# NM_058246.4(DNAJB6):c.287C>G (p.Pro96Arg)

https://sugi.bio/variant/dnajb6-p-pro96arg

## Summary

**DNAJB6 p.Pro96Arg (c.287C>G)** is classified **Pathogenic** in DNAJB6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). AlphaMissense: likely pathogenic (0.9925); Absent from gnomAD v4.1; Associated with autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6).

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs387907047 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DNAJB6 gene that is considered disease-causing, submitted by 3 submitters, 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.Pro96Arg |
| Coding change (HGVS c.) | c.287C>G |
| MANE Select transcript | [NM_058246](https://www.ncbi.nlm.nih.gov/nuccore/NM_058246) |
| dbSNP | [rs387907047](https://www.ncbi.nlm.nih.gov/snp/rs387907047/) |
| Variant type | single nucleotide variant |
| Location | chr7:157367424-157367424 (GRCh38) |
| ClinVar | [VCV30905](https://www.ncbi.nlm.nih.gov/clinvar/variation/30905/) |

**All HGVS expressions:** `NC_000007.13:g.157160118C>G`, `NC_000007.14:g.157367424C>G`, `NG_032573.1:g.35409C>G`, `NM_001363676.1:c.287C>G`, `NM_005494.3:c.287C>G`, `NM_058246.4:c.287C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9925) — concordant with the pathogenic call
- REVEL 0.778 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -18.02 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.378, GERP 2.03, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in DNAJB6 (of 1,889 modeled).
- CADD: **PHRED 26.1**. 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.*
- Regional missense constraint: **o/e 0.19** across the covering region of the MANE Select transcript (157,367,391–157,367,453), spanning 62 bp — the region is depleted of missense variation. Chi-square p 2.7e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **96** lies in a UniProt-annotated variant site (found in a family with autosomal-dominantly inherited distal-onset myopathy; significant loss of its ability to suppress aggregation of polyglutamine-containing proteins); a UniProt-annotated variant site (in lgmdd1); an α-helix; the 'interaction with hsp70' 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.Pro96Arg falls in the interaction with hsp70 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-23.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2012–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-03-01 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-23 |

## 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), not provided, none provided, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1D, Autosomal dominant limb-girdle muscular dystrophy type 1D, MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT, WITH RIMMED VACUOLES, Muscular dystrophy, limb-girdle, autosomal dominant 1.

## Same-residue context {#hotspot}

Residue **96** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DNAJB6 p.Pro96Leu](/variant/dnajb6-p-pro96leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DNAJB6 variant pages (same residue, condition, or type): [DNAJB6 p.Pro96Leu](/variant/dnajb6-p-pro96leu), [DNAJB6 p.Phe89Ile](/variant/dnajb6-p-phe89ile), [DNAJB6 p.Phe91Leu](/variant/dnajb6-p-phe91leu), [DNAJB6 p.Phe91Val](/variant/dnajb6-p-phe91val), [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), [DNAJB6 p.Ala237Pro](/variant/dnajb6-p-ala237pro).

### 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 30905). 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.*