Is COPB2 p.Ser258Leu (c.773C>T) pathogenic?

COPB2 p.Ser258Leu (c.773C>T) is classified Uncertain significance in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-16). AlphaMissense: ambiguous (0.5327); Very rare (popmax 8.47e-05%, nfe).

How common is COPB2 p.Ser258Leu (c.773C>T) in the general population?

COPB2 p.Ser258Leu (c.773C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about COPB2 p.Ser258Leu (c.773C>T)?

AlphaMissense predicts ambiguous (score 0.5327) — an in-silico prediction, not a clinical call.

COPB2 p.Ser258Leu

c.773C>T · VCV3359815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5327	ambiguous
REVEL	0.491	indeterminate
SaProt	LLR -13.40	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	28.4	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 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.84e-05% 1/1,461,824 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: COPB2
Protein: p.Ser258Leu
Coding: c.773C>T
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139373787 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 258: a turn

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-ser258leu (accessed [today's date]).

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