# NM_015560.2(OPA1):c.985del

https://sugi.bio/variant/opa1-c-985del

## Summary

**OPA1 c.985del** is classified **Pathogenic** in OPA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-12). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2109039412 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the OPA1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [OPA1](https://sugi.bio/atlas/gene/OPA1/) |
| Coding change (HGVS c.) | c.985del |
| MANE Select transcript | [NM_130837](https://www.ncbi.nlm.nih.gov/nuccore/NM_130837) (variant reported on NM_015560) |
| dbSNP | [rs2109039412](https://www.ncbi.nlm.nih.gov/snp/rs2109039412/) |
| Variant type | Deletion |
| Location | chr3:193642764-193642764 (GRCh38) |
| ClinVar | [VCV995147](https://www.ncbi.nlm.nih.gov/clinvar/variation/995147/) |

**All HGVS expressions:** `LRG_337:g.54622del`, `LRG_337t1:c.985del`, `NC_000003.11:g.193360554del`, `NC_000003.12:g.193642765del`, `NG_011605.1:g.54622del`

## 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 11.259, GERP 2.19, phastCons 1 — highly conserved position (PP3-type support)
- Non-coding constraint (Gnocchi): **Z 1.31**, o/e 0.91 (1 kb window 193,642,000–193,643,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**OPA1** population constraint: LOEUF 0.503, pLI 0.92269, missense-Z 2.7012. *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):

- **Leigh syndrome** — Moderate (AR)
- **OPA1-related optic atrophy with or without extraocular features** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.02, 23% of residues very-high.

**11 experimental structure(s)** (PDB): [6JTG](https://www.rcsb.org/structure/6JTG), [8CT1](https://www.rcsb.org/structure/8CT1), [8CT9](https://www.rcsb.org/structure/8CT9), [8EEW](https://www.rcsb.org/structure/8EEW), [8EF7](https://www.rcsb.org/structure/8EF7), [8EFF](https://www.rcsb.org/structure/8EFF).

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

*Describes the biological roles of OPA1 (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:** OPA1's established molecular role includes GTPase activity.


### Pathways affected {#pathways}

OPA1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Apoptosis](https://reactome.org/content/detail/R-HSA-169911) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | electronic |

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

**Molecular function:** GTPase activity, phosphatidic acid binding, GTPase-dependent fusogenic activity, membrane bending activity, cardiolipin binding.

**Biological process:** mitochondrion organization, inner mitochondrial membrane organization, visual perception, mitochondrial fusion, cristae formation, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-02-12.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-02-12 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related OPA1 variant pages (same residue, condition, or type): [OPA1 c.1377_1377+4del](/variant/opa1-c-1377-1377-plus-4del), [OPA1 c.2012+4_2012+7del](/variant/opa1-c-2012-plus-4-2012-plus-7del), [OPA1 c.2873_2876del](/variant/opa1-c-2873-2876del), [OPA1 c.2885_2983+8del](/variant/opa1-c-2885-2983-plus-8del), [OPA1 c.2984-1_2986del](/variant/opa1-c-2984-minus-1-2986del), [OPA1 p.Asp266fs](/variant/opa1-p-asp266fs), [OPA1 p.Gln714fs](/variant/opa1-p-gln714fs), [OPA1 p.His686fs](/variant/opa1-p-his686fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 995147). 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.*