Is COPB2 p.Ser135Ala (c.403T>G) pathogenic?

COPB2 p.Ser135Ala (c.403T>G) is classified Uncertain significance in COPB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0688); Ultra-rare (popmax 0.0168%, mid); Associated with Inborn genetic diseases.

What condition is associated with COPB2 p.Ser135Ala (c.403T>G)?

COPB2 p.Ser135Ala (c.403T>G) is associated with Inborn genetic diseases (ClinVar).

How common is COPB2 p.Ser135Ala (c.403T>G) in the general population?

COPB2 p.Ser135Ala (c.403T>G) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about COPB2 p.Ser135Ala (c.403T>G)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

COPB2 p.Ser135Ala

c.403T>G · VCV3495963

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -6.99	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 28 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	23.3	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 0.0168% Middle Eastern · 1/5,970 alleles

Filtering AF 0.000436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000318%

Overall 0.000757% 12/1,585,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,970
African / African-American	0.00134%	74,670
European (non-Finnish)	0.000863%	115,897

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.Ser135Ala
Coding: c.403T>G
MANE Select: NM_004766
Type: single nucleotide variant
Location: chr3:139378142 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 135: 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.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.Asn285Ser Benign/Likely benign ★★ same condition
COPB2 p.Ala480Thr Uncertain significance ★ ⚠ same condition
COPB2 p.Ala719Thr Uncertain significance ★ ⚠ same condition
COPB2 p.Ala719Val 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-ser135ala (accessed [today's date]).

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