Is COPS6 p.Thr296Ser (c.887C>G) pathogenic?

COPS6 p.Thr296Ser (c.887C>G) is classified Uncertain significance in COPS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). AlphaMissense: likely pathogenic (0.6387); Very rare (popmax 0.000254%, nfe).

How common is COPS6 p.Thr296Ser (c.887C>G) in the general population?

COPS6 p.Thr296Ser (c.887C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about COPS6 p.Thr296Ser (c.887C>G)?

AlphaMissense predicts likely pathogenic (score 0.6387) — an in-silico prediction, not a clinical call.

COPS6 p.Thr296Ser

c.887C>G · rs2546921700 · VCV2494927

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6387	likely pathogenic
REVEL	0.337	indeterminate
SaProt	LLR -8.28	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 2,097 bp · p 7.5e-07 · regional, not allelic
Overall
CADD	26.7	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 0.000254% European (non-Finnish) · 3/1,180,044 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,894 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: COPS6
Protein: p.Thr296Ser
Coding: c.887C>G
MANE Select: NM_006833
dbSNP: rs2546921700
Type: single nucleotide variant
Location: chr7:100091692 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 29 PDB
Residue 296: the 'interaction with vpr' region

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-thr296ser (accessed [today's date]).

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