Is COX10 p.Ala175Val (c.524C>T) pathogenic?

COX10 p.Ala175Val (c.524C>T) is classified Uncertain significance in COX10 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.2476); Ultra-rare (popmax 0.0165%, mid); Associated with mitochondrial complex IV deficiency, nuclear type 3.

What condition is associated with COX10 p.Ala175Val (c.524C>T)?

COX10 p.Ala175Val (c.524C>T) is associated with mitochondrial complex IV deficiency, nuclear type 3 (ClinVar).

How common is COX10 p.Ala175Val (c.524C>T) in the general population?

COX10 p.Ala175Val (c.524C>T) is ultra-rare (popmax 0.0165%, 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.Ala175Val (c.524C>T)?

AlphaMissense predicts likely benign (score 0.2476) — an in-silico prediction, not a clinical call.

COX10 p.Ala175Val

c.524C>T · rs141466324 · VCV2176831

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2476 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 3

Computational evidence

Protein change
AlphaMissense	0.2476	likely benign
REVEL	0.729	pathogenic-leaning
SaProt	LLR -10.19	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.97 · regional, not allelic
Overall
CADD	27.4	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0113% 183/1,613,592 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	0.0146%	6,859
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0048%	20,819
African / African-American	0.00267%	37,438

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.Ala175Val
Coding: c.524C>T
MANE Select: NM_001303
dbSNP: rs141466324
Type: single nucleotide variant
Location: chr17:14102142 (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.Ala175Ser Uncertain significance ★★ ⚠ same residue
COX10 p.Ala175Gly 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

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-ala175val (accessed [today's date]).

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