Is COA6 p.Trp96Arg (c.286T>C) pathogenic?

COA6 p.Trp96Arg (c.286T>C) is classified Pathogenic in COA6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-01-01). AlphaMissense: likely pathogenic (0.9831); Absent from gnomAD v4.1; Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4.

How common is COA6 p.Trp96Arg (c.286T>C) in the general population?

COA6 p.Trp96Arg (c.286T>C) is absent from gnomAD v4.1 (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.Trp96Arg (c.286T>C)?

AlphaMissense predicts likely pathogenic (score 0.9831) — an in-silico prediction, not a clinical call.

COA6 p.Trp96Arg

Q: What condition is associated with COA6 p.Trp96Arg (c.286T>C)?

COA6 p.Trp96Arg (c.286T>C) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 (ClinVar).

c.286T>C · rs875989827 · VCV204622

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9831 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9831	likely pathogenic ✓ concordant with ClinVar · top 4% in COA6
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -11.67	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 10 kb · p 0.00042 · regional, not allelic
Overall
CADD	32.0	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 W66R vs ClinVar W96R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COA6
Protein: p.Trp96Arg
Coding: c.286T>C
MANE Select: NM_001206641
dbSNP: rs875989827
Type: single nucleotide variant
Location: chr1:234374303 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.74 · 3 PDB
Residue 96: the chch domain; an α-helix

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 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.Trp89Cys 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
COA6 p.Met82Val 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-trp96arg (accessed [today's date]).

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