Is COX10 p.Arg354Gln (c.1061G>A) pathogenic?

COX10 p.Arg354Gln (c.1061G>A) is classified Uncertain significance in COX10 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.1756); Very rare (popmax 0.00988%, sas); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Arg354Gln (c.1061G>A)?

COX10 p.Arg354Gln (c.1061G>A) is associated with mitochondrial complex IV deficiency, nuclear type 3, Leigh syndrome, mitochondrial complex IV deficiency, nuclear type 1 (ClinVar).

How common is COX10 p.Arg354Gln (c.1061G>A) in the general population?

COX10 p.Arg354Gln (c.1061G>A) is very rare (popmax 0.00988%, sas) (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 COX10 p.Arg354Gln (c.1061G>A)?

AlphaMissense predicts likely benign (score 0.1756) — an in-silico prediction, not a clinical call.

COX10 p.Arg354Gln

c.1061G>A · rs745492359 · VCV444401

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.1756	likely benign
REVEL	0.704	pathogenic-leaning
SaProt	LLR -12.41	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.68, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 372 bp · p 0.13 · regional, not allelic
Overall
CADD	26.5	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 0.00988% South Asian · 9/91,060 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00614% 99/1,613,534 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,118
European (non-Finnish)	0.00729%	13,719
Remaining individualsnot grpmax-eligible	0.0048%	20,823
East Asian	0.00223%	44,862

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: COX10
Protein: p.Arg354Gln
Coding: c.1061G>A
MANE Select: NM_001303
dbSNP: rs745492359
Type: single nucleotide variant
Location: chr17:14206942 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.11

Full COX10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leigh syndrome mitochondrial complex IV deficiency, nuclear type 1

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

COX10 p.Arg354Trp Uncertain significance ★ ⚠ same residue
COX10 p.Asp336Val Pathogenic/Likely pathogenic ★★ same condition
COX10 p.Gln230Ter Likely pathogenic ★★ same condition
COX10 p.Pro225Leu Likely pathogenic ★★ same condition
COX10 c.-89G>C Uncertain significance ★★ same condition
COX10 c.-89G>T Uncertain significance ★★ same condition
COX10 p.Ala174Thr Uncertain significance ★★ ⚠ same condition
COX10 p.Ala175Val 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/cox10-p-arg354gln (accessed [today's date]).

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