Is COPA p.Val494Ile (c.1480G>A) pathogenic?

COPA p.Val494Ile (c.1480G>A) is classified Conflicting classifications of pathogenicity in COPA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.1411); Very rare (popmax 0.00667%, amr); Associated with autoimmune interstitial lung disease-arthritis syndrome.

What condition is associated with COPA p.Val494Ile (c.1480G>A)?

COPA p.Val494Ile (c.1480G>A) is associated with autoimmune interstitial lung disease-arthritis syndrome (ClinVar).

How common is COPA p.Val494Ile (c.1480G>A) in the general population?

COPA p.Val494Ile (c.1480G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about COPA p.Val494Ile (c.1480G>A)?

AlphaMissense predicts likely benign (score 0.1411) — an in-silico prediction, not a clinical call.

COPA p.Val494Ile

Q: How is Autoimmune interstitial lung disease-arthritis syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1480G>A · rs750319602 · VCV969535

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune interstitial lung disease-arthritis syndrome

Computational evidence

Protein change
AlphaMissense	0.1411	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -10.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 42 kb · p 1.1e-24 · regional, not allelic
Overall
CADD	24.8	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 0.00667% Admixed American · 4/59,988 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00136% 22/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,997
African / African-American	0.00534%	18,724
East Asian	0.00445%	22,451
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000847%	118,005

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: COPA
Protein: p.Val494Ile
Coding: c.1480G>A
MANE Select: NM_004371
dbSNP: rs750319602
Type: single nucleotide variant
Location: chr1:160305736 (GRCh38)
Gene constraint: LOEUF 0.098 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.85 · 3 PDB

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

Disease context

autoimmune interstitial lung disease-arthritis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autoimmune interstitial lung disease-arthritis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

COPA p.Arg233His Pathogenic/Likely pathogenic ★★ same condition
COPA p.Glu241Lys Pathogenic ★★ same condition
COPA p.Ala111Thr Uncertain significance ★★ ⚠ same condition
COPA p.Ala176Val Uncertain significance ★★ ⚠ same condition
COPA p.Ala407Val Uncertain significance ★★ ⚠ same condition
COPA p.Ala422Thr Uncertain significance ★★ ⚠ same condition
COPA p.Ala469Val Uncertain significance ★★ ⚠ same condition
COPA p.Ala510Thr Uncertain significance ★★ ⚠ same condition

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/copa-p-val494ile (accessed [today's date]).

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