Is COPS8 p.Asn94Ser (c.281A>G) pathogenic?

COPS8 p.Asn94Ser (c.281A>G) is classified Uncertain significance in COPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely benign (0.0408); Ultra-rare (popmax 0.0178%, eas).

How common is COPS8 p.Asn94Ser (c.281A>G) in the general population?

COPS8 p.Asn94Ser (c.281A>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about COPS8 p.Asn94Ser (c.281A>G)?

AlphaMissense predicts likely benign (score 0.0408) — an in-silico prediction, not a clinical call.

COPS8 p.Asn94Ser

c.281A>G · VCV3835601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0408 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0408	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.07	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 -3.4	GERP -3.8
Regional constraint	o/e 0.84	unconstrained · MANE · 12 kb · p 0.012 · regional, not allelic
Overall
CADD	0.61	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 0.0178% East Asian · 8/44,882 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00198% 32/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
Admixed American	0.005%	20,000
South Asian	0.0022%	45,538
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.00144%	69,411
African / African-American	0.00133%	74,918

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: COPS8
Protein: p.Asn94Ser
Coding: c.281A>G
MANE Select: NM_006710
Type: single nucleotide variant
Location: chr2:237089944 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.42 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 28 PDB
Residue 94: the pci domain

Full COPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS8 p.Ala119Gly Uncertain significance ★ ⚠ same type
COPS8 p.Ala119Thr Uncertain significance ★ ⚠ same type
COPS8 p.Ala144Val Uncertain significance ★ ⚠ same type
COPS8 p.Ala95Thr Uncertain significance ★ ⚠ same type
COPS8 p.Arg110Lys Uncertain significance ★ ⚠ same type
COPS8 p.Arg116Cys Uncertain significance ★ ⚠ same type
COPS8 p.Arg160Ser Uncertain significance ★ ⚠ same type
COPS8 p.Arg80Ser 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/cops8-p-asn94ser (accessed [today's date]).

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