Is COPS8 p.Lys15Met (c.44A>T) pathogenic?

COPS8 p.Lys15Met (c.44A>T) is classified Uncertain significance in COPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely benign (0.2627); Ultra-rare (popmax 0.0161%, nfe).

How common is COPS8 p.Lys15Met (c.44A>T) in the general population?

COPS8 p.Lys15Met (c.44A>T) is ultra-rare (popmax 0.0161%, nfe) (gnomAD).

What do computational predictors say about COPS8 p.Lys15Met (c.44A>T)?

AlphaMissense predicts likely benign (score 0.2627) — an in-silico prediction, not a clinical call.

COPS8 p.Lys15Met

c.44A>T · VCV3835600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2627	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -8.24	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 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 12 kb · p 0.012 · regional, not allelic
Overall
CADD	24.3	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 0.0161% European (non-Finnish) · 190/1,179,818 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.0121% 195/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0161%	6,210
Remaining individualsnot grpmax-eligible	0.0032%	31,226
African / African-American	0.00267%	37,473
South Asian	0.0011%	91,006

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.Lys15Met
Coding: c.44A>T
MANE Select: NM_006710
Type: single nucleotide variant
Location: chr2:237086008 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.42 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 28 PDB
Residue 15: the pci domain

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

Similar variants

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
COPS8 p.Arg80Ser 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-lys15met (accessed [today's date]).

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