Is COPB2 p.Ile114= (c.342T>C) pathogenic?

COPB2 p.Ile114= (c.342T>C) is classified Benign/Likely benign in COPB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). Low-frequency (popmax 3.31%, eas); Associated with microcephaly 19, primary, autosomal recessive.

What condition is associated with COPB2 p.Ile114= (c.342T>C)?

COPB2 p.Ile114= (c.342T>C) is associated with microcephaly 19, primary, autosomal recessive (ClinVar).

How common is COPB2 p.Ile114= (c.342T>C) in the general population?

COPB2 p.Ile114= (c.342T>C) is low-frequency (popmax 3.31%, eas) (gnomAD).

COPB2 p.Ile114=

c.342T>C · rs74860267 · VCV1585446

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.31%, eas)

Conditions

microcephaly 19, primary, autosomal recessive

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 1.2	GERP -0.75, phastCons 1
Overall
CADD	7.616	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.31% East Asian · 1,479/44,750 alleles

Filtering AF 3.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.11%

Overall 0.691% 11,049/1,599,032 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	3.31%	30
Admixed American	0.837%	119
European (non-Finnish)	0.679%	147
Remaining individualsnot grpmax-eligible	0.593%	169
South Asian	0.552%	181
Finnishnot grpmax-eligible	0.219%	456
Ashkenazi Jewishnot grpmax-eligible	0.174%	574
Middle Eastern	0.15%	665
African / African-American	0.103%	975

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.Ile114=
Coding: c.342T>C
MANE Select: NM_004766
dbSNP: rs74860267
Type: single nucleotide variant
Location: chr3:139379060 (GRCh38)
Gene constraint: LOEUF 0.177 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.75 · 2 PDB
Residue 114: a β-strand

Full COPB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 19, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COPB2 c.1095-23T>C Benign ★★ same condition
COPB2 c.141+20G>T Benign ★★ same condition
COPB2 c.2626-20C>A Benign ★★ same condition
COPB2 p.Arg254Cys Pathogenic same condition
COPB2 p.Val222fs Conflicting classifications of pathogenicity ★ same condition
COPB2 p.Glu646Lys Uncertain significance ★★ ⚠ same type
COPB2 p.Glu879Lys Uncertain significance ★★ ⚠ same type
COPB2 p.Ile864Thr Uncertain significance ★★ ⚠ 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-ile114 (accessed [today's date]).

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