Is DNAJB2 p.Pro209Ser (c.625C>T) pathogenic?

DNAJB2 p.Pro209Ser (c.625C>T) is classified Uncertain significance in DNAJB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-24). AlphaMissense: likely benign (0.1219); Very rare (popmax 0.000259%, nfe); Associated with neuronopathy, distal hereditary motor, autosomal recessive 5.

What condition is associated with DNAJB2 p.Pro209Ser (c.625C>T)?

DNAJB2 p.Pro209Ser (c.625C>T) is associated with neuronopathy, distal hereditary motor, autosomal recessive 5 (ClinVar).

How common is DNAJB2 p.Pro209Ser (c.625C>T) in the general population?

DNAJB2 p.Pro209Ser (c.625C>T) is very rare (popmax 0.000259%, 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.

What do computational predictors say about DNAJB2 p.Pro209Ser (c.625C>T)?

AlphaMissense predicts likely benign (score 0.1219) — an in-silico prediction, not a clinical call.

DNAJB2 p.Pro209Ser

c.625C>T · rs769946182 · VCV1423377

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronopathy, distal hereditary motor, autosomal recessive 5

Computational evidence

Protein change
AlphaMissense	0.1219	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,150 bp · p 0.0024 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000259% European (non-Finnish) · 3/1,160,490 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00021% 3/1,431,428 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.Pro209Ser
Coding: c.625C>T
MANE Select: NM_006736
dbSNP: rs769946182
Type: single nucleotide variant
Location: chr2:219284637 (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

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 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-pro209ser (accessed [today's date]).

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