# NM_005787.6(ALG3):c.540G>A (p.Val180=)

https://sugi.bio/variant/alg3-p-val180

## Summary

**ALG3 p.Val180= (c.540G>A)** is classified **Likely benign** in ALG3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-03-27). Very rare (popmax 0.00134%, afr); Associated with ALG3-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs369032582 · 1 submitter · 1 linked condition · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the ALG3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ALG3-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 | [ALG3](https://sugi.bio/atlas/gene/ALG3/) |
| Protein change (HGVS p.) | p.Val180= |
| Coding change (HGVS c.) | c.540G>A |
| MANE Select transcript | [NM_005787](https://www.ncbi.nlm.nih.gov/nuccore/NM_005787) |
| dbSNP | [rs369032582](https://www.ncbi.nlm.nih.gov/snp/rs369032582/) |
| Variant type | single nucleotide variant |
| Location | chr3:184245263-184245263 (GRCh38) |
| ClinVar | [VCV3047306](https://www.ncbi.nlm.nih.gov/clinvar/variation/3047306/) |

**All HGVS expressions:** `NC_000003.11:g.183963051C>T`, `NC_000003.12:g.184245263C>T`, `NG_008924.2:g.9250G>A`, `NM_001006941.2:c.396G>A`, `NM_001006942.1:c.435G>A`, `NM_005787.6:c.540G>A`, `NR_024533.1:n.471G>A`, `NR_024534.1:n.534G>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 gain** (Δ 0.82) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -8.983, GERP -3.14 — fast-evolving / accelerated position
- CADD: **PHRED 16.49**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.17**, acceptor gain **0.00**, donor gain **0.82**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.82**.
- Pangolin: Δ**0.45** (gain), gain 0.45 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · 1/74,902 in the highest group · 1/152,172 alleles overall — very rare (popmax 0.00134%, afr).

*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}

**ALG3** population constraint: LOEUF 0.972, pLI 1.7952e-10, missense-Z 0.75767. *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):

- **ALG3-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.05, 71% of residues very-high.

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

*Describes the biological roles of ALG3 (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:** ALG3's established molecular role includes dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity. In Reactome, ALG3 is annotated in disease pathway(s) including **Defective ALG3 causes CDG-1d**.

**Disease mechanism (Reactome):** ALG3 loss or alteration is curated in [Defective ALG3 causes CDG-1d](https://reactome.org/content/detail/R-HSA-4720475).

### Pathways affected {#pathways}

ALG3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG3 causes CDG-1d](https://reactome.org/content/detail/R-HSA-4720475) | 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:** dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity.

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

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-03-27.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-03-27 |

## Associated conditions {#conditions}

[ALG3-related disorder](https://sugi.bio/atlas/disease/alg3-related-disorder/).

**Reported phenotype names (ClinVar):** ALG3-related disorder, ALG3-related condition.

## Similar variants {#similar}

Related ALG3 variant pages (same residue, condition, or type): [ALG3 c.1154+5C>T](/variant/alg3-c-1154-plus-5c-t), [ALG3 c.*5C>T](/variant/alg3-c-star-5c-t), [ALG3 p.Gln5=](/variant/alg3-p-gln5), [ALG3 p.Glu18=](/variant/alg3-p-glu18), [ALG3 p.His62=](/variant/alg3-p-his62), [ALG3 c.444+1G>T](/variant/alg3-c-444-plus-1g-t), [ALG3 p.Arg171Gln](/variant/alg3-p-arg171gln), [ALG3 p.Arg266Cys](/variant/alg3-p-arg266cys).

### 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 2026-10-14); 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 3047306). 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.*