# NM_198076.6(COX20):c.19C>T (p.Pro7Ser)

https://sugi.bio/variant/cox20-p-pro7ser

## Summary

**COX20 p.Pro7Ser (c.19C>T)** is classified **Uncertain significance** in COX20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-28). AlphaMissense: likely benign (0.1002); Very rare (popmax 0.00139%, nfe); Associated with mitochondrial complex IV deficiency, nuclear type 11.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00139%, nfe)

## For patients & families {#patients}

This is a change in the COX20 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to mitochondrial complex IV deficiency, nuclear type 11.

*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 | COX20 is a diagnostic-grade gene on 15 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016409/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COX20](https://sugi.bio/atlas/gene/COX20/) |
| Protein change (HGVS p.) | p.Pro7Ser |
| Coding change (HGVS c.) | c.19C>T |
| MANE Select transcript | [NM_198076](https://www.ncbi.nlm.nih.gov/nuccore/NM_198076) |
| Variant type | single nucleotide variant |
| Location | chr1:244835733-244835733 (GRCh38) |
| ClinVar | [VCV3582935](https://www.ncbi.nlm.nih.gov/clinvar/variation/3582935/) |

**All HGVS expressions:** `NC_000001.10:g.244999035C>T`, `NC_000001.11:g.244835733C>T`, `NG_042825.1:g.5428C>T`, `NG_165936.1:g.202C>T`, `NG_165937.1:g.112C>T`, `NM_001312871.1:c.19C>T`, `NM_001312872.1:c.19C>T`, `NM_001312873.1:c.19C>T`, `NM_001312874.1:c.19C>T`, `NM_198076.6:c.19C>T`, `NR_132419.1:n.258C>T`, `NR_132420.1:n.258C>T`, `NR_132421.1:n.258C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1002)
- REVEL 0.03 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.44 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.257, GERP 0.693 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.81**. 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 1.05** across the covering region of the MANE Select transcript (244,835,715–244,843,173), spanning 7,458 bp. Chi-square p 0.56. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.20 donor loss), 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 **0.00139%** (nfe) · FAF95 0.000808% · FAF99 0.000632% · 14/1,005,790 in the highest group · 15/1,272,516 alleles overall — very rare (popmax 0.00139%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00279% | 35,868 |
| European (non-Finnish) (grpmax) | 0.00139% | 71,842 |

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}

**COX20** population constraint: LOEUF 1.927, pLI 0.056908, missense-Z -1.449; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 66.42, 0% of residues very-high.

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

*Describes the biological roles of COX20 (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}

COX20 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex IV assembly](https://reactome.org/content/detail/R-HSA-9864848) | curated |

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

**Biological process:** mitochondrial respiratory chain complex IV assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-28 |

## Associated conditions {#conditions}

[mitochondrial complex IV deficiency, nuclear type 11](https://sugi.bio/atlas/disease/mitochondrial-complex-iv-deficiency-nuclear-type-11/).

**Reported phenotype names (ClinVar):** Mitochondrial complex IV deficiency, nuclear type 11, Mitochondrial complex 4 deficiency, nuclear type 11.

## Similar variants {#similar}

Related COX20 variant pages (same residue, condition, or type): [COX20 p.Pro7=](/variant/cox20-p-pro7), [COX20 c.157+3G>C](/variant/cox20-c-157-plus-3g-c), [COX20 p.Lys14Arg](/variant/cox20-p-lys14arg), [COX20 p.Tyr36Ter](/variant/cox20-p-tyr36ter), [COX20 p.Ala3Thr](/variant/cox20-p-ala3thr), [COX20 p.Arg31Trp](/variant/cox20-p-arg31trp), [COX20 p.Asp107Asn](/variant/cox20-p-asp107asn), [COX20 p.Asp107His](/variant/cox20-p-asp107his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3582935). 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.*