# NM_024079.5(ALG8):c.121C>T (p.Arg41Ter)

https://sugi.bio/variant/alg8-p-arg41ter

## Summary

**ALG8 p.Arg41Ter (c.121C>T)** is classified **Pathogenic/Likely pathogenic** in ALG8 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-08-31). Very rare (popmax 0.00801%, afr); Associated with polycystic liver disease 3 with or without kidney cysts.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs200888240 · 9 submitters · 3 linked conditions · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the ALG8 gene that is considered likely disease-causing, submitted by 9 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.Arg41Ter |
| Coding change (HGVS c.) | c.121C>T |
| MANE Select transcript | [NM_024079](https://www.ncbi.nlm.nih.gov/nuccore/NM_024079) |
| dbSNP | [rs200888240](https://www.ncbi.nlm.nih.gov/snp/rs200888240/) |
| Variant type | single nucleotide variant |
| Location | chr11:78127411-78127411 (GRCh38) |
| ClinVar | [VCV96090](https://www.ncbi.nlm.nih.gov/clinvar/variation/96090/) |

**All HGVS expressions:** `NC_000011.10:g.78127411G>A`, `NC_000011.9:g.77838457G>A`, `NG_008926.1:g.17243C>T`, `NM_001007027.3:c.121C>T`, `NM_024079.5:c.121C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.23) — consistent with the pathogenic call
- Conservation: phyloP 8.086, 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 2 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 46.0**. 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 deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
- Pangolin: Δ**0.36** (loss), gain 0.02 / loss 0.36. 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 **0.00801%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,924 in the highest group · 47/1,613,550 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00801% | 12,487 |
| Admixed American | 0.005% | 19,987 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| European (non-Finnish) | 0.00297% | 33,711 |

*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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-08-31.

**Submitter consensus:** conflicting (8 Pathogenic, 1 Likely pathogenic).

**Submission history:** 9 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-09-22 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-05-08 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-18 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-08-31 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-03 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2012-12-21 |
| Mayo Translational Polycystic Kidney Disease Center, Mayo Clinic | Pathogenic | criteria provided, single submitter | research | 2025-06-01 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-28 |

## 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/), [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, Familial cystic renal disease, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ih, ALG8-CDG, CDG Ih, none provided.

## Same-residue context {#hotspot}

Residue **41** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALG8 p.Arg41Gln](/variant/alg8-p-arg41gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALG8 variant pages (same residue, condition, or type): [ALG8 p.Arg41Gln](/variant/alg8-p-arg41gln), [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 96090). 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.*