Is COPS8 p.Ala144Val (c.431C>T) pathogenic?

COPS8 p.Ala144Val (c.431C>T) is classified Uncertain significance in COPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.5819); Very rare (popmax 0.00991%, sas).

How common is COPS8 p.Ala144Val (c.431C>T) in the general population?

COPS8 p.Ala144Val (c.431C>T) is very rare (popmax 0.00991%, sas) (gnomAD).

What do computational predictors say about COPS8 p.Ala144Val (c.431C>T)?

AlphaMissense predicts likely pathogenic (score 0.5819) — an in-silico prediction, not a clinical call.

COPS8 p.Ala144Val

c.431C>T · VCV4232845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00991%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5819	likely pathogenic
REVEL	0.595	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 12 kb · p 0.012 · regional, not allelic
Overall
CADD	28.1	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 0.00991% South Asian · 9/90,860 alleles

Filtering AF 0.00515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.000685% 10/1,460,762 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00991%	10,096
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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: COPS8
Protein: p.Ala144Val
Coding: c.431C>T
MANE Select: NM_006710
Type: single nucleotide variant
Location: chr2:237094189 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.42 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 28 PDB
Residue 144: the pci domain

Full COPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS8 p.Ala119Gly Uncertain significance ★ ⚠ same type
COPS8 p.Ala119Thr Uncertain significance ★ ⚠ same type
COPS8 p.Ala95Thr Uncertain significance ★ ⚠ same type
COPS8 p.Arg110Lys Uncertain significance ★ ⚠ same type
COPS8 p.Arg116Cys Uncertain significance ★ ⚠ same type
COPS8 p.Arg160Ser Uncertain significance ★ ⚠ same type
COPS8 p.Arg80Ser Uncertain significance ★ ⚠ same type
COPS8 p.Asn68His 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/cops8-p-ala144val (accessed [today's date]).

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