Is COX10 p.Pro246= (c.738G>A) pathogenic?

COX10 p.Pro246= (c.738G>A) is classified Conflicting classifications of pathogenicity in COX10 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0313%, afr); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Pro246= (c.738G>A)?

COX10 p.Pro246= (c.738G>A) is associated with mitochondrial complex IV deficiency, nuclear type 3 (ClinVar).

How common is COX10 p.Pro246= (c.738G>A) in the general population?

COX10 p.Pro246= (c.738G>A) is ultra-rare (popmax 0.0313%, afr) (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.

COX10 p.Pro246=

c.738G>A · rs587780910 · VCV136996

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0313%, afr)

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.82	acceptor gain · deltas
Pangolin	Δ0.49	gain · loss 0.31 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -7.7	GERP -3
Overall
CADD	15.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0313% African / African-American · 21/67,040 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.0083% 124/1,493,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0428%	2,335
African / African-Americangrpmax	0.0313%	3,192
Admixed American	0.00925%	10,812
South Asian	0.00823%	12,144
Ashkenazi Jewishnot grpmax-eligible	0.00754%	13,260
European (non-Finnish)	0.00574%	17,423
East Asian	0.00468%	21,376

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro246=
Coding: c.738G>A
MANE Select: NM_001303
dbSNP: rs587780910
Type: single nucleotide variant
Location: chr17:14192031 (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.Pro246Leu 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-pro246 (accessed [today's date]).

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