Is COG2 p.Ile346Val (c.1036A>G) pathogenic?

COG2 p.Ile346Val (c.1036A>G) is classified Benign in COG2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0566); Common (popmax 9.43%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital disorder of glycosylation, type IIq.

What condition is associated with COG2 p.Ile346Val (c.1036A>G)?

COG2 p.Ile346Val (c.1036A>G) is associated with congenital disorder of glycosylation, type IIq (ClinVar).

How is COG2-CDG inherited?

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

What do computational predictors say about COG2 p.Ile346Val (c.1036A>G)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

COG2 p.Ile346Val

Q: How common is COG2 p.Ile346Val (c.1036A>G) in the general population?

COG2 p.Ile346Val (c.1036A>G) is common (popmax 9.43%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1036A>G · rs11558606 · VCV1165357

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.43%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type IIq

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -5.65	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 -1.7	GERP 0.86
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	3.959	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.43% East Asian · 4,228/44,818 alleles

Filtering AF 9.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1%

Overall 5.49% 88,494/1,611,504 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	9.43%	11
Ashkenazi Jewishnot grpmax-eligible	8.7%	11
Admixed American	7.96%	13
Middle Eastern	7.4%	14
African / African-American	6.01%	17
Remaining individualsnot grpmax-eligible	5.71%	18
European (non-Finnish)	5.35%	19
South Asian	4.39%	23
Amishnot grpmax-eligible	2.3%	43
Finnishnot grpmax-eligible	2.06%	48

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.Ile346Val
Coding: c.1036A>G
MANE Select: NM_007357
dbSNP: rs11558606
Type: single nucleotide variant
Location: chr1:230678922 (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

Disease context

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

For COG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

COG2 p.Ala160Val Uncertain significance ★★ ⚠ same condition
COG2 p.Ala339Pro Uncertain significance ★★ ⚠ same condition
COG2 p.Arg138Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg241Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg356Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg356Trp Uncertain significance ★★ ⚠ same condition
COG2 p.Arg39Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg39Trp 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/cog2-p-ile346val (accessed [today's date]).

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