Is COX6A2 p.Cys43Arg (c.127T>C) pathogenic?

COX6A2 p.Cys43Arg (c.127T>C) is classified Conflicting classifications of pathogenicity in COX6A2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.9722); Ultra-rare (popmax 0.0288%, eas); Associated with mitochondrial complex IV deficiency, nuclear type 18.

What condition is associated with COX6A2 p.Cys43Arg (c.127T>C)?

COX6A2 p.Cys43Arg (c.127T>C) is associated with mitochondrial complex IV deficiency, nuclear type 18 (ClinVar).

How common is COX6A2 p.Cys43Arg (c.127T>C) in the general population?

COX6A2 p.Cys43Arg (c.127T>C) is ultra-rare (popmax 0.0288%, eas) (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 COX6A2 p.Cys43Arg (c.127T>C)?

AlphaMissense predicts likely pathogenic (score 0.9722) — an in-silico prediction, not a clinical call.

COX6A2 p.Cys43Arg

c.127T>C · rs1275864234 · VCV638272

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9722 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0288%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial complex IV deficiency, nuclear type 18

Computational evidence

Protein change
AlphaMissense	0.9722	likely pathogenic · top 2% in COX6A2
REVEL	0.634	indeterminate
SaProt	LLR -15.91	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 11	GERP 0.42, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 548 bp · p 0.002 · regional, not allelic
Overall
CADD	28.4	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

Grpmax group 0.0288% East Asian · 12/41,664 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.00288% 45/1,562,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0288%	3,472
European (non-Finnish)	0.00286%	34,995

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: COX6A2
Protein: p.Cys43Arg
Coding: c.127T>C
MANE Select: NM_005205
dbSNP: rs1275864234
Type: single nucleotide variant
Location: chr16:31428098 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30
Residue 43: a UniProt-annotated variant site (in mc4dn18; reduced complex iv assembly; decreased cox6a2 protein stability)

Full COX6A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 18 — 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

COX6A2 p.Ser39Arg Likely pathogenic ★ ⚠ same condition
COX6A2 p.Leu81Val Uncertain significance ★★ ⚠ same type
COX6A2 p.Ala2Thr Uncertain significance ★ ⚠ same type
COX6A2 p.Arg54Leu Uncertain significance ★ ⚠ same type
COX6A2 p.Arg60Cys Uncertain significance ★ ⚠ same type
COX6A2 p.Arg66Gly Uncertain significance ★ ⚠ same type
COX6A2 p.Arg68His Uncertain significance ★ ⚠ same type
COX6A2 p.Asn46Ile 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/cox6a2-p-cys43arg (accessed [today's date]).

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