# NM_024079.5(ALG8):c.63G>T (p.Val21=)

https://sugi.bio/variant/alg8-p-val21

## Summary

**ALG8 p.Val21= (c.63G>T)** is classified **Likely benign** in ALG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). Very rare (popmax 0.00355%, nfe); Associated with ALG8-congenital disorder of glycosylation.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00355%, nfe)

## For patients & families {#patients}

This is a change in the ALG8 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ALG8-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) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | ALG8 is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of ALG8-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Abnormality of the eye — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Edema — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009834/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG8](https://sugi.bio/atlas/gene/ALG8/) |
| Protein change (HGVS p.) | p.Val21= |
| Coding change (HGVS c.) | c.63G>T |
| MANE Select transcript | [NM_024079](https://www.ncbi.nlm.nih.gov/nuccore/NM_024079) |
| Variant type | single nucleotide variant |
| Location | chr11:78139526-78139526 (GRCh38) |
| ClinVar | [VCV4698556](https://www.ncbi.nlm.nih.gov/clinvar/variation/4698556/) |

**All HGVS expressions:** `NC_000011.10:g.78139526C>A`, `NC_000011.9:g.77850572C>A`, `NG_008926.1:g.5128G>T`, `NG_185937.1:g.228C>A`, `NM_001007027.3:c.63G>T`, `NM_001425219.1:c.63G>T`, `NM_001425220.1:c.63G>T`, `NM_001425221.1:c.63G>T`, `NM_001425222.1:c.63G>T`, `NM_001425223.1:c.63G>T`, `NM_001425224.1:c.63G>T`, `NM_001425225.1:c.63G>T`, `NM_001425226.1:c.-12G>T`, `NM_001425227.1:c.63G>T`, `NM_001425228.1:c.63G>T`, `NM_001425229.1:c.63G>T`, `NM_001425230.1:c.63G>T`, `NM_001425231.1:c.63G>T`, `NM_001425232.1:c.63G>T`, `NM_001425233.1:c.63G>T`, `NM_001425234.1:c.-170+3G>T`, `NM_001425235.1:c.-12G>T`, `NM_001425236.1:c.-12G>T`, `NM_001425237.1:c.63G>T`, `NM_001425238.1:c.63G>T`, `NM_001425239.1:c.-320G>T`, `NM_001425240.1:c.63G>T`, `NM_001425241.1:c.-450G>T`, `NM_001425242.1:c.-488G>T`, `NM_001425243.1:c.63G>T`, `NM_024079.5:c.63G>T`, `NR_189148.1:n.101G>T`, `NR_189149.1:n.101G>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 (below), not from a missing predictor score.
- Conservation: phyloP 2.557, GERP 1.53, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.47**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.71 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 **0.00355%** (nfe) · FAF95 0.00264% · FAF99 0.00238% · 41/1,153,346 in the highest group · 42/1,563,254 alleles overall — very rare (popmax 0.00355%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00355% | 28,130 |
| Admixed American | 0.0019% | 52,542 |

*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}

**ALG8** population constraint: LOEUF 0.909, pLI 1.8738e-10, missense-Z 0.42414. *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):

- **autosomal dominant polycystic kidney disease** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.07, 82% of residues very-high.

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

*Describes the biological roles of ALG8 (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:** ALG8's established molecular role includes dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity. In Reactome, ALG8 is annotated in disease pathway(s) including **Defective ALG8 causes CDG-1h**.

**Disease mechanism (Reactome):** ALG8 loss or alteration is curated in [Defective ALG8 causes CDG-1h](https://reactome.org/content/detail/R-HSA-4724325).

### Pathways affected {#pathways}

ALG8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG8 causes CDG-1h](https://reactome.org/content/detail/R-HSA-4724325) | 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 Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity.

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-10.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-10 |

## Associated conditions {#conditions}

[ALG8-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg8-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** ALG8 congenital disorder of glycosylation, CDG Ih, ALG8-CDG, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ih.

## Similar variants {#similar}

Related ALG8 variant pages (same residue, condition, or type): [ALG8 c.368+2T>G](/variant/alg8-c-368-plus-2t-g), [ALG8 c.674-2A>G](/variant/alg8-c-674-minus-2a-g), [ALG8 c.777+1G>A](/variant/alg8-c-777-plus-1g-a), [ALG8 c.95+1G>A](/variant/alg8-c-95-plus-1g-a), [ALG8 p.Arg179Ter](/variant/alg8-p-arg179ter), [ALG8 p.Arg229Ter](/variant/alg8-p-arg229ter), [ALG8 p.Arg268Ter](/variant/alg8-p-arg268ter), [ALG8 p.Arg364Ter](/variant/alg8-p-arg364ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4698556). 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.*