Is COPS7B p.Thr223Ala (c.667A>G) pathogenic?

COPS7B p.Thr223Ala (c.667A>G) is classified Uncertain significance in COPS7B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-12). AlphaMissense: likely benign (0.0975); Ultra-rare (popmax 0.0165%, mid).

How common is COPS7B p.Thr223Ala (c.667A>G) in the general population?

COPS7B p.Thr223Ala (c.667A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about COPS7B p.Thr223Ala (c.667A>G)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

COPS7B p.Thr223Ala

c.667A>G · rs750633175 · VCV2559654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -5.28	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 9.3	GERP 0.77, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 19 kb · p 2e-05 · regional, not allelic
Overall
CADD	20.9	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000205% 3/1,461,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
East Asian	0.00446%	22,422

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: COPS7B
Protein: p.Thr223Ala
Coding: c.667A>G
MANE Select: NM_022730
dbSNP: rs750633175
Type: single nucleotide variant
Location: chr2:231807517 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 85.00 · 25 PDB
Residue 223: the 'disordered' region

Full COPS7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS7B p.Ala222Pro Uncertain significance ★ ⚠ same type
COPS7B p.Ala244Thr Uncertain significance ★ ⚠ same type
COPS7B p.Ala29Thr Uncertain significance ★ ⚠ same type
COPS7B p.Arg160Cys Uncertain significance ★ ⚠ same type
COPS7B p.Arg160His Uncertain significance ★ ⚠ same type
COPS7B p.Arg163Gly Uncertain significance ★ ⚠ same type
COPS7B p.Arg263His Uncertain significance ★ ⚠ same type
COPS7B p.Asn215Ile 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/cops7b-p-thr223ala (accessed [today's date]).

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