Is DDOST p.Phe251Ser (c.752T>C) pathogenic?

DDOST p.Phe251Ser (c.752T>C) is classified Uncertain significance in DDOST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.7401); Ultra-rare (popmax 0.086%, mid); Associated with DDOST-congenital disorder of glycosylation.

What condition is associated with DDOST p.Phe251Ser (c.752T>C)?

DDOST p.Phe251Ser (c.752T>C) is associated with DDOST-congenital disorder of glycosylation (ClinVar).

How common is DDOST p.Phe251Ser (c.752T>C) in the general population?

DDOST p.Phe251Ser (c.752T>C) is ultra-rare (popmax 0.086%, mid) (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.Phe251Ser (c.752T>C)?

AlphaMissense predicts likely pathogenic (score 0.7401) — an in-silico prediction, not a clinical call.

DDOST p.Phe251Ser

c.752T>C · rs199782279 · VCV1479323

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7401 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.086%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DDOST-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.7401	likely pathogenic
REVEL	0.701	pathogenic-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,968 bp · p 0.046 · regional, not allelic
Overall
CADD	26.8	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 F268S vs ClinVar F251S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.086% Middle Eastern · 5/5,816 alleles

Filtering AF 0.0338% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0114% 177/1,551,672 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.086%	1,163
Admixed American	0.0451%	2,219
Remaining individualsnot grpmax-eligible	0.0383%	2,612
European (non-Finnish)	0.011%	9,104

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.Phe251Ser
Coding: c.752T>C
MANE Select: NM_005216
dbSNP: rs199782279
Type: single nucleotide variant
Location: chr1:20654265 (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.Phe251= Likely benign ★ 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
DDOST p.Arg237His 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-phe251ser (accessed [today's date]).

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