Is COP1 p.Ile592Val (c.1774A>G) pathogenic?

COP1 p.Ile592Val (c.1774A>G) is classified Uncertain significance in COP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0963); Ultra-rare (popmax 0.0661%, mid).

How common is COP1 p.Ile592Val (c.1774A>G) in the general population?

COP1 p.Ile592Val (c.1774A>G) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

What do computational predictors say about COP1 p.Ile592Val (c.1774A>G)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

COP1 p.Ile592Val

c.1774A>G · VCV4005720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 136 kb · p 5.4e-19 · regional, not allelic
Overall
CADD	21.2	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 0.0661% Middle Eastern · 4/6,048 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000808% 13/1,609,808 alleles · ultra-rare exomes 11/1,457,486 · genomes 2/152,322 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,512
Admixed American	0.00333%	30,010
Remaining individualsnot grpmax-eligible	0.00321%	31,173
Finnishnot grpmax-eligible	0.00156%	64,022
European (non-Finnish)	0.00034%	294,034

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: COP1
Protein: p.Ile592Val
Coding: c.1774A>G
MANE Select: NM_022457
Type: single nucleotide variant
Location: chr1:175989435 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 75.64 · 7 PDB
Residue 592: a β-strand

Full COP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COP1 p.Ile592Ser Uncertain significance ★ ⚠ same residue
COP1 c.1142-7C>T Likely benign ★★ same type
COP1 p.Arg295Thr Benign ★★ same type
COP1 p.Met299Val Benign ★★ same type
COP1 p.Ala117Val Uncertain significance ★ ⚠ same type
COP1 p.Ala12Ser Uncertain significance ★ ⚠ same type
COP1 p.Ala354Val Uncertain significance ★ ⚠ same type
COP1 p.Ala457Val 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/cop1-p-ile592val (accessed [today's date]).

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