Is COPE p.Arg231His (c.692G>A) pathogenic?

COPE p.Arg231His (c.692G>A) is classified Uncertain significance in COPE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.0853); Very rare (popmax 0.00267%, afr).

How common is COPE p.Arg231His (c.692G>A) in the general population?

COPE p.Arg231His (c.692G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about COPE p.Arg231His (c.692G>A)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

COPE p.Arg231His

c.692G>A · VCV3268953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.49 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00267% African / African-American · 2/74,774 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000808% 13/1,609,688 alleles · very rare exomes 11/1,457,486 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,387
Admixed American	0.00168%	59,484
South Asian	0.0011%	90,648
European (non-Finnish)	0.000764%	130,910

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.Arg231His
Coding: c.692G>A
MANE Select: NM_007263
Type: single nucleotide variant
Location: chr19:18903311 (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-arg231his (accessed [today's date]).

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