# NM_001303.4(COX10):c.738G>A (p.Pro246=)

https://sugi.bio/variant/cox10-p-pro246

## Summary

**COX10 p.Pro246= (c.738G>A)** is classified **Conflicting classifications of pathogenicity** in COX10 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0313%, afr); Associated with mitochondrial complex IV deficiency, nuclear type 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs587780910 · 5 submitters · 1 linked condition · ultra-rare (popmax 0.0313%, afr)

## 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 5 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.Pro246= |
| Coding change (HGVS c.) | c.738G>A |
| MANE Select transcript | [NM_001303](https://www.ncbi.nlm.nih.gov/nuccore/NM_001303) |
| dbSNP | [rs587780910](https://www.ncbi.nlm.nih.gov/snp/rs587780910/) |
| Variant type | single nucleotide variant |
| Location | chr17:14192031-14192031 (GRCh38) |
| ClinVar | [VCV136996](https://www.ncbi.nlm.nih.gov/clinvar/variation/136996/) |

**All HGVS expressions:** `NC_000017.10:g.14095348G>A`, `NC_000017.11:g.14192031G>A`, `NG_008034.1:g.127630G>A`, `NG_042191.1:g.21598G>A`, `NM_001303.4:c.738G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.82) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -7.7, GERP -3.05 — fast-evolving / accelerated position
- CADD: **PHRED 15.32**. 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 deltas (raw): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.82**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.82**, donor gain **0.00**.
- Pangolin: Δ**0.49** (gain), gain 0.49 / loss 0.31. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0313%** (afr) · FAF95 0.021% · FAF99 0.0176% · 21/67,040 in the highest group · 124/1,493,740 alleles overall — ultra-rare (popmax 0.0313%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0428% | 2,335 |
| African / African-American (grpmax) | 0.0313% | 3,192 |
| Admixed American | 0.00925% | 10,812 |
| South Asian | 0.00823% | 12,144 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00754% | 13,260 |
| European (non-Finnish) | 0.00574% | 17,423 |
| East Asian | 0.00468% | 21,376 |

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.*

## 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 2026-02-03.

**Submitter consensus:** conflicting (2 Benign, 1 Uncertain significance, 1 Likely benign).

**Submission history:** 5 submissions (2011–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-01 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2011-11-13 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

## 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 specified, not provided, Thyroid cancer, nonmedullary, 1, Mitochondrial complex 4 deficiency, nuclear type 3, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related COX10 variant pages (same residue, condition, or type): [COX10 p.Pro246Leu](/variant/cox10-p-pro246leu), [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).

### 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 136996). 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.*