Is DNAJB2 p.Arg165Cys (c.493C>T) pathogenic?

DNAJB2 p.Arg165Cys (c.493C>T) is classified Uncertain significance in DNAJB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-20). AlphaMissense: likely benign (0.2885); Rare (popmax 0.135%, sas); Associated with Charcot-Marie-Tooth disease.

What condition is associated with DNAJB2 p.Arg165Cys (c.493C>T)?

DNAJB2 p.Arg165Cys (c.493C>T) is associated with Charcot-Marie-Tooth disease, neuronopathy, distal hereditary motor, autosomal recessive 5 (ClinVar).

How common is DNAJB2 p.Arg165Cys (c.493C>T) in the general population?

DNAJB2 p.Arg165Cys (c.493C>T) is rare (popmax 0.135%, sas) (gnomAD).

What do computational predictors say about DNAJB2 p.Arg165Cys (c.493C>T)?

AlphaMissense predicts likely benign (score 0.2885) — an in-silico prediction, not a clinical call.

DNAJB2 p.Arg165Cys

c.493C>T · rs544935330 · VCV573941

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2885 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.2885	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -12.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,150 bp · p 0.0024 · regional, not allelic
Overall
CADD	28.1	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 0.135% South Asian · 123/91,084 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.108%

Overall 0.0083% 134/1,614,228 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.135%	741
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,627
East Asian	0.00446%	22,443
European (non-Finnish)	0.000339%	295,015

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.Arg165Cys
Coding: c.493C>T
MANE Select: NM_006736
dbSNP: rs544935330
Type: single nucleotide variant
Location: chr2:219283180 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.73 · 1 PDB

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

Disease context

Charcot-Marie-Tooth disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronopathy, distal hereditary motor, autosomal recessive 5

Similar variants

DNAJB2 p.Arg165His Uncertain significance ★ ⚠ 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.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-arg165cys (accessed [today's date]).

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