# NM_033087.4(ALG2):c.367G>A (p.Val123Met)

https://sugi.bio/variant/alg2-p-val123met

## Summary

**ALG2 p.Val123Met (c.367G>A)** is classified **Uncertain significance** in ALG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-19). AlphaMissense: likely benign (0.3012); Absent from gnomAD v4.1; Associated with ALG2-congenital disorder of glycosylation.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1828745406 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## 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 ALG2-congenital disorder of glycosylation.

*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/0009836/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.Val123Met |
| Coding change (HGVS c.) | c.367G>A |
| MANE Select transcript | [NM_033087](https://www.ncbi.nlm.nih.gov/nuccore/NM_033087) |
| dbSNP | [rs1828745406](https://www.ncbi.nlm.nih.gov/snp/rs1828745406/) |
| Variant type | single nucleotide variant |
| Location | chr9:99218818-99218818 (GRCh38) |
| ClinVar | [VCV1041393](https://www.ncbi.nlm.nih.gov/clinvar/variation/1041393/) |

**All HGVS expressions:** `NC_000009.11:g.101981100C>T`, `NC_000009.12:g.99218818C>T`, `NG_008928.1:g.8147G>A`, `NM_033087.4:c.367G>A`, `NR_024532.2:n.574G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.3012)
- REVEL 0.314 (indeterminate)
- SaProt LLR -8.48 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.656, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.7**. 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.*
- Regional missense constraint: **o/e 1.09** across the covering region of the MANE Select transcript (99,217,937–99,221,894), spanning 3,957 bp. Chi-square p 0.038. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.20 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 2020-08-19.

**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 | 2020-08-19 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related ALG2 variant pages (same residue, condition, or type): [ALG2 p.Val123Ala](/variant/alg2-p-val123ala), [ALG2 p.Ala29Pro](/variant/alg2-p-ala29pro), [ALG2 p.Ala36Val](/variant/alg2-p-ala36val), [ALG2 p.Ala71Gly](/variant/alg2-p-ala71gly), [ALG2 p.Ala71Val](/variant/alg2-p-ala71val), [ALG2 p.Arg129Gln](/variant/alg2-p-arg129gln), [ALG2 p.Arg130Gln](/variant/alg2-p-arg130gln), [ALG2 p.Arg251His](/variant/alg2-p-arg251his).

### 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 1041393). 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.*