# NM_033087.4(ALG2):c.385CGG[1] (p.Arg130del)

https://sugi.bio/variant/alg2-p-arg130del

## Summary

**ALG2 p.Arg130del (c.385CGG[1])** is classified **Uncertain significance** in ALG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-17). Very rare (popmax 0.00186%, nfe); Associated with congenital myasthenic syndrome 14.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs779134943 · 1 submitter · 2 linked conditions · very rare (popmax 0.00186%, nfe)

## For patients & families {#patients}

This is a change in the ALG2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital myasthenic syndrome 14.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | ALG2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of ALG2-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Type I transferrin isoform profile — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Epicanthus — Frequent (79-30%)
- Wide nasal bridge — Frequent (79-30%)
- Downslanted palpebral fissures — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Esotropia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018454/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG2](https://sugi.bio/atlas/gene/ALG2/) |
| Protein change (HGVS p.) | p.Arg130del |
| Coding change (HGVS c.) | c.385CGG[1] |
| MANE Select transcript | [NM_033087](https://www.ncbi.nlm.nih.gov/nuccore/NM_033087) |
| dbSNP | [rs779134943](https://www.ncbi.nlm.nih.gov/snp/rs779134943/) |
| Variant type | Microsatellite |
| Location | chr9:99218795-99218797 (GRCh38) |
| ClinVar | [VCV2069581](https://www.ncbi.nlm.nih.gov/clinvar/variation/2069581/) |

**All HGVS expressions:** `NC_000009.11:g.101981077CCG[1]`, `NC_000009.12:g.99218795CCG[1]`, `NG_008928.1:g.8165CGG[1]`, `NM_033087.4:c.385CGG[1]`, `NR_024532.2:n.592CGG[1]`

## 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 7.885, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00186%** (nfe) · FAF95 0.00122% · FAF99 0.00104% · 22/1,180,006 in the highest group · 22/1,457,656 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}

**ALG2** population constraint: LOEUF 1.408, pLI 5.5991e-12, missense-Z -0.93806; 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):

- **ALG2-congenital disorder of glycosylation** — Strong (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.03, 75% of residues very-high.

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

*Describes the biological roles of ALG2 (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:** ALG2's established molecular role includes alpha-1,3-mannosyltransferase activity. In Reactome, ALG2 is annotated in disease pathway(s) including **Defective ALG2 causes CDG-1i**.

**Disease mechanism (Reactome):** ALG2 loss or alteration is curated in [Defective ALG2 causes CDG-1i](https://reactome.org/content/detail/R-HSA-4549349).

### Pathways affected {#pathways}

ALG2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG2 causes CDG-1i](https://reactome.org/content/detail/R-HSA-4549349) | 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) | electronic |

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

**Molecular function:** alpha-1,3-mannosyltransferase activity, GDP-Man:Man(1)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity, GDP-Man:Man(2)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-17 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 14](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-14/), [ALG2-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg2-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** Congenital myasthenic syndrome 14, ALG2-congenital disorder of glycosylation, Myasthenic syndrome, congenital, 14, with tubular aggregates, ALG2-CDG, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ii, CDG Ii.

## Similar variants {#similar}

Related ALG2 variant pages (same residue, condition, or type): [ALG2 p.Arg130Gln](/variant/alg2-p-arg130gln), [ALG2 p.Arg130Trp](/variant/alg2-p-arg130trp), [ALG2 p.Arg130=](/variant/alg2-p-arg130), [ALG2 p.Ala87dup](/variant/alg2-p-ala87dup), [ALG2 p.Asp148fs](/variant/alg2-p-asp148fs), [ALG2 p.Gly85dup](/variant/alg2-p-gly85dup), [ALG2 p.Gly347fs](/variant/alg2-p-gly347fs), [ALG2 p.Gly72_Leu75delinsSerProArg](/variant/alg2-p-gly72-leu75delinsserproarg).

### 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 2026-07-14); 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 2069581). 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.*