# NM_145261.4(DNAJC19):c.300del (p.Ala101fs)

https://sugi.bio/variant/dnajc19-p-ala101fs

## Summary

**DNAJC19 p.Ala101fs (c.300del)** is classified **Likely pathogenic** in DNAJC19 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-03). Very rare (popmax 0.00017%, nfe); Associated with DNAJC19-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs587777224 · 2 submitters · 2 linked conditions · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the DNAJC19 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to DNAJC19-related disorder.

*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 | [DNAJC19](https://sugi.bio/atlas/gene/DNAJC19/) |
| Protein change (HGVS p.) | p.Ala101fs |
| Coding change (HGVS c.) | c.300del |
| MANE Select transcript | [NM_145261](https://www.ncbi.nlm.nih.gov/nuccore/NM_145261) |
| dbSNP | [rs587777224](https://www.ncbi.nlm.nih.gov/snp/rs587777224/) |
| Variant type | Deletion |
| Location | chr3:180984691-180984691 (GRCh38) |
| ClinVar | [VCV120181](https://www.ncbi.nlm.nih.gov/clinvar/variation/120181/) |

**All HGVS expressions:** `LRG_743:g.10084del`, `LRG_743t1:c.300del`, `NC_000003.11:g.180702479del`, `NC_000003.12:g.180984691del`, `NG_022933.1:g.10084del`, `NM_001190233.2:c.225del`, `NM_145261.4:c.300del`, `NR_033721.2:n.382del`, `NR_033722.2:n.354del`, `NR_033723.1:n.417del`, `NR_046073.1:n.266del`

## Computational & population evidence {#evidence}

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

- **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 7.675, GERP 1.96, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.547, pLI 7.1195e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 33.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,176,050 in the highest group · 55/1,608,072 alleles overall — very rare (popmax 0.00017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0815% | 1,227 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,230 |
| European (non-Finnish) (grpmax) | 0.00017% | 588,024 |

Finnish 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}

**DNAJC19** population constraint: LOEUF 1.547, pLI 7.1195e-05, missense-Z 1.0653. *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):

- **3-methylglutaconic aciduria type 5** — Definitive (AR)

## Protein context {#protein}

Residue **101** lies in the j domain.

AlphaFold model confidence (whole protein): pLDDT 87.50, 56% of residues very-high.

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

*Describes the biological roles of DNAJC19 (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.*


### Pathways affected {#pathways}

DNAJC19 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Biological process:** visual perception, genitalia development.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-03.

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

**Submission history:** 2 submissions (2012–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-10-01 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-03 |

## Associated conditions {#conditions}

[DNAJC19-related disorder](https://sugi.bio/atlas/disease/dnajc19-related-disorder/), [3-methylglutaconic aciduria type 5](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-type-5/).

**Reported phenotype names (ClinVar):** DNAJC19-related disorder, 3-methylglutaconic aciduria type 5, DNAJC19-related condition, MGA, TYPE V, CARDIOMYOPATHY, DILATED, WITH ATAXIA, 3 alpha methylglutaconic aciduria type V, MGA 5.

## Similar variants {#similar}

Related DNAJC19 variant pages (same residue, condition, or type): [DNAJC19 c.280+1_280+5del](/variant/dnajc19-c-280-plus-1-280-plus-5del), [DNAJC19 p.Arg20_Tyr21insTer](/variant/dnajc19-p-arg20-tyr21inster), [DNAJC19 c.4-24_15del](/variant/dnajc19-c-4-minus-24-15del), [DNAJC19 p.Leu10fs](/variant/dnajc19-p-leu10fs), [DNAJC19 p.Leu87_Leu88insTer](/variant/dnajc19-p-leu87-leu88inster), [DNAJC19 p.Lys34fs](/variant/dnajc19-p-lys34fs), [DNAJC19 p.Phe17fs](/variant/dnajc19-p-phe17fs), [DNAJC19 p.Pro41fs](/variant/dnajc19-p-pro41fs).

### 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 120181). 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.*