# NM_001098.3(ACO2):c.1966_1969del (p.Arg656fs)

https://sugi.bio/variant/aco2-p-arg656fs

## Summary

**ACO2 p.Arg656fs (c.1966_1969del)** is classified **Pathogenic** in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). No gnomAD frequency available for this variant; Associated with infantile cerebellar-retinal degeneration.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1601936467 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ACO2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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 |
| Diagnostic panels | ACO2 is a diagnostic-grade gene on 14 Genomics England panels |

**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.Arg656fs |
| Coding change (HGVS c.) | c.1966_1969del |
| MANE Select transcript | [NM_001098](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098) |
| dbSNP | [rs1601936467](https://www.ncbi.nlm.nih.gov/snp/rs1601936467/) |
| Variant type | Deletion |
| Location | chr22:41527300-41527303 (GRCh38) |
| ClinVar | [VCV803706](https://www.ncbi.nlm.nih.gov/clinvar/variation/803706/) |

**All HGVS expressions:** `NC_000022.10:g.41923304_41923307del`, `NC_000022.11:g.41527300_41527303del`, `NG_032143.1:g.63176_63179del`, `NM_001018050.4:c.*1980_*1983del`, `NM_001018052.4:c.*1980_*1983del`, `NM_001098.3:c.1966_1969del`, `NM_001282884.2:c.*1980_*1983del`, `NM_001282885.2:c.*1980_*1983del`, `NM_138338.5:c.*1980_*1983del`

## 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 3.278, GERP 0.471, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.489, pLI 0.98113), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 18**, so the transcript is predicted to undergo NMD.
- 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}

**ACO2** population constraint: LOEUF 0.489, pLI 0.98113, missense-Z 4.3358. *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 9** — Definitive (SD)
- **mitochondrial disease** — Strong (AD)
- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 95.44, 95% of residues very-high.

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

*Describes the biological roles of ACO2 (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:** ACO2's established molecular role includes iron ion binding.


### Pathways affected {#pathways}

ACO2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | other |
| [Maturation of TCA enzymes and regulation of TCA cycle](https://reactome.org/content/detail/R-HSA-9854311) | other |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | other |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | other |

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

**Molecular function:** iron ion binding.

**Biological process:** tricarboxylic acid cycle, citrate metabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-05-28 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ACO2 variant pages (same residue, condition, or type): [ACO2 p.Cys592_Asp595delinsTer](/variant/aco2-p-cys592-asp595delinster), [ACO2 p.Lys776fs](/variant/aco2-p-lys776fs), [ACO2 p.Arg656Ser](/variant/aco2-p-arg656ser), [ACO2 p.Arg656Thr](/variant/aco2-p-arg656thr), [ACO2 p.Arg656=](/variant/aco2-p-arg656), [ACO2 p.Glu464Ter](/variant/aco2-p-glu464ter), [ACO2 p.Ala647Gly](/variant/aco2-p-ala647gly), [ACO2 p.Ala768Thr](/variant/aco2-p-ala768thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 803706). 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.*