Is COA8 p.Ala27= (c.81T>C) pathogenic?

COA8 p.Ala27= (c.81T>C) is classified Likely benign in COA8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-10). Ultra-rare (popmax 0.0169%, eas); Associated with mitochondrial complex IV deficiency, nuclear type 17.

What condition is associated with COA8 p.Ala27= (c.81T>C)?

COA8 p.Ala27= (c.81T>C) is associated with mitochondrial complex IV deficiency, nuclear type 17 (ClinVar).

How common is COA8 p.Ala27= (c.81T>C) in the general population?

COA8 p.Ala27= (c.81T>C) is ultra-rare (popmax 0.0169%, eas) (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.Ala27=

c.81T>C · rs1268847789 · VCV715529

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, eas)

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.
REVEL	0.016	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -2
Overall
CADD	6.493	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% East Asian · 7/41,502 alleles

Filtering AF 0.00788% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00558%

Overall 0.00182% 28/1,540,570 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.025%	4,003
East Asiangrpmax	0.0169%	5,929
South Asian	0.00237%	42,222
African / African-American	0.00137%	73,214
European (non-Finnish)	0.000261%	382,756

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: COA8
Protein: p.Ala27=
Coding: c.81T>C
MANE Select: NM_001370595
dbSNP: rs1268847789
Type: single nucleotide variant
Location: chr14:103563082 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.19
Residue 27: a UniProt-annotated variant site (in)

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.Ala27Val Uncertain significance ★★ ⚠ same residue
COA8 p.Arg66Ter Pathogenic ★★ same condition
COA8 p.Arg34Leu Uncertain significance ★★ ⚠ same condition
COA8 p.Arg66Gln 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

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-ala27 (accessed [today's date]).

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