Is COG2 p.Glu469Lys (c.1405G>A) pathogenic?

COG2 p.Glu469Lys (c.1405G>A) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.101); Very rare (popmax 0.00192%, nfe).

How common is COG2 p.Glu469Lys (c.1405G>A) in the general population?

COG2 p.Glu469Lys (c.1405G>A) is very rare (popmax 0.00192%, nfe) (gnomAD).

What do computational predictors say about COG2 p.Glu469Lys (c.1405G>A)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

COG2 p.Glu469Lys

c.1405G>A · VCV4004822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00192%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 0.93, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00192% European (non-Finnish) · 22/1,147,226 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00148% 23/1,555,968 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00192%	52,147
African / African-American	0.00137%	73,088

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: COG2
Protein: p.Glu469Lys
Coding: c.1405G>A
MANE Select: NM_007357
Type: single nucleotide variant
Location: chr1:230686959 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38

Full COG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COG2 p.Glu469= Likely benign ★ same residue
COG2 p.Ala160Val Uncertain significance ★★ ⚠ same type
COG2 p.Ala339Pro Uncertain significance ★★ ⚠ same type
COG2 p.Arg138Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg241Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg356Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg356Trp Uncertain significance ★★ ⚠ same type
COG2 p.Arg39Gln 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/cog2-p-glu469lys (accessed [today's date]).

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