Is COPB2 p.Val345Ile (c.1033G>A) pathogenic?

COPB2 p.Val345Ile (c.1033G>A) is classified Benign in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely benign (0.0684); Low-frequency (popmax 1.12%, eas).

How common is COPB2 p.Val345Ile (c.1033G>A) in the general population?

COPB2 p.Val345Ile (c.1033G>A) is low-frequency (popmax 1.12%, eas) (gnomAD).

What do computational predictors say about COPB2 p.Val345Ile (c.1033G>A)?

AlphaMissense predicts likely benign (score 0.0684) — an in-silico prediction, not a clinical call.

COPB2 p.Val345Ile

c.1033G>A · VCV4797066

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0684 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0684	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -8.59	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	22.2	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 1.12% East Asian · 502/44,872 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.0331% 534/1,614,162 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.12%	89
Remaining individualsnot grpmax-eligible	0.0384%	2,605
Middle Eastern	0.0165%	6,060
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,084
European (non-Finnish)	0.000424%	236,002

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: COPB2
Protein: p.Val345Ile
Coding: c.1033G>A
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139373274 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 345: a β-strand

Full COPB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPB2 p.Glu646Lys Uncertain significance ★★ ⚠ same type
COPB2 p.Glu879Lys Uncertain significance ★★ ⚠ same type
COPB2 p.Ile864Thr Uncertain significance ★★ ⚠ same type
COPB2 p.Leu649Phe Uncertain significance ★★ ⚠ same type
COPB2 p.Ser135Ala Uncertain significance ★★ ⚠ same type
COPB2 c.1095-23T>C Benign ★★ same type
COPB2 c.1401+12C>T Likely benign ★★ same type
COPB2 c.141+20G>T 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/copb2-p-val345ile (accessed [today's date]).

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