# NM_001349723.3(DNAJB5):c.43C>T (p.Pro15Ser)

https://sugi.bio/variant/dnajb5-p-pro15ser

## Summary

**DNAJB5 p.Pro15Ser (c.43C>T)** is classified **Conflicting classifications of pathogenicity** in DNAJB5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-12-01). Ultra-rare (popmax 0.0167%, nfe); Associated with peripheral neuropathy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs774909609 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0167%, nfe)

## For patients & families {#patients}

This is a change in the DNAJB5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to peripheral neuropathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 346 registered for this condition — see ClinicalTrials.gov |

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAJB5](https://sugi.bio/atlas/gene/DNAJB5/) |
| Protein change (HGVS p.) | p.Pro15Ser |
| Coding change (HGVS c.) | c.43C>T |
| MANE Select transcript | [NM_001349723](https://www.ncbi.nlm.nih.gov/nuccore/NM_001349723) |
| dbSNP | [rs774909609](https://www.ncbi.nlm.nih.gov/snp/rs774909609/) |
| Variant type | single nucleotide variant |
| Location | chr9:34990673-34990673 (GRCh38) |
| ClinVar | [VCV243086](https://www.ncbi.nlm.nih.gov/clinvar/variation/243086/) |

**All HGVS expressions:** `NC_000009.11:g.34990670C>T`, `NC_000009.12:g.34990673C>T`, `NG_053054.1:g.6305C>T`, `NM_001135004.3:c.-72C>T`, `NM_001135005.3:c.43C>T`, `NM_001349723.3:c.43C>T`, `NM_001349724.2:c.-35+62C>T`, `NM_001349725.2:c.-72C>T`, `NM_012266.6:c.-35+842C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.839, GERP -0.23, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 23.4**. 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 0.99** across the covering region of the MANE Select transcript (34,990,631–34,993,289), spanning 2,658 bp. Chi-square p 0.88. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0167%** (nfe) · FAF95 0.0148% · FAF99 0.014% · 192/1,147,008 in the highest group · 201/1,551,582 alleles overall — ultra-rare (popmax 0.0167%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0167% | 5,974 |
| Finnish (not grpmax-eligible) | 0.00668% | 14,978 |
| Admixed American | 0.00392% | 25,494 |
| African / African-American | 0.00274% | 36,510 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,094 |

*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}

**DNAJB5** population constraint: LOEUF 0.605, pLI 0.65152, missense-Z 3.3647. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **15** lies in the j domain.

AlphaFold model confidence (whole protein): pLDDT 80.69, 48% of residues very-high.

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

*Describes the biological roles of DNAJB5 (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:** DNAJB5's established molecular role includes protein-folding chaperone binding. p.Pro15Ser falls in the j domain.


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

**Molecular function:** protein-folding chaperone binding.

**Biological process:** response to unfolded protein.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2019-12-01.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2015–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Likely pathogenic | criteria provided, single submitter | research | 2015-08-18 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-12-01 |

## Associated conditions {#conditions}

[peripheral neuropathy](https://sugi.bio/atlas/disease/peripheral-neuropathy/), [skeletal muscle disorder](https://sugi.bio/atlas/disease/skeletal-muscle-disorder/).

**Reported phenotype names (ClinVar):** Peripheral neuropathy, Skeletal myopathy, not provided, none provided, Neuropathy, Skeletal muscle disease, Skeletal muscle disorder.

## Similar variants {#similar}

Related DNAJB5 variant pages (same residue, condition, or type): [DNAJB5 p.Arg277His](/variant/dnajb5-p-arg277his), [DNAJB5 p.Glu141=](/variant/dnajb5-p-glu141), [DNAJB5 p.Thr406Pro](/variant/dnajb5-p-thr406pro), [DNAJB5 c.40G>A](/variant/dnajb5-c-40g-a), [DNAJB5 c.50T>C](/variant/dnajb5-c-50t-c), [DNAJB5 c.55G>C](/variant/dnajb5-c-55g-c), [DNAJB5 c.58C>T](/variant/dnajb5-c-58c-t), [DNAJB5 c.-133+6G>A](/variant/dnajb5-c-minus-133-plus-6g-a).

### 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 243086). 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.*