Is DDOST p.Pro209Leu (c.626C>T) pathogenic?

DDOST p.Pro209Leu (c.626C>T) is classified Uncertain significance in DDOST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-06). AlphaMissense: ambiguous (0.4146); Ultra-rare (popmax 0.0435%, sas); Associated with DDOST-congenital disorder of glycosylation.

What condition is associated with DDOST p.Pro209Leu (c.626C>T)?

DDOST p.Pro209Leu (c.626C>T) is associated with DDOST-congenital disorder of glycosylation (ClinVar).

How common is DDOST p.Pro209Leu (c.626C>T) in the general population?

DDOST p.Pro209Leu (c.626C>T) is ultra-rare (popmax 0.0435%, sas) (gnomAD).

How is DDOST-CDG inherited?

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

What do computational predictors say about DDOST p.Pro209Leu (c.626C>T)?

AlphaMissense predicts ambiguous (score 0.4146) — an in-silico prediction, not a clinical call.

DDOST p.Pro209Leu

c.626C>T · rs144656615 · VCV1966450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0435%, sas)

Conditions

DDOST-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.4146	ambiguous
REVEL	0.504	indeterminate
SaProt	LLR -11.19	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.68 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,968 bp · p 0.046 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P226L vs ClinVar P209L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0435% South Asian · 37/85,062 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0285%

Overall 0.00825% 129/1,563,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0435%	2,299
African / African-American	0.0339%	2,951
East Asian	0.0308%	3,251
Remaining individualsnot grpmax-eligible	0.0066%	15,149
European (non-Finnish)	0.00425%	23,527
Admixed American	0.00189%	52,972

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.Pro209Leu
Coding: c.626C>T
MANE Select: NM_005216
dbSNP: rs144656615
Type: single nucleotide variant
Location: chr1:20654633 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB
Residue 209: a β-strand

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.Pro209= Uncertain significance ★ same residue
DDOST p.Pro209Ser Uncertain significance ★ same residue
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

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-pro209leu (accessed [today's date]).

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