Is COPS6 p.Met181Val (c.541A>G) pathogenic?

COPS6 p.Met181Val (c.541A>G) is classified Uncertain significance in COPS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.2699); Very rare (popmax 0.00133%, afr).

How common is COPS6 p.Met181Val (c.541A>G) in the general population?

COPS6 p.Met181Val (c.541A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about COPS6 p.Met181Val (c.541A>G)?

AlphaMissense predicts likely benign (score 0.2699) — an in-silico prediction, not a clinical call.

COPS6 p.Met181Val

c.541A>G · VCV3496000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2699	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 2,097 bp · p 7.5e-07 · regional, not allelic
Overall
CADD	21.9	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 0.00133% African / African-American · 1/75,050 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000681% 11/1,614,178 alleles · very rare exomes 11/1,461,882 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-Americangrpmax	0.00133%	75,050
European (non-Finnish)	0.000763%	131,114

Ashkenazi Jewish 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: COPS6
Protein: p.Met181Val
Coding: c.541A>G
MANE Select: NM_006833
Type: single nucleotide variant
Location: chr7:100091044 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 29 PDB
Residue 181: a β-strand

Full COPS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS6 p.Ala290Thr Uncertain significance ★ ⚠ same type
COPS6 p.Ala42Val Uncertain significance ★ ⚠ same type
COPS6 p.Ala7Val Uncertain significance ★ ⚠ same type
COPS6 p.Asn307Lys Uncertain significance ★ ⚠ same type
COPS6 p.Asp101Glu Uncertain significance ★ ⚠ same type
COPS6 p.Asp173Gly Uncertain significance ★ ⚠ same type
COPS6 p.Glu240Ala Uncertain significance ★ ⚠ same type
COPS6 p.Gly129Glu 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/cops6-p-met181val (accessed [today's date]).

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