# NM_013338.5(ALG5):c.589C>T (p.Arg197Ter)

https://sugi.bio/variant/alg5-p-arg197ter

## Summary

**ALG5 p.Arg197Ter (c.589C>T)** is classified **Uncertain significance** in ALG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). Very rare (popmax 0.00034%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00034%, nfe)

## For patients & families {#patients}

This is a change in the ALG5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG5](https://sugi.bio/atlas/gene/ALG5/) |
| Protein change (HGVS p.) | p.Arg197Ter |
| Coding change (HGVS c.) | c.589C>T |
| MANE Select transcript | [NM_013338](https://www.ncbi.nlm.nih.gov/nuccore/NM_013338) |
| Variant type | single nucleotide variant |
| Location | chr13:36972009-36972009 (GRCh38) |
| ClinVar | [VCV4919892](https://www.ncbi.nlm.nih.gov/clinvar/variation/4919892/) |

**All HGVS expressions:** `NC_000013.10:g.37546146G>A`, `NC_000013.11:g.36972009G>A`, `NM_001142364.1:c.499C>T`, `NM_013338.5:c.589C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.616, GERP 2.2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.823, pLI 0.015945. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 45.0**. 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 **0.21**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00034%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,174,742 in the highest group · 4/1,604,430 alleles overall — very rare (popmax 0.00034%, 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}

**ALG5** population constraint: LOEUF 0.823, pLI 0.015945, missense-Z 1.2373. *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** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.29, 80% of residues very-high.

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

*Describes the biological roles of ALG5 (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:** ALG5's established molecular role includes dolichyl-phosphate beta-glucosyltransferase activity.


### Pathways affected {#pathways}

ALG5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of dolichyl-phosphate-glucose](https://reactome.org/content/detail/R-HSA-480985) | curated |

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

**Molecular function:** dolichyl-phosphate beta-glucosyltransferase activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ALG5 variant pages (same residue, condition, or type): [ALG5 p.Arg197Gln](/variant/alg5-p-arg197gln), [ALG5 p.Thr249Met](/variant/alg5-p-thr249met), [ALG5 c.239-2A>G](/variant/alg5-c-239-minus-2a-g), [ALG5 p.Arg39Ter](/variant/alg5-p-arg39ter), [ALG5 p.Arg97Ter](/variant/alg5-p-arg97ter), [ALG5 p.Trp224Ter](/variant/alg5-p-trp224ter), [ALG5 p.Ala14Thr](/variant/alg5-p-ala14thr), [ALG5 p.Ala16Ser](/variant/alg5-p-ala16ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4919892). 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.*