Is DDOST p.Gly221= (c.663G>A) pathogenic?

DDOST p.Gly221= (c.663G>A) is classified Benign in DDOST (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.01%, nfe); Associated with DDOST-congenital disorder of glycosylation.

What condition is associated with DDOST p.Gly221= (c.663G>A)?

DDOST p.Gly221= (c.663G>A) is associated with DDOST-congenital disorder of glycosylation (ClinVar).

How common is DDOST p.Gly221= (c.663G>A) in the general population?

DDOST p.Gly221= (c.663G>A) is low-frequency (popmax 1.01%, nfe) (gnomAD).

How is DDOST-CDG inherited?

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

DDOST p.Gly221=

c.663G>A · rs41307775 · VCV295141

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, nfe)

Conditions

DDOST-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.52	GERP -3.9, phastCons 0.027
Overall
CADD	6.371	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.01% European (non-Finnish) · 11,607/1,150,862 alleles

Filtering AF 0.993% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.987%

Overall 0.853% 13,307/1,559,992 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.64%	61
European (non-Finnish)grpmax	1.01%	99
Remaining individualsnot grpmax-eligible	0.625%	160
Admixed American	0.232%	430
Ashkenazi Jewishnot grpmax-eligible	0.136%	738
African / African-American	0.124%	808
Middle Eastern	0.117%	857
South Asian	0.085%	1,177

Finnish 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: DDOST
Protein: p.Gly221=
Coding: c.663G>A
MANE Select: NM_005216
dbSNP: rs41307775
Type: single nucleotide variant
Location: chr1:20654354 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB

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

Disease context

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

For DDOST-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DDOST p.Gln215His Pathogenic/Likely pathogenic ★★ ⚠ same condition
DDOST c.-18T>G Uncertain significance ★★ ⚠ same condition
DDOST p.Ala11Val Uncertain significance ★★ ⚠ same condition
DDOST p.Ala219Val Uncertain significance ★★ ⚠ same condition
DDOST p.Ala232Ser Uncertain significance ★★ ⚠ same condition
DDOST p.Ala415Thr Uncertain significance ★★ ⚠ same condition
DDOST p.Arg237His Uncertain significance ★★ ⚠ same condition
DDOST p.Arg280Cys 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/ddost-p-gly221 (accessed [today's date]).

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