Is COPS3 p.Thr76Met (c.227C>T) pathogenic?

COPS3 p.Thr76Met (c.227C>T) is classified Uncertain significance in COPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-18). AlphaMissense: likely benign (0.1084); Rare (popmax 0.462%, mid).

How common is COPS3 p.Thr76Met (c.227C>T) in the general population?

COPS3 p.Thr76Met (c.227C>T) is rare (popmax 0.462%, mid) (gnomAD).

What do computational predictors say about COPS3 p.Thr76Met (c.227C>T)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

COPS3 p.Thr76Met

c.227C>T · rs147175757 · VCV2346768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.462%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 34 kb · p 4.5e-15 · regional, not allelic
Overall
CADD	29.6	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 0.462% Middle Eastern · 28/6,062 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.283%

Overall 0.0275% 444/1,613,978 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.462%	216
Admixed American	0.07%	1,428
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
South Asian	0.0593%	1,687
Remaining individualsnot grpmax-eligible	0.0448%	2,232
European (non-Finnish)	0.0228%	4,387
African / African-American	0.00267%	37,505
East Asian	0.00223%	44,878

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: COPS3
Protein: p.Thr76Met
Coding: c.227C>T
MANE Select: NM_003653
dbSNP: rs147175757
Type: single nucleotide variant
Location: chr17:17270967 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.64 · 28 PDB

Full COPS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS3 p.Ala371Gly Uncertain significance ★ ⚠ same type
COPS3 p.Arg119Gln Uncertain significance ★ same type
COPS3 p.Asn109Ile Uncertain significance ★ ⚠ same type
COPS3 p.Gln308Arg Uncertain significance ★ same type
COPS3 p.Gln82His Uncertain significance ★ ⚠ same type
COPS3 p.Glu75Lys Uncertain significance ★ ⚠ same type
COPS3 p.Ile228Thr Uncertain significance ★ ⚠ same type
COPS3 p.Ile351Val 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/cops3-p-thr76met (accessed [today's date]).

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