Is COPA p.Met332Val (c.994A>G) pathogenic?

COPA p.Met332Val (c.994A>G) is classified Benign/Likely benign in COPA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0524); Low-frequency (popmax 1.06%, afr); Associated with autoimmune interstitial lung disease-arthritis syndrome.

What condition is associated with COPA p.Met332Val (c.994A>G)?

COPA p.Met332Val (c.994A>G) is associated with autoimmune interstitial lung disease-arthritis syndrome (ClinVar).

How common is COPA p.Met332Val (c.994A>G) in the general population?

COPA p.Met332Val (c.994A>G) is low-frequency (popmax 1.06%, afr) (gnomAD).

What do computational predictors say about COPA p.Met332Val (c.994A>G)?

AlphaMissense predicts likely benign (score 0.0524) — an in-silico prediction, not a clinical call.

COPA p.Met332Val

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.994A>G · rs115066135 · VCV542646

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0524 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.06%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune interstitial lung disease-arthritis syndrome

Computational evidence

Protein change
AlphaMissense	0.0524	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -4.97	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 1.6	GERP 2.2, phastCons 0.98
Regional constraint	o/e 0.72	unconstrained · MANE · 42 kb · p 1.1e-24 · regional, not allelic
Overall
CADD	16.33	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 1.06% African / African-American · 792/75,006 alleles

Filtering AF 0.995% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.971%

Overall 0.0551% 890/1,614,080 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.06%	95
Remaining individualsnot grpmax-eligible	0.0816%	1,226
Middle Eastern	0.066%	1,516
Admixed American	0.0583%	1,715
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000339%	295,003

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.Met332Val
Coding: c.994A>G
MANE Select: NM_004371
dbSNP: rs115066135
Type: single nucleotide variant
Location: chr1:160311950 (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.Met332Leu Uncertain significance ★ ⚠ 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-met332val (accessed [today's date]).

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