Is COG2 p.Lys327Arg (c.980A>G) pathogenic?

COG2 p.Lys327Arg (c.980A>G) is classified Uncertain significance in COG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0664); Ultra-rare (popmax 0.0201%, eas); Associated with congenital disorder of glycosylation, type IIq.

What condition is associated with COG2 p.Lys327Arg (c.980A>G)?

COG2 p.Lys327Arg (c.980A>G) is associated with congenital disorder of glycosylation, type IIq (ClinVar).

How common is COG2 p.Lys327Arg (c.980A>G) in the general population?

COG2 p.Lys327Arg (c.980A>G) is ultra-rare (popmax 0.0201%, eas) (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.Lys327Arg (c.980A>G)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

COG2 p.Lys327Arg

c.980A>G · VCV3716942

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type IIq

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -6.67	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 7.9	GERP 6.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	18.17	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 0.0201% East Asian · 9/44,846 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.000806% 13/1,612,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,983
Remaining individualsnot grpmax-eligible	0.0016%	62,468
South Asian	0.0011%	90,734
European (non-Finnish)	0.00017%	589,730

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.Lys327Arg
Coding: c.980A>G
MANE Select: NM_007357
Type: single nucleotide variant
Location: chr1:230675078 (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

COG2 p.Ala160Val Uncertain significance ★★ ⚠ same condition
COG2 p.Ala339Pro Uncertain significance ★★ ⚠ same condition
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-lys327arg (accessed [today's date]).

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