Is COX20 p.Cys73Trp (c.219C>G) pathogenic?

COX20 p.Cys73Trp (c.219C>G) is classified Uncertain significance in COX20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: ambiguous (0.4714); Absent from gnomAD v4.1; Associated with mitochondrial complex IV deficiency, nuclear type 11.

What condition is associated with COX20 p.Cys73Trp (c.219C>G)?

COX20 p.Cys73Trp (c.219C>G) is associated with mitochondrial complex IV deficiency, nuclear type 11 (ClinVar).

How common is COX20 p.Cys73Trp (c.219C>G) in the general population?

COX20 p.Cys73Trp (c.219C>G) is absent from gnomAD v4.1 (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.

What do computational predictors say about COX20 p.Cys73Trp (c.219C>G)?

AlphaMissense predicts ambiguous (score 0.4714) — an in-silico prediction, not a clinical call.

COX20 p.Cys73Trp

c.219C>G · VCV3583038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4714 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mitochondrial complex IV deficiency, nuclear type 11

Computational evidence

Protein change
AlphaMissense	0.4714	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -4.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.23	donor loss · deltas
Pangolin	Δ0.35	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.37	GERP 0.98, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 7,458 bp · p 0.56 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COX20
Protein: p.Cys73Trp
Coding: c.219C>G
MANE Select: NM_198076
Type: single nucleotide variant
Location: chr1:244842256 (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 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
COX20 p.Asp107His Uncertain significance ★★ same condition
COX20 p.Cys59Arg 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-cys73trp (accessed [today's date]).

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