Is COG8 p.Arg336Trp (c.1006C>T) pathogenic?

COG8 p.Arg336Trp (c.1006C>T) is classified Conflicting classifications of pathogenicity in COG8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-08-19). AlphaMissense: likely benign (0.1095); Ultra-rare (popmax 0.0183%, amr); Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Arg336Trp (c.1006C>T)?

COG8 p.Arg336Trp (c.1006C>T) is associated with Inborn genetic diseases, COG8-congenital disorder of glycosylation (ClinVar).

How common is COG8 p.Arg336Trp (c.1006C>T) in the general population?

COG8 p.Arg336Trp (c.1006C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about COG8 p.Arg336Trp (c.1006C>T)?

AlphaMissense predicts likely benign (score 0.1095) — an in-silico prediction, not a clinical call.

COG8 p.Arg336Trp

c.1006C>T · rs757877420 · VCV286530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1095	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -13.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.44, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	25.5	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 0.0183% Admixed American · 11/60,002 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00774% 125/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
South Asian	0.00878%	11,385
European (non-Finnish)	0.00856%	11,684
African / African-American	0.004%	25,006
East Asian	0.00223%	44,874
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Arg336Trp
Coding: c.1006C>T
MANE Select: NM_032382
dbSNP: rs757877420
Type: single nucleotide variant
Location: chr16:69334928 (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

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

Also linked: COG8-congenital disorder of glycosylation

Similar variants

COG8 p.Arg336Gln Uncertain significance ★ ⚠ same residue
COG8 p.Arg336Leu Uncertain significance ★ ⚠ same residue
COG8 c.1583-1G>A Pathogenic/Likely pathogenic ★★ same condition
COG8 p.Ala16Gly Uncertain significance ★★ ⚠ 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.Arg102Cys 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-arg336trp (accessed [today's date]).

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