Is COG8 p.Arg450Cys (c.1348C>T) pathogenic?

COG8 p.Arg450Cys (c.1348C>T) is classified Uncertain significance in COG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.2697); Very rare (popmax 0.01%, amr); Associated with COG8-congenital disorder of glycosylation.

What condition is associated with COG8 p.Arg450Cys (c.1348C>T)?

COG8 p.Arg450Cys (c.1348C>T) is associated with COG8-congenital disorder of glycosylation (ClinVar).

How common is COG8 p.Arg450Cys (c.1348C>T) in the general population?

COG8 p.Arg450Cys (c.1348C>T) is very rare (popmax 0.01%, amr) (gnomAD).

How is COG8-CDG inherited?

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

What do computational predictors say about COG8 p.Arg450Cys (c.1348C>T)?

AlphaMissense predicts likely benign (score 0.2697) — an in-silico prediction, not a clinical call.

COG8 p.Arg450Cys

c.1348C>T · rs776576528 · VCV1054626

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG8-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.2697	likely benign
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -14.97	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	33.0	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 0.01% Admixed American · 6/60,012 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00204% 33/1,614,080 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,002
Remaining individualsnot grpmax-eligible	0.0096%	10,415
African / African-American	0.004%	24,979
East Asian	0.00223%	44,886
European (non-Finnish)	0.00136%	73,753
South Asian	0.0011%	91,094

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: COG8
Protein: p.Arg450Cys
Coding: c.1348C>T
MANE Select: NM_032382
dbSNP: rs776576528
Type: single nucleotide variant
Location: chr16:69334586 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.67

Full COG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG8-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG8-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COG8 p.Arg450His Uncertain significance ★ ⚠ same residue
COG8 c.1583-1G>A Pathogenic/Likely pathogenic ★★ same condition
COG8 p.Ala2Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala458Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala5Val Uncertain significance ★★ ⚠ same condition
COG8 p.Arg140Gln Uncertain significance ★★ ⚠ same condition
COG8 p.Arg244Lys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg256Trp 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/cog8-p-arg450cys (accessed [today's date]).

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