Is COG4 p.Asp606His (c.1816G>C) pathogenic?

COG4 p.Asp606His (c.1816G>C) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). Absent from gnomAD v4.1; Associated with COG4-congenital disorder of glycosylation.

What condition is associated with COG4 p.Asp606His (c.1816G>C)?

COG4 p.Asp606His (c.1816G>C) is associated with COG4-congenital disorder of glycosylation (ClinVar).

How common is COG4 p.Asp606His (c.1816G>C) in the general population?

COG4 p.Asp606His (c.1816G>C) is absent from gnomAD v4.1 (gnomAD).

How is COG4-CDG inherited?

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

COG4 p.Asp606His

c.1816G>C · rs2151739637 · VCV1506269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

COG4-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.135	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

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: COG4
Protein: p.Asp606His
Coding: c.1816G>C
MANE Select: NM_015386
dbSNP: rs2151739637
Type: single nucleotide variant
Location: chr16:70483864 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29 · 1 PDB
Residue 606: an α-helix

Full COG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG4-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG4-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Arg733Trp Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Glu614Ter Pathogenic ★★ same condition
COG4 p.Gly25Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Gly516Arg Pathogenic ★★ same condition
COG4 p.Ala251Thr Uncertain significance ★★ same condition
COG4 p.Ala544Val Uncertain significance ★★ same condition
COG4 p.Arg198His 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/cog4-p-asp606his (accessed [today's date]).

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