Is COPS5 p.Met67Lys (c.200T>A) pathogenic?

COPS5 p.Met67Lys (c.200T>A) is classified Uncertain significance in COPS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.9854); Very rare (popmax 0.00322%, nfe).

How common is COPS5 p.Met67Lys (c.200T>A) in the general population?

COPS5 p.Met67Lys (c.200T>A) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about COPS5 p.Met67Lys (c.200T>A)?

AlphaMissense predicts likely pathogenic (score 0.9854) — an in-silico prediction, not a clinical call.

COPS5 p.Met67Lys

c.200T>A · rs144850801 · VCV3076278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9854	likely pathogenic
REVEL	0.59	indeterminate
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.66, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 19 kb · p 7e-36 · regional, not allelic
Overall
CADD	27.9	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 0.00322% European (non-Finnish) · 38/1,180,048 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0026% 42/1,614,134 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	0.00322%	31,054
African / African-American	0.00133%	74,946

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met67Lys
Coding: c.200T>A
MANE Select: NM_006837
dbSNP: rs144850801
Type: single nucleotide variant
Location: chr8:67059389 (GRCh38)
Gene constraint: LOEUF 0.218 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.68 · 31 PDB
Residue 67: an α-helix; the mpn domain

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-met67lys (accessed [today's date]).

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