# NM_001004127.3(ALG11):c.887del (p.Lys296fs)

https://sugi.bio/variant/alg11-p-lys296fs

## Summary

**ALG11 p.Lys296fs (c.887del)** is classified **Pathogenic** in ALG11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). Very rare (popmax 0.00305%, nfe); Associated with ALG11-congenital disorder of glycosylation.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00305%, nfe)

## For patients & families {#patients}

This is a change in the ALG11 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to ALG11-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 | ALG11 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of ALG11-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Abnormal isoelectric focusing of serum transferrin — Very frequent (99-80%)
- Type I transferrin isoform profile — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Reduced social responsiveness — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012396/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG11](https://sugi.bio/atlas/gene/ALG11/) |
| Protein change (HGVS p.) | p.Lys296fs |
| Coding change (HGVS c.) | c.887del |
| MANE Select transcript | [NM_001004127](https://www.ncbi.nlm.nih.gov/nuccore/NM_001004127) |
| Variant type | Deletion |
| Location | chr13:52024613-52024613 (GRCh38) |
| ClinVar | [VCV3632809](https://www.ncbi.nlm.nih.gov/clinvar/variation/3632809/) |

**All HGVS expressions:** `NC_000013.10:g.52598753del`, `NC_000013.11:g.52024617del`, `NG_028038.2:g.17221del`, `NM_001004127.3:c.887del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 1.391, GERP 0.011, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.908, pLI 1.5591e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 4**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 27.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00305%** (nfe) · FAF95 0.00223% · FAF99 0.00198% · 36/1,179,804 in the highest group · 38/1,613,678 alleles overall — very rare (popmax 0.00305%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00305% | 32,772 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,468 |
| African / African-American | 0.00133% | 74,914 |

*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}

**ALG11** population constraint: LOEUF 0.908, pLI 1.5591e-06, missense-Z 1.1209. *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):

- **ALG11-congenital disorder of glycosylation** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.40, 74% of residues very-high.

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

*Describes the biological roles of ALG11 (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:** ALG11's established molecular role includes GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity. In Reactome, ALG11 is annotated in disease pathway(s) including **Defective ALG11 causes CDG-1p**.

**Disease mechanism (Reactome):** ALG11 loss or alteration is curated in [Defective ALG11 causes CDG-1p](https://reactome.org/content/detail/R-HSA-4551295).

### Pathways affected {#pathways}

ALG11 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG11 causes CDG-1p](https://reactome.org/content/detail/R-HSA-4551295) | 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) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity.

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

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-16.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-16 |

## Associated conditions {#conditions}

[ALG11-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg11-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG11-congenital disorder of glycosylation, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip, ALG11-CDG.

## Similar variants {#similar}

Related ALG11 variant pages (same residue, condition, or type): [ALG11 p.Lys296Asn](/variant/alg11-p-lys296asn), [ALG11 p.Lys492fs](/variant/alg11-p-lys492fs), [ALG11 p.Ser208fs](/variant/alg11-p-ser208fs), [ALG11 c.45-2A>T](/variant/alg11-c-45-minus-2a-t), [ALG11 p.Arg468Cys](/variant/alg11-p-arg468cys), [ALG11 p.Arg468His](/variant/alg11-p-arg468his), [ALG11 p.Met1Val](/variant/alg11-p-met1val), [ALG11 c.*540T>A](/variant/alg11-c-star-540t-a).

### 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 3632809). 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.*