Is COX10 p.Arg431Pro (c.1292G>C) pathogenic?

COX10 p.Arg431Pro (c.1292G>C) is classified Likely benign in COX10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-24). AlphaMissense: likely benign (0.1924); Rare (popmax 0.195%, sas); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Arg431Pro (c.1292G>C)?

COX10 p.Arg431Pro (c.1292G>C) is associated with mitochondrial complex IV deficiency, nuclear type 3 (ClinVar).

How common is COX10 p.Arg431Pro (c.1292G>C) in the general population?

COX10 p.Arg431Pro (c.1292G>C) is rare (popmax 0.195%, 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.Arg431Pro (c.1292G>C)?

AlphaMissense predicts likely benign (score 0.1924) — an in-silico prediction, not a clinical call.

COX10 p.Arg431Pro

c.1292G>C · VCV3581683

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1924 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.195%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.1924	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -2.2
Regional constraint	o/e 0.89	unconstrained · MANE · 372 bp · p 0.13 · regional, not allelic
Overall
CADD	1.17	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 0.195% South Asian · 177/90,992 alleles

Filtering AF 0.171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.0112% 181/1,608,938 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.195%	514
Middle Eastern	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.00321%	31,198
European (non-Finnish)	8.49e-05%	1,178,510

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.Arg431Pro
Coding: c.1292G>C
MANE Select: NM_001303
Type: single nucleotide variant
Location: chr17:14207173 (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

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

COX10 p.Arg431Gln Uncertain significance ★ ⚠ same residue
COX10 p.Arg431Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
COX10 p.Arg431= Likely benign ★ 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

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-arg431pro (accessed [today's date]).

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