Is COPE p.Arg85Cys (c.253C>T) pathogenic?

COPE p.Arg85Cys (c.253C>T) is classified Uncertain significance in COPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.2152); Very rare (popmax 0.00446%, eas).

How common is COPE p.Arg85Cys (c.253C>T) in the general population?

COPE p.Arg85Cys (c.253C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about COPE p.Arg85Cys (c.253C>T)?

AlphaMissense predicts likely benign (score 0.2152) — an in-silico prediction, not a clinical call.

COPE p.Arg85Cys

c.253C>T · rs770121303 · VCV2556385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2152 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2152	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.49 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00273% 44/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
European (non-Finnish)	0.00347%	28,781
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: COPE
Protein: p.Arg85Cys
Coding: c.253C>T
MANE Select: NM_007263
dbSNP: rs770121303
Type: single nucleotide variant
Location: chr19:18911008 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 2 PDB
Residue 85: an α-helix

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

Similar variants

COPE p.Ala124Thr Uncertain significance ★ ⚠ same type
COPE p.Ala139Val Uncertain significance ★ ⚠ same type
COPE p.Ala185Thr Uncertain significance ★ ⚠ same type
COPE p.Ala224Thr Uncertain significance ★ ⚠ same type
COPE p.Ala25Thr Uncertain significance ★ ⚠ same type
COPE p.Ala2Gly Uncertain significance ★ ⚠ same type
COPE p.Ala308Thr Uncertain significance ★ ⚠ same type
COPE p.Ala59Val 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/cope-p-arg85cys (accessed [today's date]).

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