# NM_013339.4(ALG6):c.866A>C (p.Lys289Thr)

https://sugi.bio/variant/alg6-p-lys289thr

## Summary

**ALG6 p.Lys289Thr (c.866A>C)** is classified **Uncertain significance** in ALG6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-13). AlphaMissense: likely benign (0.2931); Absent from gnomAD v4.1; Associated with ALG6-congenital disorder of glycosylation 1C.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ALG6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to ALG6-congenital disorder of glycosylation 1C.

*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 | ALG6 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of ALG6-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal enzyme/coenzyme activity — Obligate (100%)
- Abnormality of the nervous system — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Feeding difficulties — Frequent (79-30%)
- Neurodevelopmental delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009829/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG6](https://sugi.bio/atlas/gene/ALG6/) |
| Protein change (HGVS p.) | p.Lys289Thr |
| Coding change (HGVS c.) | c.866A>C |
| MANE Select transcript | [NM_013339](https://www.ncbi.nlm.nih.gov/nuccore/NM_013339) |
| Variant type | single nucleotide variant |
| Location | chr1:63414110-63414110 (GRCh38) |
| ClinVar | [VCV4057474](https://www.ncbi.nlm.nih.gov/clinvar/variation/4057474/) |

**All HGVS expressions:** `LRG_1260:g.51521A>C`, `LRG_1260t1:c.866A>C`, `NC_000001.10:g.63879781A>C`, `NC_000001.11:g.63414110A>C`, `NG_008925.2:g.51521A>C`, `NM_013339.4:c.866A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2931)
- REVEL 0.432 (indeterminate)
- SaProt LLR -10.717 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 4.782, GERP -0.753, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.0**. 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 0.86** across the covering region of the MANE Select transcript (63,370,978–63,437,017), spanning 66,039 bp. Chi-square p 0.00074. 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 (A>G, Δ0.58 acceptor loss), 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: **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}

**ALG6** population constraint: LOEUF 0.892, pLI 2.2406e-05, missense-Z 1.3207; 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):

- **ALG6-congenital disorder of glycosylation 1C** — Definitive (AR)
- **cystic kidney disease** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.08, 83% of residues very-high.

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

*Describes the biological roles of ALG6 (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:** ALG6's established molecular role includes dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity. In Reactome, ALG6 is annotated in disease pathway(s) including **Defective ALG6 causes CDG-1c**.

**Disease mechanism (Reactome):** ALG6 loss or alteration is curated in [Defective ALG6 causes CDG-1c](https://reactome.org/content/detail/R-HSA-4724289).

### Pathways affected {#pathways}

ALG6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG6 causes CDG-1c](https://reactome.org/content/detail/R-HSA-4724289) | 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:** dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity, glucosyltransferase activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2025-03-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2025-03-13 |

## Associated conditions {#conditions}

[ALG6-congenital disorder of glycosylation 1C](https://sugi.bio/atlas/disease/alg6-congenital-disorder-of-glycosylation-1c/).

**Reported phenotype names (ClinVar):** ALG6-congenital disorder of glycosylation 1C, CDG Ic, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE I, WITH DEFICIENT GLYCOSYLATION OF DOLICHOL-LINKED OLIGOSACCHARIDE, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE V, Congenital disorder of glycosylation type 1C, Congenital disorder of glycosylation, type Ic.

## Same-residue context {#hotspot}

Residue **289** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALG6 p.Lys289Ter](/variant/alg6-p-lys289ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALG6 variant pages (same residue, condition, or type): [ALG6 p.Lys289=](/variant/alg6-p-lys289), [ALG6 p.Lys289Ter](/variant/alg6-p-lys289ter), [ALG6 c.1128-1G>A](/variant/alg6-c-1128-minus-1g-a), [ALG6 c.1128-2A>C](/variant/alg6-c-1128-minus-2a-c), [ALG6 c.1326+1G>A](/variant/alg6-c-1326-plus-1g-a), [ALG6 c.257+5G>A](/variant/alg6-c-257-plus-5g-a), [ALG6 c.429+1G>T](/variant/alg6-c-429-plus-1g-t), [ALG6 c.495-2A>G](/variant/alg6-c-495-minus-2a-g).

### 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 4057474). 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.*