Is COX10 p.Val366Leu (c.1096G>T) pathogenic?

COX10 p.Val366Leu (c.1096G>T) is classified Conflicting classifications of pathogenicity in COX10 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0917); Low-frequency (popmax 1.45%, afr); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Val366Leu (c.1096G>T)?

COX10 p.Val366Leu (c.1096G>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.Val366Leu (c.1096G>T) in the general population?

COX10 p.Val366Leu (c.1096G>T) is low-frequency (popmax 1.45%, 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.

What do computational predictors say about COX10 p.Val366Leu (c.1096G>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

COX10 p.Val366Leu

c.1096G>T · rs111541535 · VCV137002

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.45%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 372 bp · p 0.13 · regional, not allelic
Overall
CADD	17.09	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 1.45% African / African-American · 1,085/75,056 alleles

Filtering AF 1.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.35%

Overall 1.12% 18,000/1,614,018 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.28%	23
African / African-Americangrpmax	1.45%	69
European (non-Finnish)	1.32%	76
Remaining individualsnot grpmax-eligible	0.931%	107
Admixed American	0.703%	142
Ashkenazi Jewishnot grpmax-eligible	0.453%	221
Middle Eastern	0.313%	319
Finnishnot grpmax-eligible	0.234%	427
South Asian	0.0472%	2,118
East Asian	0.00446%	22,425

Amish 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.Val366Leu
Coding: c.1096G>T
MANE Select: NM_001303
dbSNP: rs111541535
Type: single nucleotide variant
Location: chr17:14206977 (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.Val366Met 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-val366leu (accessed [today's date]).

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