Is COG1 p.Ala798Thr (c.2392G>A) pathogenic?

COG1 p.Ala798Thr (c.2392G>A) is classified Uncertain significance in COG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-30). AlphaMissense: likely benign (0.0649); Very rare (popmax 0.00223%, eas); Associated with COG1-congenital disorder of glycosylation.

What condition is associated with COG1 p.Ala798Thr (c.2392G>A)?

COG1 p.Ala798Thr (c.2392G>A) is associated with COG1-congenital disorder of glycosylation (ClinVar).

How common is COG1 p.Ala798Thr (c.2392G>A) in the general population?

COG1 p.Ala798Thr (c.2392G>A) is very rare (popmax 0.00223%, eas) (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.Ala798Thr (c.2392G>A)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

COG1 p.Ala798Thr

c.2392G>A · rs747936961 · VCV2142665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.72	GERP 0.55
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	12.4	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

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,614,046 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,242
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	0.000593%	168,576

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COG1
Protein: p.Ala798Thr
Coding: c.2392G>A
MANE Select: NM_018714
dbSNP: rs747936961
Type: single nucleotide variant
Location: chr17:73205562 (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 p.Ala798Val Uncertain significance ★ ⚠ same residue
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

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-ala798thr (accessed [today's date]).

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