Is COA8 p.Pro14Ala (c.40C>G) pathogenic?

COA8 p.Pro14Ala (c.40C>G) is classified Benign/Likely benign in COA8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0613); Common (popmax 35.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with mitochondrial complex IV deficiency, nuclear type 17.

What condition is associated with COA8 p.Pro14Ala (c.40C>G)?

COA8 p.Pro14Ala (c.40C>G) is associated with mitochondrial complex IV deficiency, nuclear type 17 (ClinVar).

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 COA8 p.Pro14Ala (c.40C>G)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

COA8 p.Pro14Ala

Q: How common is COA8 p.Pro14Ala (c.40C>G) in the general population?

COA8 p.Pro14Ala (c.40C>G) is common (popmax 35.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.40C>G · rs2274268 · VCV379942

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 35.9%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 17

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -2
Regional constraint	o/e 1.16	unconstrained · MANE · 27 kb · p 0.018 · regional, not allelic
Overall
CADD	0.03	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 P27A vs ClinVar P14A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.9% Middle Eastern · 2,014/5,608 alleles

Filtering AF 35% ClinGen BA1/BS1 input FAF95, joint · FAF99 34.9%

Overall 32.6% 502,927/1,541,778 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	35.9%	3
European (non-Finnish)	35.1%	3
Ashkenazi Jewishnot grpmax-eligible	34.5%	3
Remaining individualsnot grpmax-eligible	31.4%	3
Amishnot grpmax-eligible	30.8%	3
African / African-American	28.8%	3
Finnishnot grpmax-eligible	28.5%	4
South Asian	23.9%	4
Admixed American	19.8%	5
East Asian	10.2%	10

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.Pro14Ala
Coding: c.40C>G
MANE Select: NM_001370595
dbSNP: rs2274268
Type: single nucleotide variant
Location: chr14:103563041 (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.Pro14Ser Uncertain significance ★★ ⚠ same residue
COA8 p.Pro14His Uncertain significance ★★ ⚠ same residue
COA8 p.Pro14Arg Benign/Likely benign ★★ same residue
COA8 p.Pro14Thr Likely benign ★★ same residue
COA8 p.Pro14Leu Uncertain significance ★ ⚠ same residue
COA8 p.Arg66Ter Pathogenic ★★ same condition
COA8 p.Arg34Leu Uncertain significance ★★ ⚠ same condition
COA8 p.Arg66Gln 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-pro14ala (accessed [today's date]).

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