Is COG5 p.Ala409Thr (c.1225G>A) pathogenic?

COG5 p.Ala409Thr (c.1225G>A) is classified Uncertain significance in COG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-30). AlphaMissense: likely benign (0.0643); Rare (popmax 0.214%, eas); Associated with Inborn genetic diseases.

What condition is associated with COG5 p.Ala409Thr (c.1225G>A)?

COG5 p.Ala409Thr (c.1225G>A) is associated with Inborn genetic diseases, COG5-congenital disorder of glycosylation (ClinVar).

How common is COG5 p.Ala409Thr (c.1225G>A) in the general population?

COG5 p.Ala409Thr (c.1225G>A) is rare (popmax 0.214%, eas) (gnomAD).

What do computational predictors say about COG5 p.Ala409Thr (c.1225G>A)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

COG5 p.Ala409Thr

c.1225G>A · rs760870083 · VCV2154254

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.04	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 -0.062	GERP -5.2, phastCons 0.22
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	11.94	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 A440T vs ClinVar A409T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% East Asian · 96/44,808 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.00601% 97/1,613,462 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.214%	467
European (non-Finnish)	8.48e-05%	1,179,522

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.Ala409Thr
Coding: c.1225G>A
MANE Select: NM_006348
dbSNP: rs760870083
Type: single nucleotide variant
Location: chr7:107298230 (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

Also linked: COG5-congenital disorder of glycosylation

Similar variants

COG5 p.Ala409= Likely benign ★ same residue
COG5 c.1475+1G>A Likely pathogenic ★★ same condition
COG5 c.2295+2T>C Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg205Ter Pathogenic ★★ same condition
COG5 p.Arg283Ter Pathogenic ★★ same condition
COG5 p.Arg461Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg690Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg708Ter Pathogenic/Likely pathogenic ★★ 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-ala409thr (accessed [today's date]).

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