Is COX10 p.Val17Ile (c.49G>A) pathogenic?

COX10 p.Val17Ile (c.49G>A) is classified Uncertain significance in COX10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-22). AlphaMissense: likely benign (0.0747); Ultra-rare (popmax 0.0657%, mid); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Val17Ile (c.49G>A)?

COX10 p.Val17Ile (c.49G>A) is associated with mitochondrial complex IV deficiency, nuclear type 3 (ClinVar).

How common is COX10 p.Val17Ile (c.49G>A) in the general population?

COX10 p.Val17Ile (c.49G>A) is ultra-rare (popmax 0.0657%, 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.Val17Ile (c.49G>A)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

COX10 p.Val17Ile

c.49G>A · rs746426795 · VCV2183450

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.91	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	GERP 1.1, phastCons 0.015
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.97 · regional, not allelic
Overall
CADD	9.033	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0124% 200/1,613,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
European (non-Finnish)	0.0152%	6,592
Remaining individualsnot grpmax-eligible	0.0112%	8,926
South Asian	0.00878%	11,385
African / African-American	0.00267%	37,451

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.Val17Ile
Coding: c.49G>A
MANE Select: NM_001303
dbSNP: rs746426795
Type: single nucleotide variant
Location: chr17:14074328 (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.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
COX10 p.Ala261Ser 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-val17ile (accessed [today's date]).

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