Is DNAJB5 p.Ser222Arg (c.666T>G) pathogenic?

DNAJB5 p.Ser222Arg (c.666T>G) is classified Uncertain significance in DNAJB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.6341); Very rare (popmax 0.0011%, sas).

How common is DNAJB5 p.Ser222Arg (c.666T>G) in the general population?

DNAJB5 p.Ser222Arg (c.666T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DNAJB5 p.Ser222Arg (c.666T>G)?

AlphaMissense predicts likely pathogenic (score 0.6341) — an in-silico prediction, not a clinical call.

DNAJB5 p.Ser222Arg

c.666T>G · VCV4013533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6341	likely pathogenic
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -3.7
Regional constraint	o/e 0.56	unconstrained · MANE · 3,966 bp · p 2.3e-20 · regional, not allelic
Overall
CADD	0.364	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S150R vs ClinVar S222R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,058 alleles

Overall 0.000205% 3/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
South Asiangrpmax	0.0011%	91,058
European (non-Finnish)	8.47e-05%	1,179,997

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DNAJB5
Protein: p.Ser222Arg
Coding: c.666T>G
MANE Select: NM_001349723
Type: single nucleotide variant
Location: chr9:34996503 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 80.69

Full DNAJB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJB5 p.Arg277His Uncertain significance ★★ ⚠ same type
DNAJB5 p.Glu141= Uncertain significance ★★ same type
DNAJB5 p.Thr406Pro Uncertain significance ★★ ⚠ same type
DNAJB5 c.40G>A Uncertain significance ★ same type
DNAJB5 c.50T>C Uncertain significance ★ same type
DNAJB5 c.55G>C Uncertain significance ★ same type
DNAJB5 c.58C>T Uncertain significance ★ same type
DNAJB5 c.-133+6G>A 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/dnajb5-p-ser222arg (accessed [today's date]).

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