Is COX6C p.Lys8Glu (c.22A>G) pathogenic?

COX6C p.Lys8Glu (c.22A>G) is classified Uncertain significance in COX6C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.3197); Very rare (popmax 0.00446%, eas).

How common is COX6C p.Lys8Glu (c.22A>G) in the general population?

COX6C p.Lys8Glu (c.22A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about COX6C p.Lys8Glu (c.22A>G)?

AlphaMissense predicts likely benign (score 0.3197) — an in-silico prediction, not a clinical call.

COX6C p.Lys8Glu

c.22A>G · VCV4006010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3197	likely benign
REVEL	0.382	indeterminate
SaProt	LLR -11.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 4,513 bp · p 0.71 · regional, not allelic
Overall
CADD	24.8	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,460,326 alleles · very rare

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: COX6C
Protein: p.Lys8Glu
Coding: c.22A>G
MANE Select: NM_004374
Type: single nucleotide variant
Location: chr8:99892000 (GRCh38)
Gene constraint: LOEUF 1.231 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 94.94 · 3 PDB

Full COX6C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COX6C p.Ala16Ser Uncertain significance ★ ⚠ same type
COX6C p.Arg18His Uncertain significance ★ ⚠ same type
COX6C p.Arg40His Uncertain significance ★ ⚠ same type
COX6C p.Arg66Lys Uncertain significance ★ ⚠ same type
COX6C p.Asn21Ser Uncertain significance ★ ⚠ same type
COX6C p.Glu4Gln Uncertain significance ★ ⚠ same type
COX6C p.Glu64Asp Uncertain significance ★ ⚠ same type
COX6C p.Met11Ile 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/cox6c-p-lys8glu (accessed [today's date]).

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