Is COX10 p.Pro104Leu (c.311C>T) pathogenic?

COX10 p.Pro104Leu (c.311C>T) is classified Conflicting classifications of pathogenicity in COX10 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0649); Rare (popmax 0.165%, mid); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Pro104Leu (c.311C>T)?

COX10 p.Pro104Leu (c.311C>T) 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.Pro104Leu (c.311C>T) in the general population?

COX10 p.Pro104Leu (c.311C>T) is rare (popmax 0.165%, mid) (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.Pro104Leu (c.311C>T)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

COX10 p.Pro104Leu

c.311C>T · rs202207627 · VCV449007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -6.28	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 1.7	GERP 2.2, phastCons 0.002
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.97 · regional, not allelic
Overall
CADD	17.2	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 0.165% Middle Eastern · 10/6,062 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0181% 292/1,614,098 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
East Asian	0.0668%	1,496
European (non-Finnish)	0.0193%	5,175
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.008%	12,503
South Asian	0.00659%	15,178
Admixed American	0.005%	20,006
Finnishnot grpmax-eligible	0.00156%	64,024

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.Pro104Leu
Coding: c.311C>T
MANE Select: NM_001303
dbSNP: rs202207627
Type: single nucleotide variant
Location: chr17:14076868 (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.Pro104= 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
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-pro104leu (accessed [today's date]).

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