Is COPB2 p.Ser876fs (c.2617_2621dup) pathogenic?

COPB2 p.Ser876fs (c.26172621dup) is classified Uncertain significance in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). Very rare (popmax 0.00017%, nfe).

How common is COPB2 p.Ser876fs (c.2617_2621dup) in the general population?

COPB2 p.Ser876fs (c.2617_2621dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

COPB2 p.Ser876fs

c.2617_2621dup · rs2472877054 · VCV2579391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (21 of 22, 3 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.62	GERP 1.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,912 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,056 alleles · very rare exomes 2/1,461,756 · genomes 0/152,300 · joint denominator

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.Ser876fs
Coding: c.2617_2621dup
MANE Select: NM_004766
dbSNP: rs2472877054
Type: Duplication
Location: chr3:139358203 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB

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

Similar variants

COPB2 c.2554dupG Pathogenic ★ same type
COPB2 p.His556fs Likely pathogenic ★ same type
COPB2 p.Val83fs Pathogenic ★ same type
COPB2 p.Ser423fs Conflicting classifications of pathogenicity ★ ⚠ same type
COPB2 p.Thr636fs Uncertain significance ★ same type
COPB2 c.2554-20_2554-17dup 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-ser876fs (accessed [today's date]).

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