Is COPS7B p.Thr138Ala (c.412A>G) pathogenic?

COPS7B p.Thr138Ala (c.412A>G) is classified Uncertain significance in COPS7B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.065); Very rare (popmax 0.00223%, eas).

How common is COPS7B p.Thr138Ala (c.412A>G) in the general population?

COPS7B p.Thr138Ala (c.412A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about COPS7B p.Thr138Ala (c.412A>G)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

COPS7B p.Thr138Ala

c.412A>G · VCV4005803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP -0.36, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 19 kb · p 2e-05 · regional, not allelic
Overall
CADD	19.12	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 0.00223% East Asian · 1/44,894 alleles

Overall 0.000137% 2/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
European (non-Finnish)	8.47e-05%	1,180,022

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.Thr138Ala
Coding: c.412A>G
MANE Select: NM_022730
Type: single nucleotide variant
Location: chr2:231796190 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 85.00 · 25 PDB
Residue 138: the pci domain

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-thr138ala (accessed [today's date]).

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