Is COX8A p.Ile37= (c.111C>A) pathogenic?

COX8A p.Ile37= (c.111C>A) is classified Benign/Likely benign in COX8A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Rare (popmax 0.856%, nfe); Associated with mitochondrial complex IV deficiency, nuclear type 15.

What condition is associated with COX8A p.Ile37= (c.111C>A)?

COX8A p.Ile37= (c.111C>A) is associated with mitochondrial complex IV deficiency, nuclear type 15 (ClinVar).

How common is COX8A p.Ile37= (c.111C>A) in the general population?

COX8A p.Ile37= (c.111C>A) is rare (popmax 0.856%, nfe) (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.

COX8A p.Ile37=

c.111C>A · rs61759492 · VCV709505

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.856%, nfe)

Conditions

mitochondrial complex IV deficiency, nuclear type 15

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.087	GERP 0.56
Overall
CADD	6.945	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.856% European (non-Finnish) · 10,048/1,173,840 alleles

Filtering AF 0.842% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.836%

Overall 0.708% 11,343/1,601,624 alleles · rare exomes 10,586/1,449,262 · genomes 757/152,362 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.01%	99
European (non-Finnish)grpmax	0.856%	117
Remaining individualsnot grpmax-eligible	0.572%	175
Middle Eastern	0.372%	269
Admixed American	0.286%	350
African / African-American	0.121%	823
South Asian	0.0268%	3,726
Ashkenazi Jewishnot grpmax-eligible	0.00687%	14,551
East Asian	0.00224%	44,554

Finnish 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: COX8A
Protein: p.Ile37=
Coding: c.111C>A
MANE Select: NM_004074
dbSNP: rs61759492
Type: single nucleotide variant
Location: chr11:63974791 (GRCh38)
Gene constraint: LOEUF 1.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.74 · 4 PDB
Residue 37: an α-helix

Full COX8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 15 — 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

COX8A c.114+17G>A Likely benign ★★ same condition
COX8A p.Ile58= Benign/Likely benign ★★ same condition
COX8A p.Pro31= Likely benign ★★ same condition
COX8A p.Trp57Cys Uncertain significance ★★ ⚠ same type
COX8A p.Arg23Cys Benign/Likely benign ★★ same type
COX8A p.Leu8= Benign ★★ same type
COX8A p.Glu39Gly Uncertain significance ★ ⚠ same type
COX8A p.Glu39Lys Uncertain significance ★ ⚠ same type

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/cox8a-p-ile37 (accessed [today's date]).

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