Is COG2 p.Arg453Gln (c.1358G>A) pathogenic?

COG2 p.Arg453Gln (c.1358G>A) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: ambiguous (0.5103); Ultra-rare (popmax 0.0156%, nfe); Associated with congenital disorder of glycosylation, type IIq.

What condition is associated with COG2 p.Arg453Gln (c.1358G>A)?

COG2 p.Arg453Gln (c.1358G>A) is associated with congenital disorder of glycosylation, type IIq (ClinVar).

How common is COG2 p.Arg453Gln (c.1358G>A) in the general population?

COG2 p.Arg453Gln (c.1358G>A) is ultra-rare (popmax 0.0156%, nfe) (gnomAD).

How is COG2-CDG inherited?

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

What do computational predictors say about COG2 p.Arg453Gln (c.1358G>A)?

AlphaMissense predicts ambiguous (score 0.5103) — an in-silico prediction, not a clinical call.

COG2 p.Arg453Gln

c.1358G>A · rs372577276 · VCV1040914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, nfe)

Conditions

congenital disorder of glycosylation, type IIq

Computational evidence

Protein change
AlphaMissense	0.5103	ambiguous
REVEL	0.55	indeterminate
SaProt	LLR -11.48	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	29.5	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 0.0156% European (non-Finnish) · 184/1,180,036 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.0128% 206/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0288%	3,471
European (non-Finnish)grpmax	0.0156%	6,413
Finnishnot grpmax-eligible	0.00469%	21,342
African / African-American	0.00133%	74,914

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: COG2
Protein: p.Arg453Gln
Coding: c.1358G>A
MANE Select: NM_007357
dbSNP: rs372577276
Type: single nucleotide variant
Location: chr1:230685214 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38

Full COG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital disorder of glycosylation, type IIq — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

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COG2 p.Arg138Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg241Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg356Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg356Trp Uncertain significance ★★ ⚠ same condition
COG2 p.Arg39Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg39Trp 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/cog2-p-arg453gln (accessed [today's date]).

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