Is COPB2 p.Arg209His (c.626G>A) pathogenic?

COPB2 p.Arg209His (c.626G>A) is classified Uncertain significance in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-09). AlphaMissense: likely benign (0.1168); Very rare (popmax 0.0044%, sas).

How common is COPB2 p.Arg209His (c.626G>A) in the general population?

COPB2 p.Arg209His (c.626G>A) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about COPB2 p.Arg209His (c.626G>A)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

COPB2 p.Arg209His

c.626G>A · VCV3709534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -9.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	26.1	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 0.0044% South Asian · 4/90,860 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000893%

Overall 0.000744% 12/1,612,728 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,715
African / African-American	0.00134%	74,870
European (non-Finnish)	0.000594%	168,457

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.Arg209His
Coding: c.626G>A
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139375493 (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.Arg209Cys Uncertain significance ★ ⚠ same residue
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

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-arg209his (accessed [today's date]).

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