Is COX15 p.Ser344Pro (c.1030T>C) pathogenic?

COX15 p.Ser344Pro (c.1030T>C) is classified Conflicting classifications of pathogenicity in COX15 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.6983); Very rare (popmax 0.000678%, nfe); Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2.

How common is COX15 p.Ser344Pro (c.1030T>C) in the general population?

COX15 p.Ser344Pro (c.1030T>C) is very rare (popmax 0.000678%, nfe) (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 COX15 p.Ser344Pro (c.1030T>C)?

AlphaMissense predicts likely pathogenic (score 0.6983) — an in-silico prediction, not a clinical call.

COX15 p.Ser344Pro

Q: What condition is associated with COX15 p.Ser344Pro (c.1030T>C)?

COX15 p.Ser344Pro (c.1030T>C) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (ClinVar).

c.1030T>C · rs397514662 · VCV40258

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2

Computational evidence

Protein change
AlphaMissense	0.6983	likely pathogenic
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -12.32	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 9.4	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 17 kb · p 0.00029 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,938 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,970 alleles · very rare exomes 7/1,461,720 · genomes 1/152,250 · joint denominator

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: COX15
Protein: p.Ser344Pro
Coding: c.1030T>C
MANE Select: NM_078470
dbSNP: rs397514662
Type: single nucleotide variant
Location: chr10:99716419 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29
Residue 344: a UniProt-annotated variant site (in mc4dn6)

Full COX15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 — 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

COX15 p.Ser344Tyr Uncertain significance ★ ⚠ same residue
COX15 c.750+1G>A Likely pathogenic ★★ same condition
COX15 c.750+1G>T Likely pathogenic ★★ same condition
COX15 p.Arg153Ter Pathogenic/Likely pathogenic ★★ same condition
COX15 p.Arg217Trp Pathogenic ★★ same condition
COX15 p.Ser151Ter Pathogenic/Likely pathogenic ★★ same condition
COX15 p.Ser229Ter Pathogenic/Likely pathogenic ★★ same condition
COX15 p.Trp102Ter Pathogenic/Likely pathogenic ★★ 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/cox15-p-ser344pro (accessed [today's date]).

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