Is COPS8 p.Glu8Lys (c.22G>A) pathogenic?

COPS8 p.Glu8Lys (c.22G>A) is classified Uncertain significance in COPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.3113); Very rare (popmax 0.00017%, nfe).

How common is COPS8 p.Glu8Lys (c.22G>A) in the general population?

COPS8 p.Glu8Lys (c.22G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about COPS8 p.Glu8Lys (c.22G>A)?

AlphaMissense predicts likely benign (score 0.3113) — an in-silico prediction, not a clinical call.

COPS8 p.Glu8Lys

c.22G>A · VCV3496011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3113 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3113	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -9.36	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 12 kb · p 0.012 · regional, not allelic
Overall
CADD	25.6	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 0.00017% European (non-Finnish) · 2/1,179,248 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,368 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: COPS8
Protein: p.Glu8Lys
Coding: c.22G>A
MANE Select: NM_006710
Type: single nucleotide variant
Location: chr2:237085986 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.42 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 28 PDB
Residue 8: the pci domain

Full COPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS8 p.Glu8Gly Uncertain significance ★ ⚠ same residue
COPS8 p.Ala119Gly Uncertain significance ★ ⚠ same type
COPS8 p.Ala119Thr Uncertain significance ★ ⚠ same type
COPS8 p.Ala144Val Uncertain significance ★ ⚠ same type
COPS8 p.Ala95Thr Uncertain significance ★ ⚠ same type
COPS8 p.Arg110Lys Uncertain significance ★ ⚠ same type
COPS8 p.Arg116Cys Uncertain significance ★ ⚠ same type
COPS8 p.Arg160Ser 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/cops8-p-glu8lys (accessed [today's date]).

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