Is COX20 p.Ala3Val (c.8C>T) pathogenic?

COX20 p.Ala3Val (c.8C>T) is classified Uncertain significance in COX20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely benign (0.1886); Very rare (popmax 0.00287%, sas); Associated with mitochondrial complex IV deficiency, nuclear type 11.

What condition is associated with COX20 p.Ala3Val (c.8C>T)?

COX20 p.Ala3Val (c.8C>T) is associated with mitochondrial complex IV deficiency, nuclear type 11 (ClinVar).

How common is COX20 p.Ala3Val (c.8C>T) in the general population?

COX20 p.Ala3Val (c.8C>T) is very rare (popmax 0.00287%, sas) (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 COX20 p.Ala3Val (c.8C>T)?

AlphaMissense predicts likely benign (score 0.1886) — an in-silico prediction, not a clinical call.

COX20 p.Ala3Val

c.8C>T · VCV3582912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00287%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 11

Computational evidence

Protein change
AlphaMissense	0.1886	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -8.40	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 1.6	GERP 1.6, phastCons 0.003
Regional constraint	o/e 1.05	unconstrained · MANE · 7,458 bp · p 0.56 · regional, not allelic
Overall
CADD	19.08	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00287% South Asian · 1/34,878 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.000473% 6/1,268,610 alleles · very rare exomes 5/1,116,622 · genomes 1/151,988 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00287%	34,878
Remaining individualsnot grpmax-eligible	0.00213%	47,024
African / African-American	0.00154%	64,936
European (non-Finnish)	0.000299%	334,870

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: COX20
Protein: p.Ala3Val
Coding: c.8C>T
MANE Select: NM_198076
Type: single nucleotide variant
Location: chr1:244835722 (GRCh38)
Gene constraint: LOEUF 1.927 · pLI 0.06 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.42

Full COX20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 11 — 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

COX20 p.Ala3Thr Uncertain significance ★★ ⚠ same residue
COX20 p.Ala3Ser Benign/Likely benign ★★ same residue
COX20 p.Ala3= Likely benign ★ same residue
COX20 c.157+3G>C Pathogenic/Likely pathogenic ★★ same condition
COX20 p.Lys14Arg Pathogenic ★★ ⚠ same condition
COX20 p.Tyr36Ter Likely pathogenic ★★ same condition
COX20 p.Arg31Trp Uncertain significance ★★ ⚠ same condition
COX20 p.Asp107Asn 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/cox20-p-ala3val (accessed [today's date]).

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