# NM_024740.2(ALG9):c.1363C>T (p.Arg455Ter)

https://sugi.bio/variant/alg9-p-arg455ter

## Summary

**ALG9 p.Arg455Ter (c.1363C>T)** is classified **Conflicting classifications of pathogenicity** in ALG9 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-09). Very rare (popmax 0.00186%, nfe); Associated with ALG9-associated autosomal dominant polycystic kidney disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs782775735 · 4 submitters · 3 linked conditions · very rare (popmax 0.00186%, nfe)

## For patients & families {#patients}

This is a change in the ALG9 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to ALG9-associated autosomal dominant polycystic kidney disease.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | ALG9 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Autosomal dominant polycystic kidney disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Very frequent (99-80%)
- Renal cyst — Very frequent (99-80%)
- Hepatic cysts — Very frequent (99-80%)
- Elevated circulating creatinine concentration — Very frequent (99-80%)
- Decreased glomerular filtration rate — Very frequent (99-80%)
- Hematuria — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Stage 5 chronic kidney disease — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026304/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG9](https://sugi.bio/atlas/gene/ALG9/) |
| Protein change (HGVS p.) | p.Arg455Ter |
| Coding change (HGVS c.) | c.1363C>T |
| MANE Select transcript | [NM_024740](https://www.ncbi.nlm.nih.gov/nuccore/NM_024740) |
| dbSNP | [rs782775735](https://www.ncbi.nlm.nih.gov/snp/rs782775735/) |
| Variant type | single nucleotide variant |
| Location | chr11:111837577-111837577 (GRCh38) |
| ClinVar | [VCV1314309](https://www.ncbi.nlm.nih.gov/clinvar/variation/1314309/) |

**All HGVS expressions:** `NC_000011.10:g.111837577G>A`, `NC_000011.9:g.111708300G>A`, `NG_009210.1:g.39005C>T`, `NM_001077690.1:c.1342C>T`, `NM_001077691.2:c.850C>T`, `NM_001077692.2:c.829C>T`, `NM_001352409.1:c.829C>T`, `NM_001352410.1:c.829C>T`, `NM_001352411.2:c.829C>T`, `NM_001352412.2:c.829C>T`, `NM_001352413.1:c.850C>T`, `NM_001352414.2:c.850C>T`, `NM_001352415.1:c.829C>T`, `NM_001352416.1:c.829C>T`, `NM_001352417.1:c.1342C>T`, `NM_001352418.1:c.1219C>T`, `NM_001352419.1:c.850C>T`, `NM_001352420.2:c.829C>T`, `NM_001352421.2:c.829C>T`, `NM_001352422.2:c.754C>T`, `NM_001352423.2:c.706C>T`, `NM_024740.2:c.1363C>T`, `NR_147984.2:n.1759C>T`

## 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 6.329, GERP 0.089, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.853, pLI 1.3976e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 15**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. 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 **0.00186%** (nfe) · FAF95 0.00122% · FAF99 0.00104% · 22/1,179,994 in the highest group · 22/1,613,926 alleles overall — very rare (popmax 0.00186%, 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}

**ALG9** population constraint: LOEUF 0.853, pLI 1.3976e-12, missense-Z 1.7414. *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):

- **ALG9-associated autosomal dominant polycystic kidney disease** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.35, 77% of residues very-high.

**2 experimental structure(s)** (PDB): [9S6S](https://www.rcsb.org/structure/9S6S), [9S6U](https://www.rcsb.org/structure/9S6U).

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

*Describes the biological roles of ALG9 (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:** ALG9's established molecular role includes dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity. In Reactome, ALG9 is annotated in disease pathway(s) including **Defective ALG9 causes CDG-1l**.

**Disease mechanism (Reactome):** ALG9 loss or alteration is curated in [Defective ALG9 causes CDG-1l](https://reactome.org/content/detail/R-HSA-4720454).

### Pathways affected {#pathways}

ALG9 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG9 causes CDG-1l](https://reactome.org/content/detail/R-HSA-4720454) | 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:** dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity, dol-P-Man:Man(6)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity.

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

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-09.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 4 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-04-12 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-09 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-05 |

## Associated conditions {#conditions}

[ALG9-associated autosomal dominant polycystic kidney disease](https://sugi.bio/atlas/disease/alg9-associated-autosomal-dominant-polycystic-kidney-disease/), [Gillessen-Kaesbach-Nishimura syndrome](https://sugi.bio/atlas/disease/gillessen-kaesbach-nishimura-syndrome/), [ALG9-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg9-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG9-associated autosomal dominant polycystic kidney disease, not provided, ALG9 congenital disorder of glycosylation, Gillessen-Kaesbach-Nishimura syndrome, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Il, ALG9-CDG, CDG Il, none provided.

## Similar variants {#similar}

Related ALG9 variant pages (same residue, condition, or type): [ALG9 p.Arg455Gln](/variant/alg9-p-arg455gln), [ALG9 p.Arg455Leu](/variant/alg9-p-arg455leu), [ALG9 p.Arg455=](/variant/alg9-p-arg455), [ALG9 c.566-1G>A](/variant/alg9-c-566-minus-1g-a), [ALG9 c.896-2A>G](/variant/alg9-c-896-minus-2a-g), [ALG9 p.Arg143Ter](/variant/alg9-p-arg143ter), [ALG9 p.Trp248Ter](/variant/alg9-p-trp248ter), [ALG9 p.Tyr287Cys](/variant/alg9-p-tyr287cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1314309). 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.*