Is COPA p.Arg745Cys (c.2233C>T) pathogenic?

COPA p.Arg745Cys (c.2233C>T) is classified Uncertain significance in COPA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.8371); Ultra-rare (popmax 0.0822%, mid); Associated with Inborn genetic diseases.

What condition is associated with COPA p.Arg745Cys (c.2233C>T)?

COPA p.Arg745Cys (c.2233C>T) is associated with Inborn genetic diseases, autoimmune interstitial lung disease-arthritis syndrome (ClinVar).

How common is COPA p.Arg745Cys (c.2233C>T) in the general population?

COPA p.Arg745Cys (c.2233C>T) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about COPA p.Arg745Cys (c.2233C>T)?

AlphaMissense predicts likely pathogenic (score 0.8371) — an in-silico prediction, not a clinical call.

COPA p.Arg745Cys

c.2233C>T · rs763748181 · VCV952472

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8371	likely pathogenic
REVEL	0.497	indeterminate
SaProt	LLR -13.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 0.63, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 42 kb · p 1.1e-24 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0822% Middle Eastern · 5/6,084 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00279% 45/1,613,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,217
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00297%	33,715
East Asian	0.00223%	44,896

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: COPA
Protein: p.Arg745Cys
Coding: c.2233C>T
MANE Select: NM_004371
dbSNP: rs763748181
Type: single nucleotide variant
Location: chr1:160297373 (GRCh38)
Gene constraint: LOEUF 0.098 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.85 · 3 PDB

Full COPA 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

Also linked: autoimmune interstitial lung disease-arthritis syndrome

Similar variants

COPA p.Arg745His Conflicting classifications of pathogenicity ★ ⚠ same residue
COPA p.Arg233His Pathogenic/Likely pathogenic ★★ same condition
COPA p.Glu241Lys Pathogenic ★★ same condition
COPA p.Ala111Thr Uncertain significance ★★ ⚠ same condition
COPA p.Ala176Val Uncertain significance ★★ ⚠ same condition
COPA p.Ala407Val Uncertain significance ★★ ⚠ same condition
COPA p.Ala422Thr Uncertain significance ★★ ⚠ same condition
COPA p.Ala469Val 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/copa-p-arg745cys (accessed [today's date]).

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