Is COPG1 p.Arg474His (c.1421G>A) pathogenic?

COPG1 p.Arg474His (c.1421G>A) is classified Uncertain significance in COPG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely pathogenic (0.9905); Ultra-rare (popmax 0.011%, sas).

How common is COPG1 p.Arg474His (c.1421G>A) in the general population?

COPG1 p.Arg474His (c.1421G>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about COPG1 p.Arg474His (c.1421G>A)?

AlphaMissense predicts likely pathogenic (score 0.9905) — an in-silico prediction, not a clinical call.

COPG1 p.Arg474His

c.1421G>A · VCV3268958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9905	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -14.06	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 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 28 kb · p 1.9e-14 · regional, not allelic
Overall
CADD	28.1	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 0.011% South Asian · 10/91,080 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00143% 23/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
East Asian	0.00891%	11,220
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Finnishnot grpmax-eligible	0.00156%	64,008
African / African-American	0.00133%	74,910
European (non-Finnish)	0.000254%	393,348

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: COPG1
Protein: p.Arg474His
Coding: c.1421G>A
MANE Select: NM_016128
Type: single nucleotide variant
Location: chr3:129265745 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.09 · 1 PDB

Full COPG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPG1 p.Arg474Gly Uncertain significance ★ ⚠ same residue
COPG1 p.Arg247His Uncertain significance ★★ ⚠ same type
COPG1 p.Leu864Met Uncertain significance ★★ ⚠ same type
COPG1 p.Thr64Met Uncertain significance ★★ ⚠ same type
COPG1 c.91-11T>C Benign ★★ same type
COPG1 c.939+13C>G Benign ★★ same type
COPG1 p.His221= Benign ★★ same type
COPG1 p.Ile92= Benign/Likely 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/copg1-p-arg474his (accessed [today's date]).

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