# NM_058246.4(DNAJB6):c.780G>A (p.Pro260=)

https://sugi.bio/variant/dnajb6-p-pro260

## Summary

**DNAJB6 p.Pro260= (c.780G>A)** is classified **Likely benign** in DNAJB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). Very rare (popmax 0.00227%, nfe); Associated with autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00227%, nfe)

## For patients & families {#patients}

This is a change in the DNAJB6 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6).

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DNAJB6 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of DNAJB6-related limb-girdle muscular dystrophy D1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Generalized muscle weakness — Very frequent (99-80%)
- Dysarthria — Frequent (79-30%)
- Dysphagia — Frequent (79-30%)
- Difficulty climbing stairs — Frequent (79-30%)
- Increased variability in muscle fiber diameter — Frequent (79-30%)
- Loss of ambulation — Occasional (29-5%)
- Myofibrillar myopathy — Occasional (29-5%)
- Rimmed vacuoles — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012528/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAJB6](https://sugi.bio/atlas/gene/DNAJB6/) |
| Protein change (HGVS p.) | p.Pro260= |
| Coding change (HGVS c.) | c.780G>A |
| MANE Select transcript | [NM_058246](https://www.ncbi.nlm.nih.gov/nuccore/NM_058246) |
| Variant type | single nucleotide variant |
| Location | chr7:157409883-157409883 (GRCh38) |
| ClinVar | [VCV4781211](https://www.ncbi.nlm.nih.gov/clinvar/variation/4781211/) |

**All HGVS expressions:** `NC_000007.13:g.157202577G>A`, `NC_000007.14:g.157409883G>A`, `NG_032573.1:g.77868G>A`, `NG_113046.1:g.597G>A`, `NM_001363676.1:c.435G>A`, `NM_058246.4:c.780G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.961, GERP -2.56, phastCons 0.457 — weakly conserved position
- CADD: **PHRED 8.08**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00227%** (nfe) · FAF95 0.00158% · FAF99 0.00134% · 26/1,145,700 in the highest group · 28/1,533,694 alleles overall — very rare (popmax 0.00227%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00335% | 29,856 |
| European (non-Finnish) (grpmax) | 0.00227% | 44,065 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DNAJB6** population constraint: LOEUF 0.92, pLI 0.00077061, missense-Z 0.090043; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **muscular dystrophy, limb-girdle, autosomal dominant** — Definitive (AD)

## Protein context {#protein}

Residue **260** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.04, 10% of residues very-high.

**4 experimental structure(s)** (PDB): [6U3R](https://www.rcsb.org/structure/6U3R), [6U3S](https://www.rcsb.org/structure/6U3S), [7JSQ](https://www.rcsb.org/structure/7JSQ), [7QBY](https://www.rcsb.org/structure/7QBY) — incl. mutant structure 6U3R.

## What this gene does {#gene-function}

*Describes the biological roles of DNAJB6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DNAJB6's established molecular role includes ATPase activator activity. p.Pro260= falls in the disordered region.


### Pathways affected {#pathways}

DNAJB6 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ATPase activator activity, heat shock protein binding, identical protein binding, obsolete unfolded protein binding, protein-folding chaperone binding.

**Biological process:** protein folding, regulation of protein localization, intermediate filament organization, nervous system process, negative regulation of inclusion body assembly.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-05.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-05 |

## Associated conditions {#conditions}

[autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)](https://sugi.bio/atlas/disease/autosomal-dominant-limb-girdle-muscular-dystrophy-type-1d-dnajb6/).

**Reported phenotype names (ClinVar):** Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6), MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1D, Autosomal dominant limb-girdle muscular dystrophy type 1D, Muscular dystrophy, limb-girdle, autosomal dominant 1, MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT, WITH RIMMED VACUOLES.

## Similar variants {#similar}

Related DNAJB6 variant pages (same residue, condition, or type): [DNAJB6 p.Pro260Leu](/variant/dnajb6-p-pro260leu), [DNAJB6 p.Phe89Ile](/variant/dnajb6-p-phe89ile), [DNAJB6 p.Phe91Leu](/variant/dnajb6-p-phe91leu), [DNAJB6 p.Phe91Val](/variant/dnajb6-p-phe91val), [DNAJB6 p.Pro96Arg](/variant/dnajb6-p-pro96arg), [DNAJB6 c.66-2A>G](/variant/dnajb6-c-66-minus-2a-g), [DNAJB6 c.-7G>A](/variant/dnajb6-c-minus-7g-a), [DNAJB6 p.Ala22Val](/variant/dnajb6-p-ala22val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4781211). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*