# NM_001098.3(ACO2):c.717C>T (p.Ser239=)

https://sugi.bio/variant/aco2-p-ser239

## Summary

**ACO2 p.Ser239= (c.717C>T)** is classified **Likely benign** in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-16). Very rare (popmax 0.00445%, eas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs138803847 · 2 submitters · very rare (popmax 0.00445%, eas)

## For patients & families {#patients}

This is a change in the ACO2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Ser239= |
| Coding change (HGVS c.) | c.717C>T |
| MANE Select transcript | [NM_001098](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098) |
| dbSNP | [rs138803847](https://www.ncbi.nlm.nih.gov/snp/rs138803847/) |
| Variant type | single nucleotide variant |
| Location | chr22:41515799-41515799 (GRCh38) |
| ClinVar | [VCV2874542](https://www.ncbi.nlm.nih.gov/clinvar/variation/2874542/) |

**All HGVS expressions:** `NC_000022.10:g.41911803C>T`, `NC_000022.11:g.41515799C>T`, `NG_032143.1:g.51675C>T`, `NM_001098.3:c.717C>T`

## 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 -13.403, GERP -3.39 — fast-evolving / accelerated position
- CADD: **PHRED 3.386**. 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>A, Δ0.45 acceptor 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 (gnomAD v4.1): grpmax **0.00445%** (eas) · FAF95 0.000763% · FAF99 0.000605% · 2/44,898 in the highest group · 21/1,613,938 alleles overall — very rare (popmax 0.00445%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00445% | 22,449 |
| African / African-American | 0.00267% | 37,457 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,480 |
| European (non-Finnish) | 0.00127% | 78,670 |
| South Asian | 0.0011% | 91,082 |

*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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-16.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-16 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-19 |

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

## Same-residue context {#hotspot}

Residue **239** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ACO2 p.Ser239fs](/variant/aco2-p-ser239fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ACO2 variant pages (same residue, condition, or type): [ACO2 p.Ser239fs](/variant/aco2-p-ser239fs), [ACO2 p.Arg378Ter](/variant/aco2-p-arg378ter), [ACO2 p.Arg58Ter](/variant/aco2-p-arg58ter), [ACO2 p.Arg84Ter](/variant/aco2-p-arg84ter), [ACO2 p.Glu464Ter](/variant/aco2-p-glu464ter), [ACO2 p.Gly503Ter](/variant/aco2-p-gly503ter), [ACO2 c.1605+5G>C](/variant/aco2-c-1605-plus-5g-c), [ACO2 c.2208+5G>C](/variant/aco2-c-2208-plus-5g-c).

### 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 2874542). 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.*