# NM_145261.4(DNAJC19):c.58C>T (p.Arg20Cys)

https://sugi.bio/variant/dnajc19-p-arg20cys

## Summary

**DNAJC19 p.Arg20Cys (c.58C>T)** is classified **Uncertain significance** in DNAJC19 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-16). AlphaMissense: likely pathogenic (0.8603); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs750384728 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the DNAJC19 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [DNAJC19](https://sugi.bio/atlas/gene/DNAJC19/) |
| Protein change (HGVS p.) | p.Arg20Cys |
| Coding change (HGVS c.) | c.58C>T |
| MANE Select transcript | [NM_145261](https://www.ncbi.nlm.nih.gov/nuccore/NM_145261) |
| dbSNP | [rs750384728](https://www.ncbi.nlm.nih.gov/snp/rs750384728/) |
| Variant type | single nucleotide variant |
| Location | chr3:180988094-180988094 (GRCh38) |
| ClinVar | [VCV3084530](https://www.ncbi.nlm.nih.gov/clinvar/variation/3084530/) |

**All HGVS expressions:** `LRG_743:g.6681C>T`, `LRG_743t1:c.58C>T`, `NC_000003.11:g.180705882G>A`, `NC_000003.12:g.180988094G>A`, `NG_022933.1:g.6681C>T`, `NM_001190233.2:c.-18C>T`, `NM_145261.4:c.58C>T`, `NR_033721.2:n.140C>T`, `NR_033722.2:n.192C>T`, `NR_033723.1:n.230C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8603)
- REVEL 0.488 (indeterminate)
- SaProt LLR -14.081 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.894, GERP 1.96, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.7**. 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 0.75** across the covering region of the MANE Select transcript (180,984,643–180,989,602), spanning 4,959 bp. Chi-square p 0.0025. 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 (G>T, Δ0.49 acceptor gain), 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · FAF95 0.000247% · FAF99 0.000159% · 1/75,002 in the highest group · 8/1,461,886 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 75,002 |
| European (non-Finnish) | 0.000593% | 168,574 |

*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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-16.

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

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-27 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Same-residue context {#hotspot}

Residue **20** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DNAJC19 p.Arg20_Tyr21insTer](/variant/dnajc19-p-arg20-tyr21inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DNAJC19 variant pages (same residue, condition, or type): [DNAJC19 p.Arg20His](/variant/dnajc19-p-arg20his), [DNAJC19 p.Arg20_Tyr21insTer](/variant/dnajc19-p-arg20-tyr21inster), [DNAJC19 p.Ala25Thr](/variant/dnajc19-p-ala25thr), [DNAJC19 p.Arg84Gln](/variant/dnajc19-p-arg84gln), [DNAJC19 p.Gly68Ser](/variant/dnajc19-p-gly68ser), [DNAJC19 p.Ile66Met](/variant/dnajc19-p-ile66met), [DNAJC19 p.Ile99Val](/variant/dnajc19-p-ile99val), [DNAJC19 p.Val22Ile](/variant/dnajc19-p-val22ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3084530). 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.*