Is DNAJB2 p.Arg221His (c.662G>A) pathogenic?

DNAJB2 p.Arg221His (c.662G>A) is classified Uncertain significance in DNAJB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-23). AlphaMissense: ambiguous (0.3546); Ultra-rare (popmax 0.0181%, mid); Associated with Inborn genetic diseases.

What condition is associated with DNAJB2 p.Arg221His (c.662G>A)?

DNAJB2 p.Arg221His (c.662G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DNAJB2 p.Arg221His (c.662G>A) in the general population?

DNAJB2 p.Arg221His (c.662G>A) is ultra-rare (popmax 0.0181%, mid) (gnomAD).

What do computational predictors say about DNAJB2 p.Arg221His (c.662G>A)?

AlphaMissense predicts ambiguous (score 0.3546) — an in-silico prediction, not a clinical call.

DNAJB2 p.Arg221His

c.662G>A · rs749289057 · VCV1754566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3546 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3546	ambiguous
REVEL	0.253	benign-leaning
SaProt	LLR -12.92	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,150 bp · p 0.0024 · regional, not allelic
Overall
CADD	32.0	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 0.0181% Middle Eastern · 1/5,510 alleles

Filtering AF 0.000877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000995% 16/1,607,340 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0181%	5,510
South Asian	0.0033%	30,273
Remaining individualsnot grpmax-eligible	0.00322%	31,058
African / African-American	0.00267%	37,411
European (non-Finnish)	0.00068%	146,997

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.Arg221His
Coding: c.662G>A
MANE Select: NM_006736
dbSNP: rs749289057
Type: single nucleotide variant
Location: chr2:219284674 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.73 · 1 PDB
Residue 221: the uim 1 domain; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAJB2 p.Arg221= Likely benign ★ same residue
DNAJB2 p.Arg178His Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Arg191Trp Uncertain significance ★★ same condition
DNAJB2 p.Asp248Asn Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Asp66Asn Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Gln224Pro Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Pro225Leu Uncertain significance ★★ ⚠ same condition
DNAJB2 p.Ser152Cys 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-arg221his (accessed [today's date]).

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