Is COG8 p.Glu64Asp (c.192G>T) pathogenic?

COG8 p.Glu64Asp (c.192G>T) is classified Uncertain significance in COG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-24). AlphaMissense: likely pathogenic (0.9866); Very rare (popmax 0.00897%, amr); Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Glu64Asp (c.192G>T)?

COG8 p.Glu64Asp (c.192G>T) is associated with Inborn genetic diseases, COG8-congenital disorder of glycosylation (ClinVar).

How common is COG8 p.Glu64Asp (c.192G>T) in the general population?

COG8 p.Glu64Asp (c.192G>T) is very rare (popmax 0.00897%, amr) (gnomAD).

What do computational predictors say about COG8 p.Glu64Asp (c.192G>T)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

COG8 p.Glu64Asp

c.192G>T · rs918646670 · VCV1909704

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00897%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic · top 2% in COG8
REVEL	0.529	indeterminate
SaProt	LLR -10.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00897% Admixed American · 5/55,732 alleles

Filtering AF 0.00346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.000568% 9/1,585,344 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00897%	11,146
Remaining individualsnot grpmax-eligible	0.00651%	15,367

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.Glu64Asp
Coding: c.192G>T
MANE Select: NM_032382
dbSNP: rs918646670
Type: single nucleotide variant
Location: chr16:69339361 (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 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
COG8 p.Arg140Gln Uncertain significance ★★ ⚠ same condition
COG8 p.Arg244Lys 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-glu64asp (accessed [today's date]).

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