# NM_001303.4(COX10):c.1015C>T (p.Arg339Trp)

https://sugi.bio/variant/cox10-p-arg339trp

## Summary

**COX10 p.Arg339Trp (c.1015C>T)** is classified **Conflicting classifications of pathogenicity** in COX10 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.8293); Ultra-rare (popmax 0.0165%, mid); Associated with mitochondrial complex IV deficiency, nuclear type 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1301537803 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the COX10 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to mitochondrial complex IV deficiency, nuclear type 3.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive, Mitochondrial inheritance |
| Diagnostic panels | COX10 is a diagnostic-grade gene on 14 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016404/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COX10](https://sugi.bio/atlas/gene/COX10/) |
| Protein change (HGVS p.) | p.Arg339Trp |
| Coding change (HGVS c.) | c.1015C>T |
| MANE Select transcript | [NM_001303](https://www.ncbi.nlm.nih.gov/nuccore/NM_001303) |
| dbSNP | [rs1301537803](https://www.ncbi.nlm.nih.gov/snp/rs1301537803/) |
| Variant type | single nucleotide variant |
| Location | chr17:14206896-14206896 (GRCh38) |
| ClinVar | [VCV2137929](https://www.ncbi.nlm.nih.gov/clinvar/variation/2137929/) |

**All HGVS expressions:** `NC_000017.10:g.14110213C>T`, `NC_000017.11:g.14206896C>T`, `NG_008034.1:g.142495C>T`, `NM_001303.4:c.1015C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8293)
- REVEL 0.916 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.387 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 3.901, GERP -0.56, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 0.89** across the covering region of the MANE Select transcript (14,206,838–14,207,210), spanning 372 bp. Chi-square p 0.13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000365% · FAF99 0.000137% · 1/6,060 in the highest group · 5/1,461,640 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| South Asian | 0.0022% | 45,538 |
| European (non-Finnish) | 0.000169% | 589,977 |

*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}

**COX10** population constraint: LOEUF 0.934, pLI 4.7226e-07, missense-Z 1.3958; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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** — Definitive (AR)
- **Leigh syndrome** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.11, 61% of residues very-high.

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

*Describes the biological roles of COX10 (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:** COX10's established molecular role includes geranylgeranyl diphosphate synthase activity.


### Pathways affected {#pathways}

COX10 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** geranylgeranyl diphosphate synthase activity.

**Biological process:** heme A biosynthetic process, respiratory chain complex IV assembly.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-01-08.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Johnston Lab, North Central College |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-01 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-08 |

## Associated conditions {#conditions}

[mitochondrial complex IV deficiency, nuclear type 3](https://sugi.bio/atlas/disease/mitochondrial-complex-iv-deficiency-nuclear-type-3/).

**Reported phenotype names (ClinVar):** Mitochondrial complex IV deficiency, nuclear type 3, not provided, Mitochondrial complex 4 deficiency, nuclear type 3, none provided.

## Similar variants {#similar}

Related COX10 variant pages (same residue, condition, or type): [COX10 p.Asp336Val](/variant/cox10-p-asp336val), [COX10 p.Gln230Ter](/variant/cox10-p-gln230ter), [COX10 p.Pro225Leu](/variant/cox10-p-pro225leu), [COX10 c.-89G>C](/variant/cox10-c-minus-89g-c), [COX10 c.-89G>T](/variant/cox10-c-minus-89g-t), [COX10 p.Ala174Thr](/variant/cox10-p-ala174thr), [COX10 p.Ala175Val](/variant/cox10-p-ala175val), [COX10 p.Ala261Ser](/variant/cox10-p-ala261ser).

### 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 2137929). 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.*