# NM_019109.5(ALG1):c.115del (p.Val39fs)

https://sugi.bio/variant/alg1-p-val39fs

## Summary

**ALG1 p.Val39fs (c.115del)** is classified **Conflicting classifications of pathogenicity** in ALG1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-18). Very rare (popmax 0.00135%, afr); Associated with ALG1-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs886042130 · 7 submitters · 2 linked conditions · very rare (popmax 0.00135%, afr)

## For patients & families {#patients}

This is a change in the ALG1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to ALG1-related disorder.

*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 | [ALG1](https://sugi.bio/atlas/gene/ALG1/) |
| Protein change (HGVS p.) | p.Val39fs |
| Coding change (HGVS c.) | c.115del |
| MANE Select transcript | [NM_019109](https://www.ncbi.nlm.nih.gov/nuccore/NM_019109) |
| dbSNP | [rs886042130](https://www.ncbi.nlm.nih.gov/snp/rs886042130/) |
| Variant type | Deletion |
| Location | chr16:5071963-5071963 (GRCh38) |
| ClinVar | [VCV281338](https://www.ncbi.nlm.nih.gov/clinvar/variation/281338/) |

**All HGVS expressions:** `NC_000016.10:g.5071964del`, `NC_000016.9:g.5121965del`, `NG_009202.1:g.5156del`, `NM_019109.4:c.115delG`, `NM_019109.5:c.115del`

## 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 6.044, GERP 1.18, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.419, pLI 1.6267e-25. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 31.0**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00135%** (afr) · FAF95 0.000125% · FAF99 9.1e-05% · 1/74,288 in the highest group · 6/1,589,538 alleles overall — very rare (popmax 0.00135%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00135% | 74,288 |
| European (non-Finnish) | 0.000428% | 233,654 |

*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}

**ALG1** population constraint: LOEUF 1.419, pLI 1.6267e-25, missense-Z -2.6689; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **ALG1-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.24, 83% of residues very-high.

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

*Describes the biological roles of ALG1 (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:** ALG1's established molecular role includes chitobiosyldiphosphodolichol beta-mannosyltransferase activity. In Reactome, ALG1 is annotated in disease pathway(s) including **Defective ALG1 causes CDG-1k**.

**Disease mechanism (Reactome):** ALG1 loss or alteration is curated in [Defective ALG1 causes CDG-1k](https://reactome.org/content/detail/R-HSA-4549380).

### Pathways affected {#pathways}

ALG1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG1 causes CDG-1k](https://reactome.org/content/detail/R-HSA-4549380) | 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:** chitobiosyldiphosphodolichol beta-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 2026-03-18.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic, 1 Uncertain significance).

**Submission history:** 7 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2016-02-26 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-09 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-14 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-10 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-02 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-18 |

## Associated conditions {#conditions}

[ALG1-related disorder](https://sugi.bio/atlas/disease/alg1-related-disorder/), [ALG1-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg1-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG1-related disorder, not provided, ALG1-congenital disorder of glycosylation, Inborn genetic diseases, ALG1-related condition, ALG1-CDG, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik, CDG Ik, none provided.

## Similar variants {#similar}

Related ALG1 variant pages (same residue, condition, or type): [ALG1 p.Ser330fs](/variant/alg1-p-ser330fs), [ALG1 c.741-13del](/variant/alg1-c-741-minus-13del), [ALG1 c.287-12_289del](/variant/alg1-c-287-minus-12-289del), [ALG1 p.Ala31fs](/variant/alg1-p-ala31fs), [ALG1 p.Arg247fs](/variant/alg1-p-arg247fs), [ALG1 p.Arg30fs](/variant/alg1-p-arg30fs), [ALG1 p.Asp155fs](/variant/alg1-p-asp155fs), [ALG1 p.Asp264fs](/variant/alg1-p-asp264fs).

### 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 281338). 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.*