Is COP1 p.Ser332Arg (c.996C>A) pathogenic?

COP1 p.Ser332Arg (c.996C>A) is classified Uncertain significance in COP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: ambiguous (0.5027); Very rare (popmax 0.00223%, eas).

How common is COP1 p.Ser332Arg (c.996C>A) in the general population?

COP1 p.Ser332Arg (c.996C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about COP1 p.Ser332Arg (c.996C>A)?

AlphaMissense predicts ambiguous (score 0.5027) — an in-silico prediction, not a clinical call.

COP1 p.Ser332Arg

c.996C>A · rs1162820625 · VCV2608221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5027	ambiguous
REVEL	0.12	moderately benign-leaning
SaProt	LLR -7.48	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 3.3	GERP 0.63, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 83 kb · p 0.064 · regional, not allelic
Overall
CADD	21.3	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 0.00223% East Asian · 1/44,754 alleles

Overall 0.000657% 1/152,168 alleles · very rare

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.Ser332Arg
Coding: c.996C>A
MANE Select: NM_022457
dbSNP: rs1162820625
Type: single nucleotide variant
Location: chr1:176116654 (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.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
COP1 p.Ala7Val 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-ser332arg (accessed [today's date]).

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