# NM_024079.5(ALG8):c.802del (p.Arg268fs)

https://sugi.bio/variant/alg8-p-arg268fs

## Summary

**ALG8 p.Arg268fs (c.802del)** is classified **Pathogenic/Likely pathogenic** in ALG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-09). No gnomAD frequency available for this variant; Associated with ALG8-congenital disorder of glycosylation.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2136899636 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ALG8 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to ALG8-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) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | ALG8 is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of ALG8-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Abnormality of the eye — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Edema — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009834/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG8](https://sugi.bio/atlas/gene/ALG8/) |
| Protein change (HGVS p.) | p.Arg268fs |
| Coding change (HGVS c.) | c.802del |
| MANE Select transcript | [NM_024079](https://www.ncbi.nlm.nih.gov/nuccore/NM_024079) |
| dbSNP | [rs2136899636](https://www.ncbi.nlm.nih.gov/snp/rs2136899636/) |
| Variant type | Deletion |
| Location | chr11:78112746-78112746 (GRCh38) |
| ClinVar | [VCV1437904](https://www.ncbi.nlm.nih.gov/clinvar/variation/1437904/) |

**All HGVS expressions:** `NC_000011.10:g.78112748del`, `NC_000011.9:g.77823794del`, `NG_008926.1:g.31908del`, `NM_001007027.3:c.802del`, `NM_024079.5:c.802del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.774, GERP 2.19, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.909, pLI 1.8738e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 13**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ALG8** population constraint: LOEUF 0.909, pLI 1.8738e-10, missense-Z 0.42414. *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):

- **autosomal dominant polycystic kidney disease** — Definitive (AD)

## Protein context {#protein}

Residue **268** lies in a UniProt-annotated variant site (in pcld3).

AlphaFold model confidence (whole protein): pLDDT 92.07, 82% of residues very-high.

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

*Describes the biological roles of ALG8 (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:** ALG8's established molecular role includes dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity. In Reactome, ALG8 is annotated in disease pathway(s) including **Defective ALG8 causes CDG-1h**.

**Disease mechanism (Reactome):** ALG8 loss or alteration is curated in [Defective ALG8 causes CDG-1h](https://reactome.org/content/detail/R-HSA-4724325).

### Pathways affected {#pathways}

ALG8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG8 causes CDG-1h](https://reactome.org/content/detail/R-HSA-4724325) | curated |
| [Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein](https://reactome.org/content/detail/R-HSA-446193) | curated |

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

**Molecular function:** dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity.

**Biological process:** protein N-linked glycosylation, dolichol-linked oligosaccharide biosynthetic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-02-09.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2021–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-09 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-29 |

## Associated conditions {#conditions}

[ALG8-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg8-congenital-disorder-of-glycosylation/), [polycystic liver disease 3 with or without kidney cysts](https://sugi.bio/atlas/disease/polycystic-liver-disease-3-with-or-without-kidney-cysts/).

**Reported phenotype names (ClinVar):** ALG8 congenital disorder of glycosylation, Polycystic liver disease 3 with or without kidney cysts, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ih, CDG Ih, ALG8-CDG.

## Same-residue context {#hotspot}

Residue **268** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALG8 p.Arg268Ter](/variant/alg8-p-arg268ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALG8 variant pages (same residue, condition, or type): [ALG8 p.Arg268Ter](/variant/alg8-p-arg268ter), [ALG8 p.Arg268Gln](/variant/alg8-p-arg268gln), [ALG8 p.Arg268Leu](/variant/alg8-p-arg268leu), [ALG8 p.Asn91fs](/variant/alg8-p-asn91fs), [ALG8 p.Gly275fs](/variant/alg8-p-gly275fs), [ALG8 p.Trp353fs](/variant/alg8-p-trp353fs), [ALG8 c.174+30del](/variant/alg8-c-174-plus-30del), [ALG8 c.174+2del](/variant/alg8-c-174-plus-2del).

### 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 1437904). 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.*