# NM_032317.3(DNAJC30):c.233C>G (p.Pro78Arg)

https://sugi.bio/variant/dnajc30-p-pro78arg

## Summary

**DNAJC30 p.Pro78Arg (c.233C>G)** is classified **Uncertain significance** in DNAJC30 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely pathogenic (0.8478); Very rare (popmax 0.0011%, sas); Associated with Leber-like hereditary optic neuropathy, autosomal recessive 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs782695672 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the DNAJC30 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Leber-like hereditary optic neuropathy, autosomal recessive 1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026960/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAJC30](https://sugi.bio/atlas/gene/DNAJC30/) |
| Protein change (HGVS p.) | p.Pro78Arg |
| Coding change (HGVS c.) | c.233C>G |
| MANE Select transcript | [NM_032317](https://www.ncbi.nlm.nih.gov/nuccore/NM_032317) |
| dbSNP | [rs782695672](https://www.ncbi.nlm.nih.gov/snp/rs782695672/) |
| Variant type | single nucleotide variant |
| Location | chr7:73683191-73683191 (GRCh38) |
| ClinVar | [VCV3251975](https://www.ncbi.nlm.nih.gov/clinvar/variation/3251975/) |

**All HGVS expressions:** `NC_000007.13:g.73097521G>C`, `NC_000007.14:g.73683191G>C`, `NG_178049.1:g.87G>C`, `NM_032317.3:c.233C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8478)
- REVEL 0.929 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.524 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.715, GERP 7.18, phastCons 1 — highly conserved (agrees)
- 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.*
- Regional missense constraint: **o/e 1.10** across the covering region of the MANE Select transcript (73,682,746–73,683,423), spanning 677 bp. Chi-square p 0.083. 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, Δ0.20 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 **0.0011%** (sas) · 1/91,090 in the highest group · 1/1,461,808 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**DNAJC30** population constraint: LOEUF 1.484, pLI 5.877e-07, missense-Z -0.20128. *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):

- **Leber-like hereditary optic neuropathy, autosomal recessive 1** — Definitive (AR)

## Protein context {#protein}

Residue **78** lies in a turn; the j domain; a UniProt-annotated variant site (in lhonar1; results in reduced turnover of n-module subunits of the respiratory chain complex i and reduced complex i activity in homozygous patient-derived cells).

AlphaFold model confidence (whole protein): pLDDT 71.87, 28% of residues very-high.

**1 experimental structure(s)** (PDB): [2YUA](https://www.rcsb.org/structure/2YUA).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-10 |

## Associated conditions {#conditions}

[Leber-like hereditary optic neuropathy, autosomal recessive 1](https://sugi.bio/atlas/disease/leber-like-hereditary-optic-neuropathy-autosomal-recessive-1/).

**Reported phenotype names (ClinVar):** Leber-like hereditary optic neuropathy, autosomal recessive 1, MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 38.

## Same-residue context {#hotspot}

Residue **78** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DNAJC30 p.Pro78Ser](/variant/dnajc30-p-pro78ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DNAJC30 variant pages (same residue, condition, or type): [DNAJC30 p.Pro78Ser](/variant/dnajc30-p-pro78ser), [DNAJC30 p.Tyr51Cys](/variant/dnajc30-p-tyr51cys), [DNAJC30 c.*122C>T](/variant/dnajc30-c-star-122c-t), [DNAJC30 p.Glu204Ter](/variant/dnajc30-p-glu204ter), [DNAJC30 p.Leu101Gln](/variant/dnajc30-p-leu101gln), [DNAJC30 p.His77del](/variant/dnajc30-p-his77del), [DNAJC30 p.Ser44fs](/variant/dnajc30-p-ser44fs), [DNAJC30 p.Gly34Arg](/variant/dnajc30-p-gly34arg).

### 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 3251975). 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.*