# NM_005787.6(ALG3):c.550C>T (p.Leu184Phe)

https://sugi.bio/variant/alg3-p-leu184phe

## Summary

**ALG3 p.Leu184Phe (c.550C>T)** is classified **Uncertain significance** in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-15). AlphaMissense: likely benign (0.0902); Very rare (popmax 0.0011%, sas); Associated with ALG3-congenital disorder of glycosylation.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1171334770 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the ALG3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to ALG3-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 | ALG3 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of ALG3-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal enzyme/coenzyme activity — Obligate (100%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Abnormal cerebral morphology — Very frequent (99-80%)
- Recurrent infections — Very frequent (99-80%)
- Abnormality of the gastrointestinal tract — Very frequent (99-80%)
- Feeding difficulties — Very frequent (99-80%)
- Abnormality of the genitourinary system — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009827/index) · [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.Leu184Phe |
| Coding change (HGVS c.) | c.550C>T |
| MANE Select transcript | [NM_005787](https://www.ncbi.nlm.nih.gov/nuccore/NM_005787) |
| dbSNP | [rs1171334770](https://www.ncbi.nlm.nih.gov/snp/rs1171334770/) |
| Variant type | single nucleotide variant |
| Location | chr3:184245253-184245253 (GRCh38) |
| ClinVar | [VCV1054881](https://www.ncbi.nlm.nih.gov/clinvar/variation/1054881/) |

**All HGVS expressions:** `NC_000003.11:g.183963041G>A`, `NC_000003.12:g.184245253G>A`, `NG_008924.2:g.9260C>T`, `NM_001006941.2:c.406C>T`, `NM_005787.6:c.550C>T`, `NR_024533.1:n.481C>T`, `NR_024534.1:n.544C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0902)
- REVEL 0.497 (indeterminate)
- SaProt LLR -9.488 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.774, GERP 1.57, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.7**. 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 (184,245,198–184,248,940), spanning 3,742 bp. Chi-square p 0.14. 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 (G>C, Δ0.46 donor 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 (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,058 in the highest group · 2/1,461,578 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,058 |
| European (non-Finnish) | 8.48e-05% | 1,179,860 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-01-15.

**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 | 2020-01-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** ALG3-congenital disorder of glycosylation, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id, CDG Id, ALG3-CDG, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE IV, CDGS, TYPE IV.

## Similar variants {#similar}

Related ALG3 variant pages (same residue, condition, or type): [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), [ALG3 p.Arg354Cys](/variant/alg3-p-arg354cys), [ALG3 p.Arg354His](/variant/alg3-p-arg354his), [ALG3 p.Asn174Ser](/variant/alg3-p-asn174ser), [ALG3 p.Gly55=](/variant/alg3-p-gly55), [ALG3 p.Ile69Thr](/variant/alg3-p-ile69thr).

### 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 1054881). 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.*