Is COX6C p.Glu64Asp (c.192G>C) pathogenic?

COX6C p.Glu64Asp (c.192G>C) is classified Uncertain significance in COX6C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.1823); Very rare (popmax 0.000849%, nfe).

How common is COX6C p.Glu64Asp (c.192G>C) in the general population?

COX6C p.Glu64Asp (c.192G>C) is very rare (popmax 0.000849%, nfe) (gnomAD).

What do computational predictors say about COX6C p.Glu64Asp (c.192G>C)?

AlphaMissense predicts likely benign (score 0.1823) — an in-silico prediction, not a clinical call.

COX6C p.Glu64Asp

c.192G>C · VCV4655971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1823	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -7.38	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 1.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 4,513 bp · p 0.71 · regional, not allelic
Overall
CADD	19.9	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 0.000849% European (non-Finnish) · 10/1,178,146 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000622% 10/1,608,982 alleles · very rare exomes 7/1,456,792 · genomes 3/152,190 · joint denominator

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.Glu64Asp
Coding: c.192G>C
MANE Select: NM_004374
Type: single nucleotide variant
Location: chr8:99887541 (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.Lys8Glu 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-glu64asp (accessed [today's date]).

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