Is COX15 p.Ser151Ter (c.452C>G) pathogenic?

COX15 p.Ser151Ter (c.452C>G) is classified Pathogenic/Likely pathogenic in COX15 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-04-18). Ultra-rare (popmax 0.043%, nfe); Associated with Leigh syndrome.

What condition is associated with COX15 p.Ser151Ter (c.452C>G)?

COX15 p.Ser151Ter (c.452C>G) is associated with Leigh syndrome, cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (ClinVar).

How common is COX15 p.Ser151Ter (c.452C>G) in the general population?

COX15 p.Ser151Ter (c.452C>G) is ultra-rare (popmax 0.043%, nfe) (gnomAD).

How is Leigh syndrome inherited?

Typically Autosomal recessive, Mitochondrial inheritance (Orphanet). A genetic counselor can assess individual risk for a family.

COX15 p.Ser151Ter

c.452C>G · rs149718203 · VCV496238

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.043%, nfe)

Conditions

Leigh syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 9
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Pangolin	Δ0.29	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.043% European (non-Finnish) · 508/1,180,040 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0387%

Overall 0.033% 533/1,614,074 alleles · ultra-rare exomes 490/1,461,878 · genomes 43/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.043%	2,323
Remaining individualsnot grpmax-eligible	0.0208%	4,807
African / African-American	0.0133%	7,493
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00156%	64,034

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.Ser151Ter
Coding: c.452C>G
MANE Select: NM_078470
dbSNP: rs149718203
Type: single nucleotide variant
Location: chr10:99727098 (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

Leigh syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2

For Leigh syndrome (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance, X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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.Ser229Ter Pathogenic/Likely pathogenic ★★ same condition
COX15 p.Trp102Ter Pathogenic/Likely pathogenic ★★ same condition
COX15 p.Trp199Ter Pathogenic/Likely pathogenic ★★ same condition
COX15 p.Trp239Ter 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-ser151ter (accessed [today's date]).

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