# NM_019109.5(ALG1):c.843C>T (p.Val281=)

https://sugi.bio/variant/alg1-p-val281

## Summary

**ALG1 p.Val281= (c.843C>T)** is classified **Conflicting classifications of pathogenicity** in ALG1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-06). Ultra-rare (popmax 0.0221%, mid); Associated with ALG1-congenital disorder of glycosylation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2505862819 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0221%, mid)

## For patients & families {#patients}

This is a change in the ALG1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to ALG1-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 | ALG1 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of ALG1-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Progressive microcephaly — Frequent (79-30%)
- Abnormality of the eye — Frequent (79-30%)
- Strabismus — Frequent (79-30%)
- Abnormality of the skeletal system — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009838/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG1](https://sugi.bio/atlas/gene/ALG1/) |
| Protein change (HGVS p.) | p.Val281= |
| Coding change (HGVS c.) | c.843C>T |
| MANE Select transcript | [NM_019109](https://www.ncbi.nlm.nih.gov/nuccore/NM_019109) |
| dbSNP | [rs2505862819](https://www.ncbi.nlm.nih.gov/snp/rs2505862819/) |
| Variant type | single nucleotide variant |
| Location | chr16:5078859-5078859 (GRCh38) |
| ClinVar | [VCV2498058](https://www.ncbi.nlm.nih.gov/clinvar/variation/2498058/) |

**All HGVS expressions:** `NC_000016.10:g.5078859C>T`, `NC_000016.9:g.5128860C>T`, `NG_009202.1:g.12051C>T`, `NM_001330504.2:c.510C>T`, `NM_019109.5:c.843C>T`

## 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 0.47) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.319, GERP -0.808, phastCons 1 — weakly conserved position
- CADD: **PHRED 17.24**. 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 **0.00**, acceptor gain **0.00**, donor gain **0.47**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.48**.
- Population frequency (gnomAD v4.1): grpmax **0.0221%** (mid) · 1/4,526 in the highest group · 3/1,459,340 alleles overall — ultra-rare (popmax 0.0221%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0221% | 4,526 |
| East Asian | 0.00223% | 44,864 |
| European (non-Finnish) | 8.48e-05% | 1,179,752 |

*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}

**ALG1** population constraint: LOEUF 1.419, pLI 1.6267e-25, missense-Z -2.6689; 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):

- **ALG1-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}

Residue **281** lies in a UniProt-annotated variant site (in cdg1k; decreased function in protein glycosylation as shown by rescue assays in an alg1-deficient yeast strain).

AlphaFold model confidence (whole protein): pLDDT 93.24, 83% of residues very-high.

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

*Describes the biological roles of ALG1 (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:** ALG1's established molecular role includes chitobiosyldiphosphodolichol beta-mannosyltransferase activity. In Reactome, ALG1 is annotated in disease pathway(s) including **Defective ALG1 causes CDG-1k**.

**Disease mechanism (Reactome):** ALG1 loss or alteration is curated in [Defective ALG1 causes CDG-1k](https://reactome.org/content/detail/R-HSA-4549380).

### Pathways affected {#pathways}

ALG1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG1 causes CDG-1k](https://reactome.org/content/detail/R-HSA-4549380) | 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:** chitobiosyldiphosphodolichol beta-mannosyltransferase activity.

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

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-05-06.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-10 |

## Associated conditions {#conditions}

[ALG1-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg1-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG1-congenital disorder of glycosylation, not provided, not specified, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik, CDG Ik, ALG1-CDG, none provided, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **281** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALG1 p.Val281Phe](/variant/alg1-p-val281phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALG1 variant pages (same residue, condition, or type): [ALG1 p.Val281Phe](/variant/alg1-p-val281phe), [ALG1 c.1187+1G>A](/variant/alg1-c-1187-plus-1g-a), [ALG1 c.1187+2T>C](/variant/alg1-c-1187-plus-2t-c), [ALG1 c.1188-2A>G](/variant/alg1-c-1188-minus-2a-g), [ALG1 c.209-2A>G](/variant/alg1-c-209-minus-2a-g), [ALG1 c.539+1G>A](/variant/alg1-c-539-plus-1g-a), [ALG1 c.630-2A>G](/variant/alg1-c-630-minus-2a-g), [ALG1 c.863-2A>G](/variant/alg1-c-863-minus-2a-g).

### 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 2026-07-14); 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 2498058). 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.*