# NM_001098.3(ACO2):c.2338_2339del (p.Gln780fs)

https://sugi.bio/variant/aco2-p-gln780fs

## Summary

**ACO2 p.Gln780fs (c.2338_2339del)** is classified **Likely pathogenic** in ACO2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-10). Very rare (popmax 8.48e-05%, nfe); Associated with infantile cerebellar-retinal degeneration.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1114167284 · 4 submitters · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the ACO2 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to infantile cerebellar-retinal degeneration.

*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) | Infancy, Neonatal |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013264/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACO2](https://sugi.bio/atlas/gene/ACO2/) |
| Protein change (HGVS p.) | p.Gln780fs |
| Coding change (HGVS c.) | c.2338_2339del |
| MANE Select transcript | [NM_001018050](https://www.ncbi.nlm.nih.gov/nuccore/NM_001018050) (variant reported on NM_001098) |
| dbSNP | [rs1114167284](https://www.ncbi.nlm.nih.gov/snp/rs1114167284/) |
| Variant type | Deletion |
| Location | chr22:41528607-41528608 (GRCh38) |
| ClinVar | [VCV242873](https://www.ncbi.nlm.nih.gov/clinvar/variation/242873/) |

**All HGVS expressions:** `NC_000022.10:g.41924612_41924613del`, `NC_000022.11:g.41528608_41528609del`, `NG_032143.1:g.64484_64485del`, `NM_001018050.4:c.*675_*676del`, `NM_001018052.4:c.*675_*676del`, `NM_001098.2:c.2338_2339delCA`, `NM_001098.3:c.2338_2339del`, `NM_001282884.2:c.*675_*676del`, `NM_001282885.2:c.*675_*676del`, `NM_138338.5:c.*675_*676del`

## 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 11.163, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,220 in the highest group · 1/1,456,966 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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.*

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-10.

**Submitter consensus:** conflicting (2 Pathogenic, 2 Likely pathogenic).

**Submission history:** 4 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Pathogenic | no assertion criteria provided | research | 2016-01-10 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2020-09-16 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-10-08 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[infantile cerebellar-retinal degeneration](https://sugi.bio/atlas/disease/infantile-cerebellar-retinal-degeneration/).

**Reported phenotype names (ClinVar):** Infantile cerebellar-retinal degeneration.

### 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 242873). 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.*