Is DDOST p.Ala259Val (c.776C>T) pathogenic?

DDOST p.Ala259Val (c.776C>T) is classified Benign/Likely benign in DDOST (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1832); Low-frequency (popmax 1.15%, eas); Associated with DDOST-congenital disorder of glycosylation.

What condition is associated with DDOST p.Ala259Val (c.776C>T)?

DDOST p.Ala259Val (c.776C>T) is associated with DDOST-congenital disorder of glycosylation (ClinVar).

How common is DDOST p.Ala259Val (c.776C>T) in the general population?

DDOST p.Ala259Val (c.776C>T) is low-frequency (popmax 1.15%, eas) (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.Ala259Val (c.776C>T)?

AlphaMissense predicts likely benign (score 0.1832) — an in-silico prediction, not a clinical call.

DDOST p.Ala259Val

c.776C>T · rs138061134 · VCV295135

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1832 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.15%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DDOST-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1832	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.53	donor gain · deltas
Pangolin	Δ0.28	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,968 bp · p 0.046 · regional, not allelic
Overall
CADD	26.0	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 A276V vs ClinVar A259V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.15% East Asian · 471/40,946 alleles

Filtering AF 1.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.03%

Overall 0.158% 2,454/1,550,972 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.34%	75
East Asiangrpmax	1.15%	87
Remaining individualsnot grpmax-eligible	0.142%	706
Middle Eastern	0.131%	761
South Asian	0.123%	816
European (non-Finnish)	0.0836%	1,196
Ashkenazi Jewishnot grpmax-eligible	0.0733%	1,364
Admixed American	0.0098%	10,202
African / African-American	0.00273%	36,572

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.Ala259Val
Coding: c.776C>T
MANE Select: NM_005216
dbSNP: rs138061134
Type: single nucleotide variant
Location: chr1:20654241 (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 259: 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.Ala259= 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-ala259val (accessed [today's date]).

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