Is COG2 p.Val589Leu (c.1765G>C) pathogenic?

COG2 p.Val589Leu (c.1765G>C) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-06). AlphaMissense: likely pathogenic (0.7076); Very rare (popmax 0.000763%, nfe); Associated with congenital disorder of glycosylation, type IIq.

What condition is associated with COG2 p.Val589Leu (c.1765G>C)?

COG2 p.Val589Leu (c.1765G>C) is associated with congenital disorder of glycosylation, type IIq (ClinVar).

How common is COG2 p.Val589Leu (c.1765G>C) in the general population?

COG2 p.Val589Leu (c.1765G>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

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.Val589Leu (c.1765G>C)?

AlphaMissense predicts likely pathogenic (score 0.7076) — an in-silico prediction, not a clinical call.

COG2 p.Val589Leu

c.1765G>C · rs34109129 · VCV1021470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type IIq

Computational evidence

Protein change
AlphaMissense	0.7076	likely pathogenic
REVEL	0.114	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.83, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	23.3	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 0.000763% European (non-Finnish) · 9/1,180,020 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,982 alleles · very rare

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.Val589Leu
Coding: c.1765G>C
MANE Select: NM_007357
dbSNP: rs34109129
Type: single nucleotide variant
Location: chr1:230688533 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38
Residue 589: a UniProt-annotated variant site (in)

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.Val589Ile Benign/Likely benign ★★ same residue
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

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-val589leu (accessed [today's date]).

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