Is COP1 p.Arg295Thr (c.884G>C) pathogenic?

COP1 p.Arg295Thr (c.884G>C) is classified Benign in COP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: ambiguous (0.5142); Low-frequency (popmax 4.4%, eas).

How common is COP1 p.Arg295Thr (c.884G>C) in the general population?

COP1 p.Arg295Thr (c.884G>C) is low-frequency (popmax 4.4%, eas) (gnomAD).

What do computational predictors say about COP1 p.Arg295Thr (c.884G>C)?

AlphaMissense predicts ambiguous (score 0.5142) — an in-silico prediction, not a clinical call.

COP1 p.Arg295Thr

c.884G>C · rs75124417 · VCV722313

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5142 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.4%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5142	ambiguous
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.28	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 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 83 kb · p 0.064 · regional, not allelic
Overall
CADD	26.1	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 4.4% East Asian · 1,953/44,432 alleles

Filtering AF 4.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.17%

Overall 0.138% 2,207/1,600,008 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	4.4%	23
South Asian	0.101%	991
Remaining individualsnot grpmax-eligible	0.0937%	1,067
Middle Eastern	0.0167%	5,990
Admixed American	0.0101%	9,880
European (non-Finnish)	0.0082%	12,188
Ashkenazi Jewishnot grpmax-eligible	0.00682%	14,671

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.Arg295Thr
Coding: c.884G>C
MANE Select: NM_022457
dbSNP: rs75124417
Type: single nucleotide variant
Location: chr1:176136495 (GRCh38)
Gene constraint: LOEUF 0.557 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 75.64 · 7 PDB

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

Similar variants

COP1 c.1142-7C>T Likely 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
COP1 p.Ala7Val Uncertain significance ★ ⚠ same type
COP1 p.Arg378Cys 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-arg295thr (accessed [today's date]).

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