Is COPG2 p.Ile125Val (c.373A>G) pathogenic?

COPG2 p.Ile125Val (c.373A>G) is classified Uncertain significance in COPG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.000424%, nfe).

How common is COPG2 p.Ile125Val (c.373A>G) in the general population?

COPG2 p.Ile125Val (c.373A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about COPG2 p.Ile125Val (c.373A>G)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

COPG2 p.Ile125Val

c.373A>G · rs377590347 · VCV2617103

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -8.17	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 7.9	GERP 1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 162 kb · p 0.046 · regional, not allelic
Overall
CADD	20.7	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 0.000424% European (non-Finnish) · 5/1,178,732 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,052 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: COPG2
Protein: p.Ile125Val
Coding: c.373A>G
MANE Select: NM_012133
dbSNP: rs377590347
Type: single nucleotide variant
Location: chr7:130617016 (GRCh38)
Gene constraint: LOEUF 1.132 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.98

Full COPG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPG2 p.Ile125Leu Uncertain significance ★ ⚠ same residue
COPG2 p.Ala96Thr Uncertain significance ★ ⚠ same type
COPG2 p.Arg130Ser Uncertain significance ★ ⚠ same type
COPG2 p.Arg32Cys Uncertain significance ★ ⚠ same type
COPG2 p.Arg75Gln Uncertain significance ★ ⚠ same type
COPG2 p.Asn179Ser Uncertain significance ★ ⚠ same type
COPG2 p.Asn189Ser Uncertain significance ★ ⚠ same type
COPG2 p.Asn40Thr 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/copg2-p-ile125val (accessed [today's date]).

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