Is COPB2 p.His467Arg (c.1400A>G) pathogenic?

COPB2 p.His467Arg (c.1400A>G) is classified Uncertain significance in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1557); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with COPB2 p.His467Arg (c.1400A>G)?

COPB2 p.His467Arg (c.1400A>G) is associated with Inborn genetic diseases (ClinVar).

How common is COPB2 p.His467Arg (c.1400A>G) in the general population?

COPB2 p.His467Arg (c.1400A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COPB2 p.His467Arg (c.1400A>G)?

AlphaMissense predicts likely benign (score 0.1557) — an in-silico prediction, not a clinical call.

COPB2 p.His467Arg

c.1400A>G · VCV3268951

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1557 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1557	likely benign
REVEL	0.615	indeterminate
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.34	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	32.0	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 0.00134% African / African-American · 1/74,692 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000374% 6/1,603,956 alleles · very rare exomes 5/1,451,688 · genomes 1/152,268 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,878
African / African-Americangrpmax	0.00134%	74,692
South Asian	0.00112%	89,538
European (non-Finnish)	0.000256%	391,291

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His467Arg
Coding: c.1400A>G
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139369262 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 467: a β-strand

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.His467Tyr Uncertain significance ★ ⚠ same residue
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

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-his467arg (accessed [today's date]).

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