Is COPB2 p.Ser423fs (c.1266dup) pathogenic?

COPB2 p.Ser423fs (c.1266dup) is classified Conflicting classifications of pathogenicity in COPB2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-08). Very rare (popmax 8.48e-05%, nfe); Associated with osteoporosis, childhood- or juvenile-onset, with developmental delay.

What condition is associated with COPB2 p.Ser423fs (c.1266dup)?

COPB2 p.Ser423fs (c.1266dup) is associated with osteoporosis, childhood- or juvenile-onset, with developmental delay (ClinVar).

How common is COPB2 p.Ser423fs (c.1266dup) in the general population?

COPB2 p.Ser423fs (c.1266dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

COPB2 p.Ser423fs

c.1266dup · rs2472899515 · VCV2431662

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

osteoporosis, childhood- or juvenile-onset, with developmental delay

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	predicted	premature termination codon in exon 11 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	GERP 2.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,850 alleles

Overall 6.85e-05% 1/1,459,696 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.Ser423fs
Coding: c.1266dup
MANE Select: NM_004766
dbSNP: rs2472899515
Type: Duplication
Location: chr3:139369483 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 423: a β-strand

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

Disease context

osteoporosis, childhood- or juvenile-onset, with developmental delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COPB2 p.His556fs Likely pathogenic ★ same condition
COPB2 p.Val83fs Pathogenic ★ same condition
COPB2 p.Thr636fs Uncertain significance ★ same condition
COPB2 c.1401+2T>A Likely pathogenic ★ same condition
COPB2 p.Glu493fs Likely pathogenic ★ same condition
COPB2 c.751+4A>G Uncertain significance ★ same condition
COPB2 p.Leu439Ser Uncertain significance ★ ⚠ same condition
COPB2 p.Lys413fs Uncertain significance ★ same condition

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-ser423fs (accessed [today's date]).

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