# NM_024079.5(ALG8):c.1090C>T (p.Arg364Ter)

https://sugi.bio/variant/alg8-p-arg364ter

## Summary

**ALG8 p.Arg364Ter (c.1090C>T)** is classified **Pathogenic/Likely pathogenic** in ALG8 (ClinVar, Multiple submitters, 24 submitters; last evaluated 2025-12-25). Ultra-rare (popmax 0.01%, nfe); Associated with polycystic liver disease 3 with or without kidney cysts.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs376161880 · 24 submitters · 4 linked conditions · ultra-rare (popmax 0.01%, nfe)

## For patients & families {#patients}

This is a change in the ALG8 gene that is considered likely disease-causing, submitted by 24 submitters, and is linked to polycystic liver disease 3 with or without kidney cysts.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025967/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.Arg364Ter |
| Coding change (HGVS c.) | c.1090C>T |
| MANE Select transcript | [NM_024079](https://www.ncbi.nlm.nih.gov/nuccore/NM_024079) |
| dbSNP | [rs376161880](https://www.ncbi.nlm.nih.gov/snp/rs376161880/) |
| Variant type | single nucleotide variant |
| Location | chr11:78106895-78106895 (GRCh38) |
| ClinVar | [VCV280116](https://www.ncbi.nlm.nih.gov/clinvar/variation/280116/) |

**All HGVS expressions:** `NC_000011.10:g.78106895G>A`, `NC_000011.9:g.77817941G>A`, `NG_008926.1:g.37759C>T`, `NM_001007027.3:c.1090C>T`, `NM_024079.5:c.1090C>T`

## 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 9.929, GERP 1.28, 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 10 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 48.0**. 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 **0.01%** (nfe) · FAF95 0.00851% · FAF99 0.00795% · 118/1,179,986 in the highest group · 133/1,614,060 alleles overall — ultra-rare (popmax 0.01%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,929 |
| European (non-Finnish) (grpmax) | 0.01% | 10,000 |
| Admixed American | 0.005% | 19,999 |
| South Asian | 0.00439% | 22,771 |
| African / African-American | 0.00133% | 75,018 |

Remaining individuals 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}

**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 **364** 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 2025-12-25.

**Submitter consensus:** conflicting (22 Pathogenic, 3 Likely pathogenic).

**Submission history:** 25 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Arkana Molecular Diagnostic Laboratory, Arkana Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-23 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-30 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Pathogenic | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| OMIM | Pathogenic | flagged submission | literature only | 2022-03-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-03-01 |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Pathogenic | criteria provided, single submitter | clinical testing | 2021-03-11 |
| Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Pathogenic | flagged submission | clinical testing | 2023-10-09 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-11-18 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-07 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-03-16 |
| Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center | Pathogenic | no assertion criteria provided | research | 2021-06-08 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-25 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-06-05 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-09 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-22 |
| Gharavi Laboratory, Columbia University | Likely pathogenic | no assertion criteria provided | case-control | 2024-11-05 |
| Mayo Translational Polycystic Kidney Disease Center, Mayo Clinic | Pathogenic | criteria provided, single submitter | research | 2025-06-01 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-21 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-19 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Polycystic liver disease 3 with or without kidney cysts, not provided, ALG8 congenital disorder of glycosylation, See cases, Inborn genetic diseases, Autosomal dominant polycystic liver disease, ALG8-related disorder, Cystic renal disease, Familial cystic renal disease, Congenital cystic disease of liver.

## Similar variants {#similar}

Related ALG8 variant pages (same residue, condition, or type): [ALG8 p.Arg364Gln](/variant/alg8-p-arg364gln), [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).

### 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 280116). 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.*