Is COPB1 p.Ile74Val (c.220A>G) pathogenic?

COPB1 p.Ile74Val (c.220A>G) is classified Uncertain significance in COPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely benign (0.0692); Ultra-rare (popmax 0.0223%, eas).

How common is COPB1 p.Ile74Val (c.220A>G) in the general population?

COPB1 p.Ile74Val (c.220A>G) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about COPB1 p.Ile74Val (c.220A>G)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

COPB1 p.Ile74Val

c.220A>G · VCV3495959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.83	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 6.2	GERP 0.96, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,669 bp · p 0.12 · regional, not allelic
Overall
CADD	20.7	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 0.0223% East Asian · 10/44,820 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00136% 22/1,613,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,482
South Asian	0.00988%	10,120
Admixed American	0.00167%	60,002
European (non-Finnish)	0.00017%	589,904

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: COPB1
Protein: p.Ile74Val
Coding: c.220A>G
MANE Select: NM_001144061
Type: single nucleotide variant
Location: chr11:14494311 (GRCh38)
Gene constraint: LOEUF 0.269 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.55

Full COPB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPB1 p.Met16Val Uncertain significance ★★ ⚠ same type
COPB1 p.Ser410Arg Uncertain significance ★★ ⚠ same type
COPB1 c.958-4T>G Likely benign ★★ same type
COPB1 p.Leu271= Likely benign ★★ same type
COPB1 p.Phe551Val Pathogenic ★ same type
COPB1 c.1455+2T>C Uncertain significance ★ same type
COPB1 c.1616+2T>C Uncertain significance ★ same type
COPB1 c.-57-2A>G Conflicting classifications of pathogenicity ★ ⚠ 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/copb1-p-ile74val (accessed [today's date]).

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