Is COPE p.Leu216Arg (c.647T>G) pathogenic?

COPE p.Leu216Arg (c.647T>G) is classified Uncertain significance in COPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: ambiguous (0.4612); Very rare (popmax 0.00788%, nfe).

How common is COPE p.Leu216Arg (c.647T>G) in the general population?

COPE p.Leu216Arg (c.647T>G) is very rare (popmax 0.00788%, nfe) (gnomAD).

What do computational predictors say about COPE p.Leu216Arg (c.647T>G)?

AlphaMissense predicts ambiguous (score 0.4612) — an in-silico prediction, not a clinical call.

COPE p.Leu216Arg

c.647T>G · VCV4232779

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00788%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4612	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -10.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.49 · regional, not allelic
Overall
CADD	23.9	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 0.00788% European (non-Finnish) · 93/1,179,578 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00609%

Overall 0.00589% 95/1,612,738 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00788%	12,684
Remaining individualsnot grpmax-eligible	0.0032%	31,216

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.Leu216Arg
Coding: c.647T>G
MANE Select: NM_007263
Type: single nucleotide variant
Location: chr19:18903356 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 2 PDB
Residue 216: an α-helix

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

Similar variants

COPE p.Leu216Met Uncertain significance ★ ⚠ same residue
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

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-leu216arg (accessed [today's date]).

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