# NM_001098.3(ACO2):c.1239dup (p.Phe414fs)

https://sugi.bio/variant/aco2-p-phe414fs

## Summary

**ACO2 p.Phe414fs (c.1239dup)** is classified **Pathogenic** in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2518229756 · 1 submitter · 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.

*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 | [ACO2](https://sugi.bio/atlas/gene/ACO2/) |
| Protein change (HGVS p.) | p.Phe414fs |
| Coding change (HGVS c.) | c.1239dup |
| MANE Select transcript | [NM_001098](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098) |
| dbSNP | [rs2518229756](https://www.ncbi.nlm.nih.gov/snp/rs2518229756/) |
| Variant type | Duplication |
| Location | chr22:41522929-41522930 (GRCh38) |
| ClinVar | [VCV2075825](https://www.ncbi.nlm.nih.gov/clinvar/variation/2075825/) |

**All HGVS expressions:** `NC_000022.10:g.41918934dup`, `NC_000022.11:g.41522930dup`, `NG_032143.1:g.58806dup`, `NM_001098.3:c.1239dup`

## 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 5.227, GERP 0.797, 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 10 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 duplication 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 2022-08-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-31 |

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

## Same-residue context {#hotspot}

Residue **414** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ACO2 p.Phe414Val](/variant/aco2-p-phe414val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACO2 variant pages (same residue, condition, or type): [ACO2 p.Phe414Val](/variant/aco2-p-phe414val), [ACO2 p.Ile275fs](/variant/aco2-p-ile275fs), [ACO2 p.Leu381fs](/variant/aco2-p-leu381fs), [ACO2 c.1370+11dup](/variant/aco2-c-1370-plus-11dup), [ACO2 p.Arg633fs](/variant/aco2-p-arg633fs), [ACO2 p.Asn612fs](/variant/aco2-p-asn612fs), [ACO2 p.Asp273fs](/variant/aco2-p-asp273fs), [ACO2 p.Gln566fs](/variant/aco2-p-gln566fs).

### 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 2026-07-14); 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 2075825). 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.*