Is COA6 p.Trp89Cys (c.267G>C) pathogenic?

COA6 p.Trp89Cys (c.267G>C) is classified Pathogenic in COA6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-07-09). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 0.000932%, nfe); Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4.

How common is COA6 p.Trp89Cys (c.267G>C) in the general population?

COA6 p.Trp89Cys (c.267G>C) is very rare (popmax 0.000932%, nfe) (gnomAD).

How is Fatal infantile cytochrome C oxidase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COA6 p.Trp89Cys (c.267G>C)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

COA6 p.Trp89Cys

Q: What condition is associated with COA6 p.Trp89Cys (c.267G>C)?

COA6 p.Trp89Cys (c.267G>C) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 (ClinVar).

c.267G>C · rs1558123786 · VCV144036

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic ✓ concordant with ClinVar · top 2% in COA6
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -15.44	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 9.8	GERP 0.82, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 10 kb · p 0.00042 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM W59C vs ClinVar W89C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,932 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,461,646 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)grpmax	0.000932%	107,267

Remaining individuals 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: COA6
Protein: p.Trp89Cys
Coding: c.267G>C
MANE Select: NM_001206641
dbSNP: rs1558123786
Type: single nucleotide variant
Location: chr1:234374284 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.74 · 3 PDB
Residue 89: the chch domain; an α-helix; a disulfide bond

Full COA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fatal infantile cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COA6 p.Trp89Ser Uncertain significance ★ ⚠ same residue
COA6 c.212+162G>A Benign/Likely benign ★★ ⚠ same condition
COA6 p.Ala91Gly Uncertain significance ★ ⚠ same condition
COA6 p.Glu117Ter Uncertain significance ★ same condition
COA6 p.Trp96Arg Pathogenic same condition
COA6 c.373-8dup Benign ★★ same condition
COA6 p.Lys140fs Likely pathogenic ★ same condition
COA6 c.212+114G>T 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/coa6-p-trp89cys (accessed [today's date]).

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