,898
European (non-Finnish)	0.000169%	590,005

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.Asp33Glu
Coding: c.99C>G
MANE Select: NM_006736
dbSNP: rs1352880084
Type: single nucleotide variant
Location: chr2:219280611 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.73 · 1 PDB
Residue 33: the j domain; a turn

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

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

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

DNAJB2 p.Asp33= Likely benign ★ same residue
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

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-asp33glu (accessed [today's date]).

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