# NM_006736.6(DNAJB2):c.571C>T (p.Arg191Trp)

https://sugi.bio/variant/dnajb2-p-arg191trp

## Summary

**DNAJB2 p.Arg191Trp (c.571C>T)** is classified **Uncertain significance** in DNAJB2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-14). AlphaMissense: ambiguous (0.5365); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs776893562 · 5 submitters · 2 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0223%, eas)

## For patients & families {#patients}

This is a change in the DNAJB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAJB2](https://sugi.bio/atlas/gene/DNAJB2/) |
| Protein change (HGVS p.) | p.Arg191Trp |
| Coding change (HGVS c.) | c.571C>T |
| MANE Select transcript | [NM_006736](https://www.ncbi.nlm.nih.gov/nuccore/NM_006736) |
| dbSNP | [rs776893562](https://www.ncbi.nlm.nih.gov/snp/rs776893562/) |
| Variant type | single nucleotide variant |
| Location | chr2:219283441-219283441 (GRCh38) |
| ClinVar | [VCV473304](https://www.ncbi.nlm.nih.gov/clinvar/variation/473304/) |

**All HGVS expressions:** `NC_000002.11:g.220148163C>T`, `NC_000002.12:g.219283441C>T`, `NG_029553.1:g.9124C>T`, `NM_001039550.2:c.571C>T`, `NM_006736.6:c.571C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5365) — no call either way
- REVEL 0.368 (indeterminate)
- SaProt LLR -13.116 (damaging)
- Conservation: phyloP 4.84, GERP 0.002, phastCons 1 — highly conserved
- CADD: **PHRED 32.0**. 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 0.85** across the covering region of the MANE Select transcript (219,279,834–219,284,984), spanning 5,150 bp. Chi-square p 0.0024. 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 (gnomAD v4.1): grpmax **0.0223%** (eas) · FAF95 0.012% · FAF99 0.00916% · 10/44,880 in the highest group · 84/1,613,912 alleles overall — ultra-rare (popmax 0.0223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0676% | 1,480 |
| East Asian (grpmax) | 0.0223% | 4,488 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| European (non-Finnish) | 0.00424% | 23,599 |
| South Asian | 0.0011% | 91,072 |

Ashkenazi Jewish 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}

**DNAJB2** population constraint: LOEUF 0.836, pLI 0.00022079, missense-Z 1.241. *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):

- **neuronopathy, distal hereditary motor, autosomal recessive 5** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.73, 25% of residues very-high.

**1 experimental structure(s)** (PDB): [2LGW](https://www.rcsb.org/structure/2LGW).

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

*Describes the biological roles of DNAJB2 (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:** DNAJB2's established molecular role includes ATPase activator activity.


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

**Molecular function:** ATPase activator activity, Hsp70 protein binding, polyubiquitin modification-dependent protein binding, ubiquitin protein ligase binding, ubiquitin binding, obsolete unfolded protein binding.

**Biological process:** protein folding, negative regulation of cell population proliferation, negative regulation of cell growth, regulation of protein ubiquitination, positive regulation of protein ubiquitination, negative regulation of protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-14.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 6 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-06 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-02-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-14 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [neuronopathy, distal hereditary motor, autosomal recessive 5](https://sugi.bio/atlas/disease/neuronopathy-distal-hereditary-motor-autosomal-recessive-5/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Neuronopathy, distal hereditary motor, autosomal recessive 5, not provided, Uterine corpus endometrial carcinoma, Malignant lymphoma, large B-cell, diffuse, none provided, Spinal muscular atrophy, distal, autosomal recessive, 5, Young adult-onset distal hereditary motor neuropathy, NEUROPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 5.

## Similar variants {#similar}

Related DNAJB2 variant pages (same residue, condition, or type): [DNAJB2 p.Arg191Gln](/variant/dnajb2-p-arg191gln), [DNAJB2 p.Arg191Leu](/variant/dnajb2-p-arg191leu), [DNAJB2 c.175+2T>A](/variant/dnajb2-c-175-plus-2t-a), [DNAJB2 c.352+1G>A](/variant/dnajb2-c-352-plus-1g-a), [DNAJB2 c.65+1G>A](/variant/dnajb2-c-65-plus-1g-a), [DNAJB2 p.Arg104Gln](/variant/dnajb2-p-arg104gln), [DNAJB2 p.Arg165Cys](/variant/dnajb2-p-arg165cys), [DNAJB2 p.Arg178His](/variant/dnajb2-p-arg178his).

### 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 473304). 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.*