Is COPS7B p.Thr250Ala (c.748A>G) pathogenic?

COPS7B p.Thr250Ala (c.748A>G) is classified Uncertain significance in COPS7B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0568); Ultra-rare (popmax 0.0179%, nfe).

How common is COPS7B p.Thr250Ala (c.748A>G) in the general population?

COPS7B p.Thr250Ala (c.748A>G) is ultra-rare (popmax 0.0179%, nfe) (gnomAD).

What do computational predictors say about COPS7B p.Thr250Ala (c.748A>G)?

AlphaMissense predicts likely benign (score 0.0568) — an in-silico prediction, not a clinical call.

COPS7B p.Thr250Ala

c.748A>G · rs368362019 · VCV2461064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0568 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0568	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.51	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 4.6	GERP 0.81, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 19 kb · p 2e-05 · regional, not allelic
Overall
CADD	17.14	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 0.0179% European (non-Finnish) · 209/1,165,586 alleles

Filtering AF 0.0159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0152%

Overall 0.0135% 214/1,585,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0179%	5,577
Remaining individualsnot grpmax-eligible	0.00488%	20,488
African / African-American	0.00269%	37,131

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.Thr250Ala
Coding: c.748A>G
MANE Select: NM_022730
dbSNP: rs368362019
Type: single nucleotide variant
Location: chr2:231807598 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 85.00 · 25 PDB
Residue 250: the 'disordered' region

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

Similar variants

COPS7B p.Thr250Pro Uncertain significance ★ ⚠ same residue
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

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-thr250ala (accessed [today's date]).

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