Is COG4 p.Leu68fs (c.202_203del) pathogenic?

COG4 p.Leu68fs (c.202203del) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-10). Ultra-rare (popmax 0.0334%, eas).

How common is COG4 p.Leu68fs (c.202_203del) in the general population?

COG4 p.Leu68fs (c.202_203del) is ultra-rare (popmax 0.0334%, eas) (gnomAD).

COG4 p.Leu68fs

c.202_203del · rs767979499 · VCV2440188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% East Asian · 15/44,900 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.000929% 15/1,613,796 alleles · ultra-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.Leu68fs
Coding: c.202_203del
MANE Select: NM_015386
dbSNP: rs767979499
Type: Deletion
Location: chr16:70519700 (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 68: the 'interaction with scfd1' 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-leu68fs (accessed [today's date]).

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