# NM_001098.3(ACO2):c.2127C>T (p.Phe709=)

https://sugi.bio/variant/aco2-p-phe709

## Summary

**ACO2 p.Phe709= (c.2127C>T)** is classified **Benign/Likely benign** in ACO2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0303%, nfe).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs182234596 · 4 submitters · ultra-rare (popmax 0.0303%, nfe)

## For patients & families {#patients}

This is a change in the ACO2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 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.Phe709= |
| Coding change (HGVS c.) | c.2127C>T |
| MANE Select transcript | [NM_001018050](https://www.ncbi.nlm.nih.gov/nuccore/NM_001018050) (variant reported on NM_001098) |
| dbSNP | [rs182234596](https://www.ncbi.nlm.nih.gov/snp/rs182234596/) |
| Variant type | single nucleotide variant |
| Location | chr22:41527941-41527941 (GRCh38) |
| ClinVar | [VCV379298](https://www.ncbi.nlm.nih.gov/clinvar/variation/379298/) |

**All HGVS expressions:** `NC_000022.10:g.41923945C>T`, `NC_000022.11:g.41527941C>T`, `NG_032143.1:g.63817C>T`, `NM_001018050.4:c.*1342G>A`, `NM_001018052.4:c.*1342G>A`, `NM_001098.3:c.2127C>T`, `NM_001282884.2:c.*1342G>A`, `NM_001282885.2:c.*1342G>A`, `NM_138338.5:c.*1342G>A`

## 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 -11.717, GERP -3.67 — fast-evolving / accelerated position
- CADD: **PHRED 3.488**. 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: **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 **0.0303%** (nfe) · FAF95 0.0277% · FAF99 0.0267% · 358/1,180,030 in the highest group · 549/1,614,198 alleles overall — ultra-rare (popmax 0.0303%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.222% | 451 |
| European (non-Finnish) (grpmax) | 0.0303% | 3,296 |
| Remaining individuals (not grpmax-eligible) | 0.024% | 4,167 |
| African / African-American | 0.0227% | 4,415 |
| Admixed American | 0.0217% | 4,617 |
| Middle Eastern | 0.0165% | 6,062 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,602 |
| South Asian | 0.0022% | 45,545 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-03-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-17 |

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

### 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 379298). 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.*