# NM_001098.3(ACO2):c.1239G>T (p.Gln413His)

https://sugi.bio/variant/aco2-p-gln413his

## Summary

**ACO2 p.Gln413His (c.1239G>T)** is classified **Uncertain significance** in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.1677); Very rare (popmax 0.0011%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the ACO2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Gln413His |
| Coding change (HGVS c.) | c.1239G>T |
| MANE Select transcript | [NM_001098](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098) |
| Variant type | single nucleotide variant |
| Location | chr22:41522930-41522930 (GRCh38) |
| ClinVar | [VCV4743170](https://www.ncbi.nlm.nih.gov/clinvar/variation/4743170/) |

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

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1677)
- REVEL 0.297 (indeterminate)
- SaProt LLR -12.694 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.44) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.564, GERP 1.85, phastCons 1 — weakly conserved position
- CADD: **PHRED 23.2**. 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.*
- Regional missense constraint: **o/e 0.70** across the covering region of the MANE Select transcript (41,515,784–41,525,297), spanning 9,513 bp. Chi-square p 5.1e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.44**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.44**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,090 in the highest group · 1/1,461,866 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-17.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-17 |

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

## Similar variants {#similar}

Related ACO2 variant pages (same residue, condition, or type): [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), [ACO2 c.2208+5G>T](/variant/aco2-c-2208-plus-5g-t).

### 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 4743170). 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.*