Is COPB2 p.Ile335= (c.1005T>C) pathogenic?

COPB2 p.Ile335= (c.1005T>C) is classified Likely benign in COPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). Very rare (popmax 0.00847%, nfe).

How common is COPB2 p.Ile335= (c.1005T>C) in the general population?

COPB2 p.Ile335= (c.1005T>C) is very rare (popmax 0.00847%, nfe) (gnomAD).

COPB2 p.Ile335=

c.1005T>C · VCV4737893

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00847%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1, phastCons 1
Overall
CADD	11.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00847% European (non-Finnish) · 100/1,180,032 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00799% 129/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,345
European (non-Finnish)grpmax	0.00847%	11,800
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00267%	37,454
Admixed American	0.00167%	60,000

Ashkenazi Jewish 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.Ile335=
Coding: c.1005T>C
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139373302 (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-ile335 (accessed [today's date]).

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