Is COX20 p.Pro108fs (c.319_322dup) pathogenic?

COX20 p.Pro108fs (c.319322dup) is classified Uncertain significance in COX20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). Very rare (popmax 0.00412%, afr); Associated with mitochondrial complex IV deficiency, nuclear type 11.

What condition is associated with COX20 p.Pro108fs (c.319_322dup)?

COX20 p.Pro108fs (c.319_322dup) is associated with mitochondrial complex IV deficiency, nuclear type 11 (ClinVar).

How common is COX20 p.Pro108fs (c.319_322dup) in the general population?

COX20 p.Pro108fs (c.319_322dup) is very rare (popmax 0.00412%, afr) (gnomAD).

How is Isolated cytochrome C oxidase deficiency inherited?

Typically Autosomal recessive, Mitochondrial inheritance (Orphanet). A genetic counselor can assess individual risk for a family.

COX20 p.Pro108fs

c.319_322dup · VCV3583047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00412%, afr)

Conditions

mitochondrial complex IV deficiency, nuclear type 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00412% African / African-American · 3/72,748 alleles

Filtering AF 0.0011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000504%

Overall 0.000188% 3/1,594,922 alleles · very rare exomes 2/1,442,798 · genomes 1/152,124 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COX20
Protein: p.Pro108fs
Coding: c.319_322dup
MANE Select: NM_198076
Type: Duplication
Location: chr1:244843135 (GRCh38)
Gene constraint: LOEUF 1.927 · pLI 0.06 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.42

Full COX20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

COX20 p.Pro108Leu Uncertain significance ★ ⚠ same residue
COX20 p.Pro108Ser Uncertain significance ★ ⚠ same residue
COX20 c.157+3G>C Pathogenic/Likely pathogenic ★★ same condition
COX20 p.Lys14Arg Pathogenic ★★ ⚠ same condition
COX20 p.Tyr36Ter Likely pathogenic ★★ same condition
COX20 p.Ala3Thr Uncertain significance ★★ ⚠ same condition
COX20 p.Arg31Trp Uncertain significance ★★ ⚠ same condition
COX20 p.Asp107Asn Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cox20-p-pro108fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown