Is COG1 p.Ser730Ile (c.2189G>T) pathogenic?

COG1 p.Ser730Ile (c.2189G>T) is classified Uncertain significance in COG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1348); Absent from gnomAD v4.1; Associated with COG1-congenital disorder of glycosylation.

What condition is associated with COG1 p.Ser730Ile (c.2189G>T)?

COG1 p.Ser730Ile (c.2189G>T) is associated with COG1-congenital disorder of glycosylation (ClinVar).

How common is COG1 p.Ser730Ile (c.2189G>T) in the general population?

COG1 p.Ser730Ile (c.2189G>T) is absent from gnomAD v4.1 (gnomAD).

How is COG1-CDG inherited?

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

What do computational predictors say about COG1 p.Ser730Ile (c.2189G>T)?

AlphaMissense predicts likely benign (score 0.1348) — an in-silico prediction, not a clinical call.

COG1 p.Ser730Ile

c.2189G>T · rs2145100344 · VCV1405138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1348 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1348	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -4.47	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 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	26.3	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: COG1
Protein: p.Ser730Ile
Coding: c.2189G>T
MANE Select: NM_018714
dbSNP: rs2145100344
Type: single nucleotide variant
Location: chr17:73203115 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.82

Full COG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG1 c.1070+5G>A Pathogenic ★★ same condition
COG1 p.Arg336Ter Pathogenic ★★ same condition
COG1 p.Trp476Ter Pathogenic/Likely pathogenic ★★ same condition
COG1 p.Ala143Thr Uncertain significance ★★ ⚠ same condition
COG1 p.Ala209Val Uncertain significance ★★ ⚠ same condition
COG1 p.Ala27Ser Uncertain significance ★★ ⚠ same condition
COG1 p.Ala380Val Uncertain significance ★★ ⚠ same condition
COG1 p.Ala385Thr 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/cog1-p-ser730ile (accessed [today's date]).

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