# NM_005216.5(DDOST):c.776C>T (p.Ala259Val)

https://sugi.bio/variant/ddost-p-ala259val

## Summary

**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.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs138061134 · 5 submitters · 1 linked condition · AlphaMissense likely benign · low-frequency (popmax 1.15%, eas)

## For patients & families {#patients}

This is a change in the DDOST gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to DDOST-congenital disorder of glycosylation.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | DDOST is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of DDOST-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Esotropia — Very frequent (99-80%)
- Osteopenia — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Generalized hypotonia — Very frequent (99-80%)
- Tremor — Very frequent (99-80%)
- Hepatic steatosis — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Constipation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012398/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DDOST](https://sugi.bio/atlas/gene/DDOST/) |
| Protein change (HGVS p.) | p.Ala259Val |
| Coding change (HGVS c.) | c.776C>T |
| MANE Select transcript | [NM_005216](https://www.ncbi.nlm.nih.gov/nuccore/NM_005216) |
| dbSNP | [rs138061134](https://www.ncbi.nlm.nih.gov/snp/rs138061134/) |
| Variant type | single nucleotide variant |
| Location | chr1:20654241-20654241 (GRCh38) |
| ClinVar | [VCV295135](https://www.ncbi.nlm.nih.gov/clinvar/variation/295135/) |

**All HGVS expressions:** `NC_000001.10:g.20980734G>A`, `NC_000001.11:g.20654241G>A`, `NG_032064.1:g.12304C>T`, `NM_005216.5:c.776C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1832)
- REVEL 0.399 (indeterminate)
- SaProt LLR -7.946 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.53) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 9.682, GERP 1.32, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A276V** vs ClinVar **A259V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (20,652,382–20,661,350), spanning 8,968 bp. Chi-square p 0.046. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.53**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.53**.
- Pangolin: Δ**0.28** (gain), gain 0.28 / loss 0.05. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.15%** (eas) · FAF95 1.06% · FAF99 1.03% · 471/40,946 in the highest group · 2,454/1,550,972 alleles overall — low-frequency (popmax 1.15%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 1.34% | 75 |
| East Asian (grpmax) | 1.15% | 87 |
| Remaining individuals (not grpmax-eligible) | 0.142% | 706 |
| Middle Eastern | 0.131% | 761 |
| South Asian | 0.123% | 816 |
| European (non-Finnish) | 0.0836% | 1,196 |
| Ashkenazi Jewish (not 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. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DDOST** population constraint: LOEUF 0.747, pLI 0.0007799, missense-Z 0.6592; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **DDOST-congenital disorder of glycosylation** — Moderate (AR)

## Protein context {#protein}

Residue **259** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.27, 85% of residues very-high.

**6 experimental structure(s)** (PDB): [6S7O](https://www.rcsb.org/structure/6S7O), [6S7T](https://www.rcsb.org/structure/6S7T), [8B6L](https://www.rcsb.org/structure/8B6L), [8PN9](https://www.rcsb.org/structure/8PN9), [9N9J](https://www.rcsb.org/structure/9N9J), [9YGY](https://www.rcsb.org/structure/9YGY).

## What this gene does {#gene-function}

*Describes the biological roles of DDOST (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DDOST's established molecular role includes enzyme activator activity. In Reactome, DDOST is annotated in disease pathway(s) including **Maturation of DENV proteins**, **Maturation of spike protein**.

**Disease mechanism (Reactome):** DDOST loss or alteration is curated in [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432), [Maturation of spike protein](https://reactome.org/content/detail/R-HSA-9694548).

### Pathways affected {#pathways}

DDOST participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432) | curated |
| ⚕ [Maturation of spike protein](https://reactome.org/content/detail/R-HSA-9694548) | curated |
| [Asparagine N-linked glycosylation](https://reactome.org/content/detail/R-HSA-446203) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [PD-L1(CD274) glycosylation and translocation to plasma membrane](https://reactome.org/content/detail/R-HSA-9931295) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [Advanced glycosylation endproduct receptor signaling](https://reactome.org/content/detail/R-HSA-879415) | electronic |
| [SRP-dependent cotranslational protein targeting to membrane](https://reactome.org/content/detail/R-HSA-1799339) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** enzyme activator activity.

**Biological process:** protein N-linked glycosylation, regulation of protein stability, response to cytokine, T cell activation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 16 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-05-16 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[DDOST-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/ddost-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** Congenital disorder of glycosylation type Ir, not provided, Ovarian serous cystadenocarcinoma, Malignant tumor of urinary bladder, Colorectal cancer, Thymoma, Hepatocellular carcinoma, Cervical cancer, Familial cancer of breast, none provided.

## Similar variants {#similar}

Related DDOST variant pages (same residue, condition, or type): [DDOST p.Ala259=](/variant/ddost-p-ala259), [DDOST p.Gln215His](/variant/ddost-p-gln215his), [DDOST c.-18T>G](/variant/ddost-c-minus-18t-g), [DDOST p.Ala11Val](/variant/ddost-p-ala11val), [DDOST p.Ala219Val](/variant/ddost-p-ala219val), [DDOST p.Ala232Ser](/variant/ddost-p-ala232ser), [DDOST p.Ala415Thr](/variant/ddost-p-ala415thr), [DDOST p.Arg237His](/variant/ddost-p-arg237his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 295135). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*