Is DNAJB6 p.Ala22= (c.66A>G) pathogenic?

DNAJB6 p.Ala22= (c.66A>G) is classified Conflicting classifications of pathogenicity in DNAJB6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.0132%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNAJB6 p.Ala22= (c.66A>G)?

DNAJB6 p.Ala22= (c.66A>G) is associated with Inborn genetic diseases, autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (ClinVar).

How common is DNAJB6 p.Ala22= (c.66A>G) in the general population?

DNAJB6 p.Ala22= (c.66A>G) is ultra-rare (popmax 0.0132%, nfe) (gnomAD).

DNAJB6 p.Ala22=

c.66A>G · rs140662370 · VCV943547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP -3.4, phastCons 0.01
Overall
CADD	2.338	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% European (non-Finnish) · 154/1,167,886 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.0103% 164/1,596,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0132%	7,584
Remaining individualsnot grpmax-eligible	0.0129%	7,743
Admixed American	0.00341%	29,297

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: DNAJB6
Protein: p.Ala22=
Coding: c.66A>G
MANE Select: NM_058246
dbSNP: rs140662370
Type: single nucleotide variant
Location: chr7:157363161 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.04 · 4 PDB
Residue 22: an α-helix; the j domain; the 'interaction with hsp70' region

Full DNAJB6 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

Also linked: autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)

Similar variants

DNAJB6 p.Ala22Val Uncertain significance ★★ ⚠ same residue
DNAJB6 p.Ala22Thr Uncertain significance ★ ⚠ same residue
DNAJB6 p.Phe89Ile Pathogenic ★★ same condition
DNAJB6 p.Phe91Leu Pathogenic ★★ same condition
DNAJB6 p.Phe91Val Pathogenic/Likely pathogenic ★★ same condition
DNAJB6 p.Pro96Arg Pathogenic ★★ same condition
DNAJB6 c.66-2A>G Uncertain significance ★★ same condition
DNAJB6 c.-7G>A 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/dnajb6-p-ala22 (accessed [today's date]).

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