Is COPS5 p.Met8Val (c.22A>G) pathogenic?

COPS5 p.Met8Val (c.22A>G) is classified Uncertain significance in COPS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0656); Very rare (popmax 8.47e-05%, nfe).

How common is COPS5 p.Met8Val (c.22A>G) in the general population?

COPS5 p.Met8Val (c.22A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about COPS5 p.Met8Val (c.22A>G)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

COPS5 p.Met8Val

c.22A>G · VCV4655864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -5.59	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 4.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 65 bp · p 0.39 · regional, not allelic
Overall
CADD	20.2	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.84e-05% 1/1,461,884 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: COPS5
Protein: p.Met8Val
Coding: c.22A>G
MANE Select: NM_006837
Type: single nucleotide variant
Location: chr8:67061975 (GRCh38)
Gene constraint: LOEUF 0.218 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.68 · 31 PDB
Residue 8: an α-helix

Full COPS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS5 p.Ala22Val Uncertain significance ★ ⚠ same type
COPS5 p.Asn17Ser Uncertain significance ★ ⚠ same type
COPS5 p.Asn18Thr Uncertain significance ★ ⚠ same type
COPS5 p.Asp234Ala Uncertain significance ★ ⚠ same type
COPS5 p.Asp48Asn Uncertain significance ★ ⚠ same type
COPS5 p.Gln279His Uncertain significance ★ ⚠ same type
COPS5 p.Ile176Val Uncertain significance ★ ⚠ same type
COPS5 p.Ile333Val 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/cops5-p-met8val (accessed [today's date]).

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