Is COG5 p.Met366Val (c.1096A>G) pathogenic?

COG5 p.Met366Val (c.1096A>G) is classified Uncertain significance in COG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-25). AlphaMissense: likely benign (0.0598); Very rare (popmax 0.0067%, amr); Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Met366Val (c.1096A>G)?

COG5 p.Met366Val (c.1096A>G) is associated with COG5-congenital disorder of glycosylation (ClinVar).

How common is COG5 p.Met366Val (c.1096A>G) in the general population?

COG5 p.Met366Val (c.1096A>G) is very rare (popmax 0.0067%, amr) (gnomAD).

How is COG5-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COG5 p.Met366Val (c.1096A>G)?

AlphaMissense predicts likely benign (score 0.0598) — an in-silico prediction, not a clinical call.

COG5 p.Met366Val

c.1096A>G · rs768962367 · VCV193889

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG5-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.0598	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -5.46	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 -0.54	GERP -5.2
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	2.515	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 M397V vs ClinVar M366V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0067% Admixed American · 4/59,684 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000556% 8/1,438,056 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0067%	14,921
East Asian	0.00225%	44,536
European (non-Finnish)	0.000258%	387,264

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.Met366Val
Coding: c.1096A>G
MANE Select: NM_006348
dbSNP: rs768962367
Type: single nucleotide variant
Location: chr7:107324452 (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

COG5-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG5-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COG5 p.Met366Thr Uncertain significance ★ ⚠ 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-met366val (accessed [today's date]).

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