# NM_024079.5(ALG8):c.219G>A (p.Trp73Ter)

https://sugi.bio/variant/alg8-p-trp73ter

## Summary

**ALG8 p.Trp73Ter (c.219G>A)** is classified **Likely pathogenic** in ALG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-29). Very rare (popmax 0.000339%, nfe); Associated with ALG8-congenital disorder of glycosylation.

**At a glance:** Likely pathogenic · review: Multiple submitters · 3 submitters · 2 linked conditions · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the ALG8 gene that is considered likely disease-causing, submitted by 3 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.Trp73Ter |
| Coding change (HGVS c.) | c.219G>A |
| MANE Select transcript | [NM_024079](https://www.ncbi.nlm.nih.gov/nuccore/NM_024079) |
| Variant type | single nucleotide variant |
| Location | chr11:78124170-78124170 (GRCh38) |
| ClinVar | [VCV3574073](https://www.ncbi.nlm.nih.gov/clinvar/variation/3574073/) |

**All HGVS expressions:** `NC_000011.10:g.78124170C>T`, `NC_000011.9:g.77835216C>T`, `NG_008926.1:g.20484G>A`, `NM_001007027.3:c.219G>A`, `NM_001425219.1:c.222G>A`, `NM_001425220.1:c.219G>A`, `NM_001425221.1:c.219G>A`, `NM_001425222.1:c.219G>A`, `NM_001425223.1:c.219G>A`, `NM_001425224.1:c.219G>A`, `NM_001425225.1:c.219G>A`, `NM_001425226.1:c.66G>A`, `NM_001425227.1:c.219G>A`, `NM_001425228.1:c.219G>A`, `NM_001425229.1:c.219G>A`, `NM_001425230.1:c.219G>A`, `NM_001425231.1:c.96-78G>A`, `NM_001425232.1:c.219G>A`, `NM_001425233.1:c.219G>A`, `NM_001425234.1:c.-46G>A`, `NM_001425235.1:c.66G>A`, `NM_001425236.1:c.66G>A`, `NM_001425237.1:c.219G>A`, `NM_001425238.1:c.219G>A`, `NM_001425239.1:c.-46G>A`, `NM_001425240.1:c.219G>A`, `NM_001425241.1:c.-294G>A`, `NM_001425242.1:c.-332G>A`, `NM_001425243.1:c.219G>A`, `NM_024079.5:c.219G>A`, `NR_189148.1:n.257G>A`, `NR_189149.1:n.257G>A`

## 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 7.585, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 3 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 41.0**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,180,028 in the highest group · 4/1,461,872 alleles overall — very rare (popmax 0.000339%, 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}

**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}


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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-29.

**Submitter consensus:** unanimous (3/3 Likely pathogenic).

**Submission history:** 3 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-08 |
| Service of Pediatric Gastrohepatology and Metabolic Diseases, University of Medicine of Tirana | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-04-29 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-09 |

## 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, ALG8-related disorder, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ih, CDG Ih, ALG8-CDG.

## Similar variants {#similar}

Related ALG8 variant pages (same residue, condition, or type): [ALG8 c.368+2T>G](/variant/alg8-c-368-plus-2t-g), [ALG8 c.674-2A>G](/variant/alg8-c-674-minus-2a-g), [ALG8 c.777+1G>A](/variant/alg8-c-777-plus-1g-a), [ALG8 c.95+1G>A](/variant/alg8-c-95-plus-1g-a), [ALG8 p.Arg179Ter](/variant/alg8-p-arg179ter), [ALG8 p.Arg229Ter](/variant/alg8-p-arg229ter), [ALG8 p.Arg268Ter](/variant/alg8-p-arg268ter), [ALG8 p.Arg364Ter](/variant/alg8-p-arg364ter).

### 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 3574073). 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.*