Is COX5A p.Ile89Ser (c.266T>G) pathogenic?

COX5A p.Ile89Ser (c.266T>G) is classified Pathogenic in COX5A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.7816); Absent from gnomAD v4.1; Associated with mitochondrial complex IV deficiency, nuclear type 20.

What condition is associated with COX5A p.Ile89Ser (c.266T>G)?

COX5A p.Ile89Ser (c.266T>G) is associated with mitochondrial complex IV deficiency, nuclear type 20 (ClinVar).

How common is COX5A p.Ile89Ser (c.266T>G) in the general population?

COX5A p.Ile89Ser (c.266T>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 COX5A p.Ile89Ser (c.266T>G)?

AlphaMissense predicts likely pathogenic (score 0.7816) — an in-silico prediction, not a clinical call.

COX5A p.Ile89Ser

c.266T>G · rs142618460 · VCV3028911

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7816 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 20

Computational evidence

Protein change
AlphaMissense	0.7816	likely pathogenic ✓ concordant with ClinVar
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -12.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.01 · regional, not allelic
Overall
CADD	29.4	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: COX5A
Protein: p.Ile89Ser
Coding: c.266T>G
MANE Select: NM_004255
dbSNP: rs142618460
Type: single nucleotide variant
Location: chr15:74926839 (GRCh38)
Gene constraint: LOEUF 0.82 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 3 PDB

Full COX5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 20 — 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

COX5A p.Arg55Cys Uncertain significance ★ ⚠ same condition
COX5A p.Arg107Cys Pathogenic same condition
COX5A p.Ser25Cys Likely benign ★★ same type
COX5A p.Ala13Thr Uncertain significance ★ ⚠ same type
COX5A p.Ala32Asp Uncertain significance ★ ⚠ same type
COX5A p.Ala32Thr Uncertain significance ★ ⚠ same type
COX5A p.Ala54Gly Uncertain significance ★ ⚠ same type
COX5A p.Arg107Ser Uncertain significance ★ ⚠ same type

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/cox5a-p-ile89ser (accessed [today's date]).

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