# NM_005787.6(ALG3):c.165C>T (p.Gly55=)

https://sugi.bio/variant/alg3-p-gly55

## Summary

**ALG3 p.Gly55= (c.165C>T)** is classified **Pathogenic/Likely pathogenic** in ALG3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-21). Very rare (popmax 0.00608%, nfe); Associated with ALG3-congenital disorder of glycosylation.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs387906273 · 5 submitters · 1 linked condition · very rare (popmax 0.00608%, nfe)

## For patients & families {#patients}

This is a change in the ALG3 gene that is considered likely disease-causing, submitted by 5 submitters, 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.Gly55= |
| Coding change (HGVS c.) | c.165C>T |
| MANE Select transcript | [NM_005787](https://www.ncbi.nlm.nih.gov/nuccore/NM_005787) |
| dbSNP | [rs387906273](https://www.ncbi.nlm.nih.gov/snp/rs387906273/) |
| Variant type | single nucleotide variant |
| Location | chr3:184248776-184248776 (GRCh38) |
| ClinVar | [VCV2128](https://www.ncbi.nlm.nih.gov/clinvar/variation/2128/) |

**All HGVS expressions:** `NC_000003.11:g.183966564G>A`, `NC_000003.12:g.184248776G>A`, `NG_008924.2:g.5737C>T`, `NM_001006941.2:c.52+450C>T`, `NM_005787.6:c.165C>T`, `NR_024533.1:n.196C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 0.84) — consistent with the pathogenic call
- Conservation: phyloP 8.479, GERP 1.5, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.3**. 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 **0.00**, donor loss **0.84**, acceptor gain **0.00**, donor gain **0.05**. Largest is donor loss, 31 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.05**.
  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.*
- Pangolin: Δ**0.49** (loss), gain 0.41 / loss 0.49. 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 **0.00608%** (nfe) · FAF95 0.00484% · FAF99 0.00439% · 62/1,019,152 in the highest group · 65/1,359,810 alleles overall — very rare (popmax 0.00608%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00608% | 16,438 |
| Remaining individuals (not grpmax-eligible) | 0.00436% | 22,958 |
| South Asian | 0.00114% | 87,576 |

*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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-21.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2005–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely pathogenic | criteria provided, single submitter | curation | 2023-05-02 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2005-08-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-05 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-21 |

## 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, not provided, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE IV, CDGS, TYPE IV, CDG Id, ALG3-CDG, none provided.

## 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.Ile69Thr](/variant/alg3-p-ile69thr), [ALG3 p.Met1Thr](/variant/alg3-p-met1thr).

### 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 2128). 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.*