# NM_006736.6(DNAJB2):c.454T>C (p.Ser152Pro)

https://sugi.bio/variant/dnajb2-p-ser152pro

## Summary

**DNAJB2 p.Ser152Pro (c.454T>C)** is classified **Uncertain significance** in DNAJB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-11-05). AlphaMissense: likely benign (0.2182); Very rare (popmax 0.000339%, nfe); Associated with neuronopathy, distal hereditary motor, autosomal recessive 5.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1951921760 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000339%, nfe)

## 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 2 submitters, and is linked to neuronopathy, distal hereditary motor, autosomal recessive 5.

*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 recessive |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | DNAJB2 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017421/index) · [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.Ser152Pro |
| Coding change (HGVS c.) | c.454T>C |
| MANE Select transcript | [NM_006736](https://www.ncbi.nlm.nih.gov/nuccore/NM_006736) |
| dbSNP | [rs1951921760](https://www.ncbi.nlm.nih.gov/snp/rs1951921760/) |
| Variant type | single nucleotide variant |
| Location | chr2:219283141-219283141 (GRCh38) |
| ClinVar | [VCV948188](https://www.ncbi.nlm.nih.gov/clinvar/variation/948188/) |

**All HGVS expressions:** `NC_000002.11:g.220147863T>C`, `NC_000002.12:g.219283141T>C`, `NG_029553.1:g.8824T>C`, `NM_001039550.2:c.454T>C`, `NM_006736.6:c.454T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2182)
- REVEL 0.18 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.963 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 4.301, GERP 2.21, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.27 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.20. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,180,036 in the highest group · 4/1,614,258 alleles overall — very rare (popmax 0.000339%, nfe).

*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 2020-11-05.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2020); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-12-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-11-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Neuronopathy, distal hereditary motor, autosomal recessive 5, Inborn genetic diseases, NEUROPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 5, Spinal muscular atrophy, distal, autosomal recessive, 5, Young adult-onset distal hereditary motor neuropathy.

## Similar variants {#similar}

Related DNAJB2 variant pages (same residue, condition, or type): [DNAJB2 p.Ser152Cys](/variant/dnajb2-p-ser152cys), [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), [DNAJB2 p.Arg182Cys](/variant/dnajb2-p-arg182cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 948188). 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.*