Is COX8A p.Trp57Cys (c.171G>T) pathogenic?

COX8A p.Trp57Cys (c.171G>T) is classified Uncertain significance in COX8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.8944); Very rare (popmax 0.005%, amr); Associated with mitochondrial complex IV deficiency, nuclear type 1.

What condition is associated with COX8A p.Trp57Cys (c.171G>T)?

COX8A p.Trp57Cys (c.171G>T) is associated with mitochondrial complex IV deficiency, nuclear type 1 (ClinVar).

How common is COX8A p.Trp57Cys (c.171G>T) in the general population?

COX8A p.Trp57Cys (c.171G>T) is very rare (popmax 0.005%, amr) (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 COX8A p.Trp57Cys (c.171G>T)?

AlphaMissense predicts likely pathogenic (score 0.8944) — an in-silico prediction, not a clinical call.

COX8A p.Trp57Cys

c.171G>T · rs146388741 · VCV1033634

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 1

Computational evidence

Protein change
AlphaMissense	0.8944	likely pathogenic · top 4% in COX8A
REVEL	0.67	pathogenic-leaning
SaProt	LLR -13.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,636 bp · p 0.063 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.005% Admixed American · 3/59,994 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000496% 8/1,614,060 alleles · very rare exomes 7/1,461,882 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,998
African / African-American	0.00133%	74,918
European (non-Finnish)	0.000339%	295,011

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: COX8A
Protein: p.Trp57Cys
Coding: c.171G>T
MANE Select: NM_004074
dbSNP: rs146388741
Type: single nucleotide variant
Location: chr11:63976281 (GRCh38)
Gene constraint: LOEUF 1.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.74 · 4 PDB
Residue 57: an α-helix

Full COX8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 1 — 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

COX8A c.115-1G>C Pathogenic same condition
COX8A c.114+17G>A Likely benign ★★ same type
COX8A p.Arg23Cys Benign/Likely benign ★★ same type
COX8A p.Ile37= Benign/Likely benign ★★ same type
COX8A p.Ile58= Benign/Likely benign ★★ same type
COX8A p.Leu8= Benign ★★ same type
COX8A p.Pro31= Likely benign ★★ same type
COX8A p.Glu39Gly Uncertain significance ★ ⚠ same type

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/cox8a-p-trp57cys (accessed [today's date]).

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