Is COX20 p.Cys59Arg (c.175T>C) pathogenic?

COX20 p.Cys59Arg (c.175T>C) is classified Uncertain significance in COX20 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.9068); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with COX20 p.Cys59Arg (c.175T>C)?

COX20 p.Cys59Arg (c.175T>C) is associated with Inborn genetic diseases, mitochondrial complex IV deficiency, nuclear type 11 (ClinVar).

How common is COX20 p.Cys59Arg (c.175T>C) in the general population?

COX20 p.Cys59Arg (c.175T>C) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about COX20 p.Cys59Arg (c.175T>C)?

AlphaMissense predicts likely pathogenic (score 0.9068) — an in-silico prediction, not a clinical call.

COX20 p.Cys59Arg

c.175T>C · rs139895317 · VCV2421254

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9068	likely pathogenic · top 6% in COX20
REVEL	0.36	indeterminate
SaProt	LLR -11.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,458 bp · p 0.56 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,772 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00162% 26/1,607,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,398
Admixed American	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.00481%	20,770

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.Cys59Arg
Coding: c.175T>C
MANE Select: NM_198076
dbSNP: rs139895317
Type: single nucleotide variant
Location: chr1:244842212 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial complex IV deficiency, nuclear type 11

Similar variants

COX20 p.Cys59Trp 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.Arg54Gly 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-cys59arg (accessed [today's date]).

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