Is COPE p.Ser247Ile (c.740G>T) pathogenic?

COPE p.Ser247Ile (c.740G>T) is classified Uncertain significance in COPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.4795); Very rare (popmax 0.00596%, sas).

How common is COPE p.Ser247Ile (c.740G>T) in the general population?

COPE p.Ser247Ile (c.740G>T) is very rare (popmax 0.00596%, sas) (gnomAD).

What do computational predictors say about COPE p.Ser247Ile (c.740G>T)?

AlphaMissense predicts ambiguous (score 0.4795) — an in-silico prediction, not a clinical call.

COPE p.Ser247Ile

c.740G>T · VCV4232789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00596%, sas)

Computational evidence

Protein change
AlphaMissense	0.4795	ambiguous
REVEL	0.38	indeterminate
SaProt	LLR -11.44	damaging
Splicing
SpliceAI	Δ0.34	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.49 · regional, not allelic
Overall
CADD	24.8	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 0.00596% South Asian · 5/83,908 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00146%

Overall 0.000517% 8/1,548,422 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00596%	16,782
Remaining individualsnot grpmax-eligible	0.00167%	59,954
European (non-Finnish)	0.000175%	572,807

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.Ser247Ile
Coding: c.740G>T
MANE Select: NM_007263
Type: single nucleotide variant
Location: chr19:18900445 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 2 PDB

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-ser247ile (accessed [today's date]).

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