# NM_033087.4(ALG2):c.686T>A (p.Leu229His)

https://sugi.bio/variant/alg2-p-leu229his

## Summary

**ALG2 p.Leu229His (c.686T>A)** is classified **Uncertain significance** in ALG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). AlphaMissense: likely pathogenic (0.9443); Absent from gnomAD v4.1; Associated with ALG2-congenital disorder of glycosylation.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1828737491 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · 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.Leu229His |
| Coding change (HGVS c.) | c.686T>A |
| MANE Select transcript | [NM_033087](https://www.ncbi.nlm.nih.gov/nuccore/NM_033087) |
| dbSNP | [rs1828737491](https://www.ncbi.nlm.nih.gov/snp/rs1828737491/) |
| Variant type | single nucleotide variant |
| Location | chr9:99218499-99218499 (GRCh38) |
| ClinVar | [VCV938218](https://www.ncbi.nlm.nih.gov/clinvar/variation/938218/) |

**All HGVS expressions:** `NC_000009.11:g.101980781A>T`, `NC_000009.12:g.99218499A>T`, `NG_008928.1:g.8466T>A`, `NM_033087.4:c.686T>A`, `NR_024532.2:n.893T>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9443)
- REVEL 0.947 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.81 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.211, GERP 2.49, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in ALG2 (of 2,433 modeled).
- CADD: **PHRED 28.4**. 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: **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: **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 2025-09-15.

**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 | 2025-09-15 |

## 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, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ii, CDG Ii, ALG2-CDG, Myasthenic syndrome, congenital, 14, with tubular aggregates.

## Similar variants {#similar}

Related ALG2 variant pages (same residue, condition, or type): [ALG2 p.Leu229=](/variant/alg2-p-leu229), [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 938218). 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.*