Is COX6A2 p.Ser39Arg (c.117C>A) pathogenic?

COX6A2 p.Ser39Arg (c.117C>A) is classified Likely pathogenic in COX6A2 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-12-04). AlphaMissense: likely pathogenic (0.9902); Very rare (popmax 0.00239%, eas); Associated with mitochondrial complex IV deficiency, nuclear type 18.

What condition is associated with COX6A2 p.Ser39Arg (c.117C>A)?

COX6A2 p.Ser39Arg (c.117C>A) is associated with mitochondrial complex IV deficiency, nuclear type 18 (ClinVar).

How common is COX6A2 p.Ser39Arg (c.117C>A) in the general population?

COX6A2 p.Ser39Arg (c.117C>A) is very rare (popmax 0.00239%, 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.Ser39Arg (c.117C>A)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

COX6A2 p.Ser39Arg

c.117C>A · rs1597176845 · VCV638271

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00239%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 18

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic ✓ concordant with ClinVar · top 1% in COX6A2
REVEL	0.168	moderately benign-leaning
SaProt	LLR -13.56	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.4	GERP -5.2
Regional constraint	o/e 1.26	unconstrained · MANE · 548 bp · p 0.002 · regional, not allelic
Overall
CADD	20.8	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 0.00239% East Asian · 1/41,880 alleles

Overall 6.38e-05% 1/1,566,724 alleles · very rare exomes 1/1,414,612 · genomes 0/152,112 · 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: COX6A2
Protein: p.Ser39Arg
Coding: c.117C>A
MANE Select: NM_005205
dbSNP: rs1597176845
Type: single nucleotide variant
Location: chr16:31428108 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30
Residue 39: 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.Cys43Arg Conflicting classifications of pathogenicity ★ ⚠ 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-ser39arg (accessed [today's date]).

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