Is COPS5 p.Ile176Val (c.526A>G) pathogenic?

COPS5 p.Ile176Val (c.526A>G) is classified Uncertain significance in COPS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.1151); Very rare (popmax 0.00255%, nfe).

How common is COPS5 p.Ile176Val (c.526A>G) in the general population?

COPS5 p.Ile176Val (c.526A>G) is very rare (popmax 0.00255%, nfe) (gnomAD).

What do computational predictors say about COPS5 p.Ile176Val (c.526A>G)?

AlphaMissense predicts likely benign (score 0.1151) — an in-silico prediction, not a clinical call.

COPS5 p.Ile176Val

c.526A>G · VCV4232820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1151 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00255%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1151	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.49	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 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 19 kb · p 7e-36 · regional, not allelic
Overall
CADD	21.5	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 0.00255% European (non-Finnish) · 30/1,178,080 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00199% 32/1,611,148 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00255%	39,269
Remaining individualsnot grpmax-eligible	0.0016%	62,358
African / African-American	0.00134%	74,838

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: COPS5
Protein: p.Ile176Val
Coding: c.526A>G
MANE Select: NM_006837
Type: single nucleotide variant
Location: chr8:67057427 (GRCh38)
Gene constraint: LOEUF 0.218 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.68 · 31 PDB
Residue 176: the mpn domain

Full COPS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS5 p.Ala22Val Uncertain significance ★ ⚠ same type
COPS5 p.Asn17Ser Uncertain significance ★ ⚠ same type
COPS5 p.Asn18Thr Uncertain significance ★ ⚠ same type
COPS5 p.Asp234Ala Uncertain significance ★ ⚠ same type
COPS5 p.Asp48Asn Uncertain significance ★ ⚠ same type
COPS5 p.Gln279His Uncertain significance ★ ⚠ same type
COPS5 p.Ile333Val Uncertain significance ★ ⚠ same type
COPS5 p.Lys125Glu 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/cops5-p-ile176val (accessed [today's date]).

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