# NM_033087.4(ALG2):c.348+568G>A

https://sugi.bio/variant/alg2-c-348-plus-568g-a

## Summary

**ALG2 c.348+568G>A** is classified **Uncertain significance** in ALG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2015-06-17). Rare (popmax 0.272%, mid).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs766463570 · 2 submitters · rare (popmax 0.272%, mid)

## 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 2 submitters.

*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 | [ALG2](https://sugi.bio/atlas/gene/ALG2/) |
| Coding change (HGVS c.) | c.348+568G>A |
| MANE Select transcript | [NM_033087](https://www.ncbi.nlm.nih.gov/nuccore/NM_033087) |
| dbSNP | [rs766463570](https://www.ncbi.nlm.nih.gov/snp/rs766463570/) |
| Variant type | single nucleotide variant |
| Location | chr9:99220979-99220979 (GRCh38) |
| ClinVar | [VCV218875](https://www.ncbi.nlm.nih.gov/clinvar/variation/218875/) |

**All HGVS expressions:** `NC_000009.11:g.101983261C>T`, `NC_000009.12:g.99220979C>T`, `NG_008928.1:g.5986G>A`, `NM_033087.4:c.348+568G>A`, `NR_024532.2:n.555G>A`

## 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 **donor loss** (Δ 0.78) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.617**. 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.*
- Splice region: **deep intronic (+568 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z -0.24**, o/e 1.02 (1 kb window 99,220,000–99,221,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.78**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.272%** (mid) · FAF95 0.161% · FAF99 0.127% · 13/4,786 in the highest group · 22/1,352,008 alleles overall — rare (popmax 0.272%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.272% | 368 |
| Remaining individuals (not grpmax-eligible) | 0.00217% | 46,008 |
| European (non-Finnish) | 0.000783% | 127,728 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2015-06-17.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2015); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-06-17 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not specified, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, none provided, RECLASSIFIED - ADRB1 POLYMORPHISM, AllHighlyPenetrant.

## Similar variants {#similar}

Related ALG2 variant pages (same residue, condition, or type): [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), [ALG2 p.Arg378Cys](/variant/alg2-p-arg378cys).

### 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 218875). 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.*