Is COPE p.Arg171Ile (c.512G>T) pathogenic?

COPE p.Arg171Ile (c.512G>T) is classified Uncertain significance in COPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: ambiguous (0.377); Ultra-rare (popmax 0.0167%, mid).

How common is COPE p.Arg171Ile (c.512G>T) in the general population?

COPE p.Arg171Ile (c.512G>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about COPE p.Arg171Ile (c.512G>T)?

AlphaMissense predicts ambiguous (score 0.377) — an in-silico prediction, not a clinical call.

COPE p.Arg171Ile

c.512G>T · VCV3835559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.377 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.377	ambiguous
REVEL	0.105	moderately benign-leaning
SaProt	LLR -9.47	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.037	GERP -1.6, phastCons 0.005
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.49 · regional, not allelic
Overall
CADD	19.53	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 0.0167% Middle Eastern · 1/5,994 alleles

Filtering AF 0.00421% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00437% 68/1,554,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,994
Remaining individualsnot grpmax-eligible	0.0083%	12,044
European (non-Finnish)	0.00531%	18,833
Admixed American	0.00194%	51,576

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.Arg171Ile
Coding: c.512G>T
MANE Select: NM_007263
Type: single nucleotide variant
Location: chr19:18904838 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 2 PDB
Residue 171: 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-arg171ile (accessed [today's date]).

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