# NM_145261.4(DNAJC19):c.202G>A (p.Gly68Ser)

https://sugi.bio/variant/dnajc19-p-gly68ser

## Summary

**DNAJC19 p.Gly68Ser (c.202G>A)** is classified **Uncertain significance** in DNAJC19 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-31). AlphaMissense: likely pathogenic (0.7808); Ultra-rare (popmax 0.045%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs754317673 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.045%, amr)

## 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 3 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.Gly68Ser |
| Coding change (HGVS c.) | c.202G>A |
| MANE Select transcript | [NM_145261](https://www.ncbi.nlm.nih.gov/nuccore/NM_145261) |
| dbSNP | [rs754317673](https://www.ncbi.nlm.nih.gov/snp/rs754317673/) |
| Variant type | single nucleotide variant |
| Location | chr3:180986950-180986950 (GRCh38) |
| ClinVar | [VCV1474649](https://www.ncbi.nlm.nih.gov/clinvar/variation/1474649/) |

**All HGVS expressions:** `LRG_743:g.7825G>A`, `LRG_743t1:c.202G>A`, `NC_000003.11:g.180704738C>T`, `NC_000003.12:g.180986950C>T`, `NG_022933.1:g.7825G>A`, `NM_001190233.2:c.127G>A`, `NM_145261.3:c.202G>A`, `NM_145261.4:c.202G>A`, `NR_033721.2:n.284G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7808)
- REVEL 0.195 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -12.665 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.722, GERP 1.96, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.1**. 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 (C>G, Δ0.29 donor 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.*
- Population frequency (gnomAD v4.1): grpmax **0.045%** (amr) · FAF95 0.0317% · FAF99 0.0273% · 27/60,004 in the highest group · 35/1,613,122 alleles overall — ultra-rare (popmax 0.045%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.045% | 2,222 |
| South Asian | 0.00769% | 13,010 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,440 |

*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 **68** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-31.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-01 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-31 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-22 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [3-methylglutaconic aciduria type 5](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-type-5/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, 3-methylglutaconic aciduria type 5, MGA, TYPE V, 3 alpha methylglutaconic aciduria type V, MGA 5, CARDIOMYOPATHY, DILATED, WITH ATAXIA.

## Similar variants {#similar}

Related DNAJC19 variant pages (same residue, condition, or type): [DNAJC19 p.Gly68Asp](/variant/dnajc19-p-gly68asp), [DNAJC19 p.Gly68Val](/variant/dnajc19-p-gly68val), [DNAJC19 c.130-1G>C](/variant/dnajc19-c-130-minus-1g-c), [DNAJC19 c.4-1G>A](/variant/dnajc19-c-4-minus-1g-a), [DNAJC19 c.55+1G>A](/variant/dnajc19-c-55-plus-1g-a), [DNAJC19 p.Ala25Thr](/variant/dnajc19-p-ala25thr), [DNAJC19 p.Ala73Thr](/variant/dnajc19-p-ala73thr), [DNAJC19 p.Arg20Cys](/variant/dnajc19-p-arg20cys).

### 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 1474649). 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.*