Is COG4 p.Trp762fs (c.2286_2299del) pathogenic?

COG4 p.Trp762fs (c.22862299del) is classified Uncertain significance in COG4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-05-23). Very rare (popmax 8.47e-05%, nfe).

How common is COG4 p.Trp762fs (c.2286_2299del) in the general population?

COG4 p.Trp762fs (c.2286_2299del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

COG4 p.Trp762fs

c.2286_2299del · rs1555572987 · VCV545074

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (19 of 19) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 0.69, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.84e-05% 1/1,461,118 alleles · very rare

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: COG4
Protein: p.Trp762fs
Coding: c.2286_2299del
MANE Select: NM_015386
dbSNP: rs1555572987
Type: Deletion
Location: chr16:70481081 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29 · 1 PDB
Residue 762: an α-helix; the 'e domain; essential for proper cell surface glycosylation' region

Full COG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COG4 c.1828delG Pathogenic ★ same type
COG4 c.369+1_369+2del Likely pathogenic ★ same type
COG4 c.739del Likely pathogenic ★ same type
COG4 p.Ala717fs Pathogenic ★ same type
COG4 p.Asp645_Tyr646insTer Likely pathogenic ★ same type
COG4 p.Glu711fs Pathogenic ★ same type
COG4 p.Gly537fs Pathogenic ★ same type
COG4 p.Lys200fs Pathogenic ★ same type

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/cog4-p-trp762fs (accessed [today's date]).

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