COG4 p.Ala669Pro
c.2005G>C · rs1555573157 · VCV545073
Likely pathogenic
No assertion criteria
Classification
Likely pathogenic
ClinVar
Review
No assertion criteria ☆☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.000254%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| REVEL | 0.098 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | Δ0.24 | acceptor gain · deltas |
| Constraint at this position | ||
| Conservation | phyloP 4.9 | GERP 1.7, phastCons 1 |
| Regional constraint | o/e 1.06 | unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic |
| Overall | ||
| CADD | 25.1 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.000254%
European (non-Finnish) · 3/1,179,426 alleles
Filtering AF
6.8e-05%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.9e-05%
Overall
0.000205%
3/1,460,576 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.Ala669Pro
- Coding
- c.2005G>C
- MANE Select
- NM_015386
- dbSNP
- rs1555573157
- Type
- single nucleotide variant
- Location
- chr16:70481865 (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 669
- an α-helix; the 'd domain' region
Similar variants
- COG4 p.Ala669Val Likely pathogenic ★ same residue
- COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same type
- COG4 p.Arg733Trp Pathogenic/Likely pathogenic ★★ same type
- COG4 p.Glu614Ter Pathogenic ★★ same type
- COG4 p.Gly25Ter Pathogenic/Likely pathogenic ★★ same type
- COG4 p.Gly516Arg Pathogenic ★★ same type
- COG4 p.Ala251Thr Uncertain significance ★★ same type
- COG4 p.Ala544Val Uncertain significance ★★ 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-ala669pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown