Is COPS4 p.Thr88Ile (c.263C>T) pathogenic?

COPS4 p.Thr88Ile (c.263C>T) is classified Uncertain significance in COPS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely pathogenic (0.594); Very rare (popmax 0.00134%, afr).

How common is COPS4 p.Thr88Ile (c.263C>T) in the general population?

COPS4 p.Thr88Ile (c.263C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COPS4 p.Thr88Ile (c.263C>T)?

AlphaMissense predicts likely pathogenic (score 0.594) — an in-silico prediction, not a clinical call.

COPS4 p.Thr88Ile

c.263C>T · VCV3495994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.594	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -8.72	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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 17 kb · p 2.2e-21 · regional, not allelic
Overall
CADD	22.0	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 0.00134% African / African-American · 1/74,728 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,458,484 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,728
South Asian	0.00111%	89,896
European (non-Finnish)	0.00017%	589,477

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: COPS4
Protein: p.Thr88Ile
Coding: c.263C>T
MANE Select: NM_016129
Type: single nucleotide variant
Location: chr4:83049274 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.79 · 29 PDB
Residue 88: an α-helix

Full COPS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS4 p.Ala10Ser Uncertain significance ★ ⚠ same type
COPS4 p.Ala4Val Uncertain significance ★ ⚠ same type
COPS4 p.Arg27Cys Uncertain significance ★ ⚠ same type
COPS4 p.Arg27His Uncertain significance ★ ⚠ same type
COPS4 p.Arg27Pro Uncertain significance ★ ⚠ same type
COPS4 p.Arg364Gln Uncertain significance ★ ⚠ same type
COPS4 p.Asn180Ser Uncertain significance ★ ⚠ same type
COPS4 p.Asp8Gly 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/cops4-p-thr88ile (accessed [today's date]).

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