Is COPS6 p.Asp101Glu (c.303C>A) pathogenic?

COPS6 p.Asp101Glu (c.303C>A) is classified Uncertain significance in COPS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely pathogenic (0.7825); Ultra-rare (popmax 0.0534%, amr).

How common is COPS6 p.Asp101Glu (c.303C>A) in the general population?

COPS6 p.Asp101Glu (c.303C>A) is ultra-rare (popmax 0.0534%, amr) (gnomAD).

What do computational predictors say about COPS6 p.Asp101Glu (c.303C>A)?

AlphaMissense predicts likely pathogenic (score 0.7825) — an in-silico prediction, not a clinical call.

COPS6 p.Asp101Glu

c.303C>A · VCV4005792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7825	likely pathogenic
REVEL	0.279	benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 2,097 bp · p 7.5e-07 · regional, not allelic
Overall
CADD	23.9	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 0.0534% Admixed American · 32/59,908 alleles

Filtering AF 0.0388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00198% 32/1,613,346 alleles · ultra-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: COPS6
Protein: p.Asp101Glu
Coding: c.303C>A
MANE Select: NM_006833
Type: single nucleotide variant
Location: chr7:100089715 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 29 PDB
Residue 101: the mpn domain

Full COPS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS6 p.Ala290Thr Uncertain significance ★ ⚠ same type
COPS6 p.Ala42Val Uncertain significance ★ ⚠ same type
COPS6 p.Ala7Val Uncertain significance ★ ⚠ same type
COPS6 p.Asn307Lys Uncertain significance ★ ⚠ same type
COPS6 p.Asp173Gly Uncertain significance ★ same type
COPS6 p.Glu240Ala Uncertain significance ★ ⚠ same type
COPS6 p.Gly129Glu Uncertain significance ★ ⚠ same type
COPS6 p.Gly293Ser 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/cops6-p-asp101glu (accessed [today's date]).

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