Is COPA p.Arg1083His (c.3248G>A) pathogenic?

COPA p.Arg1083His (c.3248G>A) is classified Conflicting classifications of pathogenicity in COPA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-10-27). AlphaMissense: likely benign (0.2098); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with COPA p.Arg1083His (c.3248G>A)?

COPA p.Arg1083His (c.3248G>A) is associated with Inborn genetic diseases, autoimmune interstitial lung disease-arthritis syndrome (ClinVar).

How common is COPA p.Arg1083His (c.3248G>A) in the general population?

COPA p.Arg1083His (c.3248G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COPA p.Arg1083His (c.3248G>A)?

AlphaMissense predicts likely benign (score 0.2098) — an in-silico prediction, not a clinical call.

COPA p.Arg1083His

c.3248G>A · rs141211632 · VCV1002708

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2098	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 42 kb · p 1.1e-24 · regional, not allelic
Overall
CADD	28.3	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 0.00134% African / African-American · 1/74,870 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,613,942 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-Americangrpmax	0.00134%	74,870
South Asian	0.0011%	91,082
European (non-Finnish)	0.000593%	168,568

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1083His
Coding: c.3248G>A
MANE Select: NM_004371
dbSNP: rs141211632
Type: single nucleotide variant
Location: chr1:160291829 (GRCh38)
Gene constraint: LOEUF 0.098 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.85 · 3 PDB
Residue 1083: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune interstitial lung disease-arthritis syndrome

Similar variants

COPA p.Arg1083Leu Likely benign ★★ same residue
COPA p.Arg1083Cys 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

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-arg1083his (accessed [today's date]).

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