Is COG5 p.Lys509Arg (c.1526A>G) pathogenic?

COG5 p.Lys509Arg (c.1526A>G) is classified Uncertain significance in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely benign (0.0666); Ultra-rare (popmax 0.0493%, mid); Associated with Inborn genetic diseases.

What condition is associated with COG5 p.Lys509Arg (c.1526A>G)?

COG5 p.Lys509Arg (c.1526A>G) is associated with Inborn genetic diseases (ClinVar).

How common is COG5 p.Lys509Arg (c.1526A>G) in the general population?

COG5 p.Lys509Arg (c.1526A>G) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about COG5 p.Lys509Arg (c.1526A>G)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

COG5 p.Lys509Arg

c.1526A>G · rs772886519 · VCV2464764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.41, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	18.57	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K540R vs ClinVar K509R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,080 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00304% 49/1,613,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
European (non-Finnish)	0.00356%	28,086
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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: COG5
Protein: p.Lys509Arg
Coding: c.1526A>G
MANE Select: NM_006348
dbSNP: rs772886519
Type: single nucleotide variant
Location: chr7:107281349 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37

Full COG5 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

Similar variants

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COG5 p.Ala15Gly Uncertain significance ★★ ⚠ same condition
COG5 p.Ala20Val Uncertain significance ★★ ⚠ same condition
COG5 p.Ala263Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Ala409Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Ala62Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Arg214Cys 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/cog5-p-lys509arg (accessed [today's date]).

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