Is COA8 p.Arg66Ter (c.196C>T) pathogenic?

COA8 p.Arg66Ter (c.196C>T) is classified Pathogenic in COA8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-02). Very rare (popmax 0.00331%, nfe); Associated with mitochondrial complex IV deficiency, nuclear type 17.

What condition is associated with COA8 p.Arg66Ter (c.196C>T)?

COA8 p.Arg66Ter (c.196C>T) is associated with mitochondrial complex IV deficiency, nuclear type 17 (ClinVar).

How common is COA8 p.Arg66Ter (c.196C>T) in the general population?

COA8 p.Arg66Ter (c.196C>T) is very rare (popmax 0.00331%, nfe) (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.

COA8 p.Arg66Ter

c.196C>T · rs587777784 · VCV156421

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Conditions

mitochondrial complex IV deficiency, nuclear type 17

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.5, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% European (non-Finnish) · 39/1,180,016 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00254% 41/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00331%	30,257
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,926

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: COA8
Protein: p.Arg66Ter
Coding: c.196C>T
MANE Select: NM_001370595
dbSNP: rs587777784
Type: single nucleotide variant
Location: chr14:103571695 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.19

Full COA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 17 — 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

COA8 p.Arg66Gln Uncertain significance ★★ ⚠ same residue
COA8 p.Arg34Leu Uncertain significance ★★ ⚠ same condition
COA8 p.Asp36Tyr Uncertain significance ★★ ⚠ same condition
COA8 p.Glu145Lys Uncertain significance ★★ ⚠ same condition
COA8 p.Glu33Lys Uncertain significance ★★ ⚠ same condition
COA8 p.Pro14Ser Uncertain significance ★★ ⚠ same condition
COA8 p.Pro58Thr Uncertain significance ★★ ⚠ same condition
COA8 c.123+10G>A Benign/Likely benign ★★ 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/coa8-p-arg66ter (accessed [today's date]).

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