# NM_005216.5(DDOST):c.846del (p.Phe283fs)

https://sugi.bio/variant/ddost-p-phe283fs

## Summary

**DDOST p.Phe283fs (c.846del)** is classified **Uncertain significance** in DDOST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-03). Very rare (popmax 0.000763%, nfe); Associated with DDOST-congenital disorder of glycosylation.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2545274455 · 1 submitter · 1 linked condition · very rare (popmax 0.000763%, nfe)

## For patients & families {#patients}

This is a change in the DDOST gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Phe283fs |
| Coding change (HGVS c.) | c.846del |
| MANE Select transcript | [NM_005216](https://www.ncbi.nlm.nih.gov/nuccore/NM_005216) |
| dbSNP | [rs2545274455](https://www.ncbi.nlm.nih.gov/snp/rs2545274455/) |
| Variant type | Deletion |
| Location | chr1:20653723-20653723 (GRCh38) |
| ClinVar | [VCV2818218](https://www.ncbi.nlm.nih.gov/clinvar/variation/2818218/) |

**All HGVS expressions:** `NC_000001.10:g.20980216del`, `NC_000001.11:g.20653723del`, `NG_032064.1:g.12822del`, `NG_032064.2:g.12646del`, `NM_005216.5:c.846del`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.136, GERP 2.25, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.747, pLI 0.0007799. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,180,000 in the highest group · 9/1,461,802 alleles overall — very rare (popmax 0.000763%, nfe).

*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 **283** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-03.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-12-03 |

## 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, DDOST-congenital disorder of glycosylation.

## Similar variants {#similar}

Related DDOST variant pages (same residue, condition, or type): [DDOST p.Ile405fs](/variant/ddost-p-ile405fs), [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 2818218). 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.*