# NM_025136.4(OPA3):c.477G>C (p.Val159=)

https://sugi.bio/variant/opa3-p-val159

## Summary

**OPA3 p.Val159= (c.477G>C)** is classified **Likely benign** in OPA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-03). Absent from gnomAD v4.1; Associated with 3-methylglutaconic aciduria type 3.

**At a glance:** Likely benign · review: Single submitter · rsID rs1014659372 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the OPA3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to 3-methylglutaconic aciduria type 3.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | OPA3 is a diagnostic-grade gene on 23 Genomics England panels |

**Commonly reported features of 3-methylglutaconic aciduria type 3** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Visual impairment — Very frequent (99-80%)
- Choreoathetosis — Very frequent (99-80%)
- 3-Methylglutaconic aciduria — Very frequent (99-80%)
- Nystagmus — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)
- Spastic paraparesis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005663/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OPA3](https://sugi.bio/atlas/gene/OPA3/) |
| Protein change (HGVS p.) | p.Val159= |
| Coding change (HGVS c.) | c.477G>C |
| MANE Select transcript | [NM_025136](https://www.ncbi.nlm.nih.gov/nuccore/NM_025136) |
| dbSNP | [rs1014659372](https://www.ncbi.nlm.nih.gov/snp/rs1014659372/) |
| Variant type | single nucleotide variant |
| Location | chr19:45553577-45553577 (GRCh38) |
| ClinVar | [VCV2019078](https://www.ncbi.nlm.nih.gov/clinvar/variation/2019078/) |

**All HGVS expressions:** `NC_000019.10:g.45553577C>G`, `NC_000019.9:g.46056835C>G`, `NG_013332.1:g.36288G>C`, `NG_141602.1:g.657C>G`, `NG_141603.1:g.26C>G`, `NM_001017989.3:c.143-24121G>C`, `NM_025136.4:c.477G>C`

## Computational & population evidence {#evidence}

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

- **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 0.549, GERP 1.4, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 5.805**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.44 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**OPA3** population constraint: LOEUF 1.92, pLI 0.00025087, missense-Z 0.53825. *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):

- **optic atrophy 3** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.13, 24% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-03.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-02-03 |

## Associated conditions {#conditions}

[3-methylglutaconic aciduria type 3](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-type-3/), [optic atrophy 3](https://sugi.bio/atlas/disease/optic-atrophy-3/).

**Reported phenotype names (ClinVar):** 3-Methylglutaconic aciduria type 3, Optic atrophy 3, OPA3-Related 3-Methylglutaconic Aciduria, Costeff Syndrome, OPA3, AUTOSOMAL RECESSIVE, OPTIC ATROPHY 3, AUTOSOMAL RECESSIVE, Optic atrophy, cataract, and neurologic disorder, OPTIC ATROPHY 3, AUTOSOMAL DOMINANT, Optic atrophy 3 with cataract.

## Similar variants {#similar}

Related OPA3 variant pages (same residue, condition, or type): [OPA3 p.Val159Met](/variant/opa3-p-val159met), [OPA3 c.142+1G>A](/variant/opa3-c-142-plus-1g-a), [OPA3 c.143-1G>A](/variant/opa3-c-143-minus-1g-a), [OPA3 c.143-1G>C](/variant/opa3-c-143-minus-1g-c), [OPA3 p.Gln105Glu](/variant/opa3-p-gln105glu), [OPA3 p.Met1Val](/variant/opa3-p-met1val), [OPA3 c.142+4A>T](/variant/opa3-c-142-plus-4a-t), [OPA3 c.143-5C>A](/variant/opa3-c-143-minus-5c-a).

### 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 2019078). 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.*