Is COPB2 c.1401+2T>A pathogenic?

COPB2 c.1401+2T>A is classified Likely pathogenic in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). Absent from gnomAD v4.1; Associated with osteoporosis, childhood- or juvenile-onset, with developmental delay.

What condition is associated with COPB2 c.1401+2T>A?

COPB2 c.1401+2T>A is associated with osteoporosis, childhood- or juvenile-onset, with developmental delay (ClinVar).

How common is COPB2 c.1401+2T>A in the general population?

COPB2 c.1401+2T>A is absent from gnomAD v4.1 (gnomAD).

COPB2 c.1401+2T>A

VCV4293146

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a LoF-intolerant gene
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.84	donor loss, 2 bp away · masked 0 · deltas
Pangolin	Δ0.89	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Non-coding constraint	Z 3.02	1 kb window · o/e 0.78 · regional · uncalibrated
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COPB2
Coding: c.1401+2T>A
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139369259 (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

Disease context

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

Similar variants

COPB2 c.751+4A>G Uncertain significance ★ same condition
COPB2 p.Leu439Ser Uncertain significance ★ ⚠ same condition
COPB2 c.1206-2A>G Pathogenic same condition
COPB2 p.Glu493fs Likely pathogenic ★ same condition
COPB2 p.His556fs Likely pathogenic ★ same condition
COPB2 p.Val83fs Pathogenic ★ same condition
COPB2 p.Lys413fs Uncertain significance ★ same condition
COPB2 p.Ser423fs Conflicting classifications of pathogenicity ★ 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-c-1401-plus-2t-a (accessed [today's date]).

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