# NM_005205.4(COX6A2):c.255C>T (p.Ser85=)

https://sugi.bio/variant/cox6a2-p-ser85

## Summary

**COX6A2 p.Ser85= (c.255C>T)** is classified **Likely benign** in COX6A2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-01). Very rare (popmax 0.00176%, sas); Associated with COX6A2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs2544834763 · 1 submitter · 1 linked condition · very rare (popmax 0.00176%, sas)

## For patients & families {#patients}

This is a change in the COX6A2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to COX6A2-related disorder.

*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 | [COX6A2](https://sugi.bio/atlas/gene/COX6A2/) |
| Protein change (HGVS p.) | p.Ser85= |
| Coding change (HGVS c.) | c.255C>T |
| MANE Select transcript | [NM_005205](https://www.ncbi.nlm.nih.gov/nuccore/NM_005205) |
| dbSNP | [rs2544834763](https://www.ncbi.nlm.nih.gov/snp/rs2544834763/) |
| Variant type | single nucleotide variant |
| Location | chr16:31427813-31427813 (GRCh38) |
| ClinVar | [VCV3045482](https://www.ncbi.nlm.nih.gov/clinvar/variation/3045482/) |

**All HGVS expressions:** `NC_000016.10:g.31427813G>A`, `NC_000016.9:g.31439134G>A`, `NG_050624.1:g.39573G>A`, `NG_050624.2:g.39480G>A`, `NM_005205.4:c.255C>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 -0.126, GERP -5.46, phastCons 0.084 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.872**. 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 (G>C, Δ0.36 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 **0.00176%** (sas) · 1/56,972 in the highest group · 1/1,415,084 alleles overall — very rare (popmax 0.00176%, 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}

**COX6A2** population constraint: LOEUF 1.913, pLI 0.00027357, missense-Z -2.7303. *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):

- **mitochondrial disease** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.30, 72% of residues very-high.

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

*Describes the biological roles of COX6A2 (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.*


### Pathways affected {#pathways}

COX6A2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex IV assembly](https://reactome.org/content/detail/R-HSA-9864848) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | curated |
| [Respiratory electron transport](https://reactome.org/content/detail/R-HSA-611105) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-11-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-11-01 |

## Associated conditions {#conditions}

[COX6A2-related disorder](https://sugi.bio/atlas/disease/cox6a2-related-disorder/).

**Reported phenotype names (ClinVar):** COX6A2-related disorder, COX6A2-related condition.

## Similar variants {#similar}

Related COX6A2 variant pages (same residue, condition, or type): [COX6A2 p.Ser85Asn](/variant/cox6a2-p-ser85asn), [COX6A2 p.Leu81Val](/variant/cox6a2-p-leu81val), [COX6A2 p.Ser39Arg](/variant/cox6a2-p-ser39arg), [COX6A2 p.Ala2Thr](/variant/cox6a2-p-ala2thr), [COX6A2 p.Arg54Leu](/variant/cox6a2-p-arg54leu), [COX6A2 p.Arg60Cys](/variant/cox6a2-p-arg60cys), [COX6A2 p.Arg66Gly](/variant/cox6a2-p-arg66gly), [COX6A2 p.Arg68His](/variant/cox6a2-p-arg68his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3045482). 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.*