Is COPB1 p.Arg539Ser (c.1617A>T) pathogenic?

COPB1 p.Arg539Ser (c.1617A>T) is classified Uncertain significance in COPB1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.8191); Ultra-rare (popmax 0.0664%, nfe).

How common is COPB1 p.Arg539Ser (c.1617A>T) in the general population?

COPB1 p.Arg539Ser (c.1617A>T) is ultra-rare (popmax 0.0664%, nfe) (gnomAD).

What do computational predictors say about COPB1 p.Arg539Ser (c.1617A>T)?

AlphaMissense predicts likely pathogenic (score 0.8191) — an in-silico prediction, not a clinical call.

COPB1 p.Arg539Ser

c.1617A>T · rs140921247 · VCV2305392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0664%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8191	likely pathogenic
REVEL	0.21	benign-leaning
SaProt	LLR -3.31	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP 0.57, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 29 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	21.4	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 0.0664% European (non-Finnish) · 783/1,179,460 alleles

Filtering AF 0.0625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.061%

Overall 0.0528% 852/1,612,232 alleles · ultra-rare exomes 802/1,460,554 · genomes 50/151,678 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0993%	1,007
European (non-Finnish)grpmax	0.0664%	1,506
African / African-American	0.00536%	18,668
Admixed American	0.00503%	19,890

Remaining individuals 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: COPB1
Protein: p.Arg539Ser
Coding: c.1617A>T
MANE Select: NM_001144061
dbSNP: rs140921247
Type: single nucleotide variant
Location: chr11:14474615 (GRCh38)
Gene constraint: LOEUF 0.269 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.55

Full COPB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPB1 p.Met16Val Uncertain significance ★★ ⚠ same type
COPB1 p.Ser410Arg Uncertain significance ★★ ⚠ same type
COPB1 c.958-4T>G Likely benign ★★ same type
COPB1 p.Leu271= Likely benign ★★ same type
COPB1 p.Phe551Val Pathogenic ★ same type
COPB1 c.1455+2T>C Uncertain significance ★ same type
COPB1 c.1616+2T>C Uncertain significance ★ same type
COPB1 c.-57-2A>G Conflicting classifications of pathogenicity ★ ⚠ 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/copb1-p-arg539ser (accessed [today's date]).

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