Is COPB2 p.His815Gln (c.2445T>G) pathogenic?

COPB2 p.His815Gln (c.2445T>G) is classified Uncertain significance in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-24). AlphaMissense: likely benign (0.1081); Ultra-rare (popmax 0.0283%, amr).

How common is COPB2 p.His815Gln (c.2445T>G) in the general population?

COPB2 p.His815Gln (c.2445T>G) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about COPB2 p.His815Gln (c.2445T>G)?

AlphaMissense predicts likely benign (score 0.1081) — an in-silico prediction, not a clinical call.

COPB2 p.His815Gln

c.2445T>G · rs765417878 · VCV2048309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1081	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -5.56	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 0.63	GERP -0.23, phastCons 0.86
Regional constraint	o/e 0.97	unconstrained · MANE · 1,470 bp · p 0.7 · regional, not allelic
Overall
CADD	15.55	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Admixed American · 17/59,970 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00186% 30/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,528
Remaining individualsnot grpmax-eligible	0.0192%	5,208
European (non-Finnish)	8.47e-05%	1,179,970

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.His815Gln
Coding: c.2445T>G
MANE Select: NM_004766
dbSNP: rs765417878
Type: single nucleotide variant
Location: chr3:139359037 (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 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-his815gln (accessed [today's date]).

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