Is COG2 p.Ser720Leu (c.2159C>T) pathogenic?

COG2 p.Ser720Leu (c.2159C>T) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). AlphaMissense: likely benign (0.0729); Absent from gnomAD v4.1; Associated with congenital disorder of glycosylation, type IIq.

What condition is associated with COG2 p.Ser720Leu (c.2159C>T)?

COG2 p.Ser720Leu (c.2159C>T) is associated with congenital disorder of glycosylation, type IIq (ClinVar).

How common is COG2 p.Ser720Leu (c.2159C>T) in the general population?

COG2 p.Ser720Leu (c.2159C>T) is absent from gnomAD v4.1 (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.Ser720Leu (c.2159C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

COG2 p.Ser720Leu

c.2159C>T · rs2527679316 · VCV2079472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type IIq

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -8.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.26	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.4	GERP 1, phastCons 0.096
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	17.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COG2
Protein: p.Ser720Leu
Coding: c.2159C>T
MANE Select: NM_007357
dbSNP: rs2527679316
Type: single nucleotide variant
Location: chr1:230693335 (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

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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-ser720leu (accessed [today's date]).

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