Is DDOST p.Arg280Cys (c.838C>T) pathogenic?

DDOST p.Arg280Cys (c.838C>T) is classified Uncertain significance in DDOST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1898); Ultra-rare (popmax 0.0329%, mid); Associated with DDOST-congenital disorder of glycosylation.

What condition is associated with DDOST p.Arg280Cys (c.838C>T)?

DDOST p.Arg280Cys (c.838C>T) is associated with DDOST-congenital disorder of glycosylation (ClinVar).

How common is DDOST p.Arg280Cys (c.838C>T) in the general population?

DDOST p.Arg280Cys (c.838C>T) is ultra-rare (popmax 0.0329%, 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.Arg280Cys (c.838C>T)?

AlphaMissense predicts likely benign (score 0.1898) — an in-silico prediction, not a clinical call.

DDOST p.Arg280Cys

c.838C>T · rs767525741 · VCV2038749

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DDOST-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1898	likely benign
REVEL	0.79	moderately pathogenic-leaning
SaProt	LLR -14.76	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,968 bp · p 0.046 · regional, not allelic
Overall
CADD	34.0	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 R297C vs ClinVar R280C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00173% 28/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.00833%	11,999
South Asian	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,918
European (non-Finnish)	0.00119%	84,284

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.Arg280Cys
Coding: c.838C>T
MANE Select: NM_005216
dbSNP: rs767525741
Type: single nucleotide variant
Location: chr1:20653731 (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.Arg280His 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
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-arg280cys (accessed [today's date]).

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