Is COX10 p.Pro181= (c.543G>A) pathogenic?

COX10 p.Pro181= (c.543G>A) is classified Conflicting classifications of pathogenicity in COX10 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-21). Rare (popmax 0.203%, sas); Associated with Leigh syndrome.

What condition is associated with COX10 p.Pro181= (c.543G>A)?

COX10 p.Pro181= (c.543G>A) is associated with Leigh syndrome, mitochondrial complex IV deficiency, nuclear type 1 (ClinVar).

How common is COX10 p.Pro181= (c.543G>A) in the general population?

COX10 p.Pro181= (c.543G>A) is rare (popmax 0.203%, sas) (gnomAD).

How is Leigh syndrome inherited?

Typically Autosomal recessive, Mitochondrial inheritance (Orphanet). A genetic counselor can assess individual risk for a family.

COX10 p.Pro181=

c.543G>A · rs371273328 · VCV321814

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.203%, sas)

Conditions

Leigh syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -3.1
Overall
CADD	2.582	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.203% South Asian · 185/91,074 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.0206% 333/1,613,650 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.203%	492
Remaining individualsnot grpmax-eligible	0.032%	3,124
European (non-Finnish)	0.01%	9,998
East Asian	0.00669%	14,952
African / African-American	0.00533%	18,746
Finnishnot grpmax-eligible	0.00312%	32,007
Admixed American	0.00167%	59,984

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.Pro181=
Coding: c.543G>A
MANE Select: NM_001303
dbSNP: rs371273328
Type: single nucleotide variant
Location: chr17:14102161 (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

Leigh syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial complex IV deficiency, nuclear type 1

For Leigh syndrome (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance, X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

COX10 p.Pro181Leu Uncertain significance ★★ ⚠ same residue
COX10 p.Pro181Ser Uncertain significance ★ ⚠ same residue
COX10 p.Asp336Val Pathogenic/Likely pathogenic ★★ same condition
COX10 c.-89G>C Uncertain significance ★★ same condition
COX10 c.-89G>T Uncertain significance ★★ same condition
COX10 p.Ala390Val Uncertain significance ★★ ⚠ same condition
COX10 p.Arg354Gln Uncertain significance ★★ ⚠ same condition
COX10 p.Arg355His 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-pro181 (accessed [today's date]).

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