Is COPS4 p.Ala4Val (c.11C>T) pathogenic?

COPS4 p.Ala4Val (c.11C>T) is classified Uncertain significance in COPS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: likely benign (0.0937); Very rare (popmax 0.00807%, nfe).

How common is COPS4 p.Ala4Val (c.11C>T) in the general population?

COPS4 p.Ala4Val (c.11C>T) is very rare (popmax 0.00807%, nfe) (gnomAD).

What do computational predictors say about COPS4 p.Ala4Val (c.11C>T)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

COPS4 p.Ala4Val

c.11C>T · rs139460382 · VCV2257995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00807%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -7.22	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 4.7	GERP 5.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.32 · regional, not allelic
Overall
CADD	22.7	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 0.00807% European (non-Finnish) · 93/1,152,152 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00623%

Overall 0.0063% 99/1,570,208 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00807%	12,389
Remaining individualsnot grpmax-eligible	0.00335%	29,836
African / African-American	0.00271%	36,929
Finnishnot grpmax-eligible	0.00171%	58,572
South Asian	0.00111%	89,906

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.Ala4Val
Coding: c.11C>T
MANE Select: NM_016129
dbSNP: rs139460382
Type: single nucleotide variant
Location: chr4:83035235 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.79 · 29 PDB
Residue 4: 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.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
COPS4 p.Cys70Ser 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-ala4val (accessed [today's date]).

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