Is COX15 p.Pro310Arg (c.929C>G) pathogenic?

COX15 p.Pro310Arg (c.929C>G) is classified Conflicting classifications of pathogenicity in COX15 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.6386); Ultra-rare (popmax 0.01%, amr); Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2.

How common is COX15 p.Pro310Arg (c.929C>G) in the general population?

COX15 p.Pro310Arg (c.929C>G) is ultra-rare (popmax 0.01%, amr) (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.Pro310Arg (c.929C>G)?

AlphaMissense predicts likely pathogenic (score 0.6386) — an in-silico prediction, not a clinical call.

COX15 p.Pro310Arg

Q: What condition is associated with COX15 p.Pro310Arg (c.929C>G)?

COX15 p.Pro310Arg (c.929C>G) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, Leigh syndrome (ClinVar).

c.929C>G · rs138293000 · VCV214263

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6386 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6386	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 17 kb · p 0.00029 · regional, not allelic
Overall
CADD	32.0	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 0.01% Admixed American · 6/59,994 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.0206% 333/1,613,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.895%	112
Remaining individualsnot grpmax-eligible	0.04%	2,499
Admixed Americangrpmax	0.01%	9,999
European (non-Finnish)	0.00314%	31,892

Ashkenazi Jewish 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: COX15
Protein: p.Pro310Arg
Coding: c.929C>G
MANE Select: NM_078470
dbSNP: rs138293000
Type: single nucleotide variant
Location: chr10:99718404 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29

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

Also linked: Leigh syndrome

For Fatal infantile cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COX15 p.Pro310Ala Uncertain significance ★★ ⚠ same residue
COX15 p.Pro310= Likely benign ★ 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

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-pro310arg (accessed [today's date]).

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