Is COPB2 p.Thr848Ile (c.2543C>T) pathogenic?

COPB2 p.Thr848Ile (c.2543C>T) is classified Conflicting classifications of pathogenicity in COPB2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-25). AlphaMissense: likely benign (0.0689); Rare (popmax 0.743%, mid); Associated with Inborn genetic diseases.

What condition is associated with COPB2 p.Thr848Ile (c.2543C>T)?

COPB2 p.Thr848Ile (c.2543C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COPB2 p.Thr848Ile (c.2543C>T) in the general population?

COPB2 p.Thr848Ile (c.2543C>T) is rare (popmax 0.743%, mid) (gnomAD).

What do computational predictors say about COPB2 p.Thr848Ile (c.2543C>T)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

COPB2 p.Thr848Ile

c.2543C>T · rs138135248 · VCV1496339

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.743%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.33	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 0.37	GERP -2.4
Regional constraint	o/e 0.97	unconstrained · MANE · 1,470 bp · p 0.7 · regional, not allelic
Overall
CADD	6.439	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 0.743% Middle Eastern · 45/6,060 alleles

Filtering AF 0.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.509%

Overall 0.023% 370/1,610,652 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.743%	135
Ashkenazi Jewishnot grpmax-eligible	0.105%	954
Admixed American	0.085%	1,176
Remaining individualsnot grpmax-eligible	0.0465%	2,151
South Asian	0.0286%	3,500
European (non-Finnish)	0.0155%	6,468
African / African-American	0.00801%	12,479

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.Thr848Ile
Coding: c.2543C>T
MANE Select: NM_004766
dbSNP: rs138135248
Type: single nucleotide variant
Location: chr3:139358754 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 848: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COPB2 p.Glu646Lys Uncertain significance ★★ ⚠ same condition
COPB2 p.Glu879Lys Uncertain significance ★★ ⚠ same condition
COPB2 p.Ile864Thr Uncertain significance ★★ ⚠ same condition
COPB2 p.Leu649Phe Uncertain significance ★★ ⚠ same condition
COPB2 p.Ser135Ala Uncertain significance ★★ ⚠ same condition
COPB2 p.Asn285Ser Benign/Likely benign ★★ ⚠ same condition
COPB2 p.Ala480Thr Uncertain significance ★ ⚠ same condition
COPB2 p.Ala719Thr 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-thr848ile (accessed [today's date]).

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