Is COA8 p.Pro14Ser (c.40C>T) pathogenic?

COA8 p.Pro14Ser (c.40C>T) is classified Uncertain significance in COA8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-11). AlphaMissense: likely benign (0.081); Ultra-rare (popmax 0.0134%, amr); Associated with mitochondrial complex IV deficiency, nuclear type 17.

What condition is associated with COA8 p.Pro14Ser (c.40C>T)?

COA8 p.Pro14Ser (c.40C>T) is associated with mitochondrial complex IV deficiency, nuclear type 17 (ClinVar).

How common is COA8 p.Pro14Ser (c.40C>T) in the general population?

COA8 p.Pro14Ser (c.40C>T) is ultra-rare (popmax 0.0134%, amr) (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.

What do computational predictors say about COA8 p.Pro14Ser (c.40C>T)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

COA8 p.Pro14Ser

c.40C>T · rs2274268 · VCV1061664

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 17

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -6.09	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	0.195	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P27S vs ClinVar P14S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% Admixed American · 7/52,208 alleles

Filtering AF 0.00625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00437%

Overall 0.00136% 21/1,543,776 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,458
East Asian	0.00716%	13,973
South Asian	0.00118%	85,026
European (non-Finnish)	0.000869%	115,023

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.Pro14Ser
Coding: c.40C>T
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.Pro14Ala Benign/Likely benign ★★ 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-pro14ser (accessed [today's date]).

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