Is COPG1 p.Val856Met (c.2566G>A) pathogenic?

COPG1 p.Val856Met (c.2566G>A) is classified Uncertain significance in COPG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.4488); Very rare (popmax 0.00267%, afr).

How common is COPG1 p.Val856Met (c.2566G>A) in the general population?

COPG1 p.Val856Met (c.2566G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about COPG1 p.Val856Met (c.2566G>A)?

AlphaMissense predicts ambiguous (score 0.4488) — an in-silico prediction, not a clinical call.

COPG1 p.Val856Met

c.2566G>A · VCV4655847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.4488	ambiguous
REVEL	0.304	indeterminate
SaProt	LLR -9.98	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP -0.3, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 28 kb · p 1.9e-14 · regional, not allelic
Overall
CADD	26.6	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 0.00267% African / African-American · 2/74,870 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00161% 26/1,613,912 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-Americangrpmax	0.00267%	37,435
European (non-Finnish)	0.00161%	62,106
Finnishnot grpmax-eligible	0.00156%	64,010

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: COPG1
Protein: p.Val856Met
Coding: c.2566G>A
MANE Select: NM_016128
Type: single nucleotide variant
Location: chr3:129277365 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.09 · 1 PDB
Residue 856: a β-strand; the 'interaction with znf289/arfgap2' region

Full COPG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPG1 p.Arg247His Uncertain significance ★★ ⚠ same type
COPG1 p.Leu864Met Uncertain significance ★★ ⚠ same type
COPG1 p.Thr64Met Uncertain significance ★★ ⚠ same type
COPG1 c.91-11T>C Benign ★★ same type
COPG1 c.939+13C>G Benign ★★ same type
COPG1 p.His221= Benign ★★ same type
COPG1 p.Ile92= Benign/Likely benign ★★ same type
COPG1 p.Leu240Val Benign/Likely benign ★★ ⚠ 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/copg1-p-val856met (accessed [today's date]).

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