Is COPA p.Val1066Met (c.3196G>A) pathogenic?

COPA p.Val1066Met (c.3196G>A) is classified Uncertain significance in COPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-12). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.0156%, eas); Associated with autoimmune interstitial lung disease-arthritis syndrome.

What condition is associated with COPA p.Val1066Met (c.3196G>A)?

COPA p.Val1066Met (c.3196G>A) is associated with autoimmune interstitial lung disease-arthritis syndrome (ClinVar).

How common is COPA p.Val1066Met (c.3196G>A) in the general population?

COPA p.Val1066Met (c.3196G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about COPA p.Val1066Met (c.3196G>A)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

COPA p.Val1066Met

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.3196G>A · rs767991810 · VCV2888839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune interstitial lung disease-arthritis syndrome

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -2.22	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 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 42 kb · p 1.1e-24 · regional, not allelic
Overall
CADD	19.06	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 0.0156% East Asian · 7/44,892 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00142% 23/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,413
Admixed American	0.005%	20,004
South Asian	0.0011%	91,084
European (non-Finnish)	0.00102%	98,337

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.Val1066Met
Coding: c.3196G>A
MANE Select: NM_004371
dbSNP: rs767991810
Type: single nucleotide variant
Location: chr1:160291881 (GRCh38)
Gene constraint: LOEUF 0.098 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.85 · 3 PDB
Residue 1066: an α-helix

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.Val1066Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-val1066met (accessed [today's date]).

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