# NM_024079.5(ALG8):c.675T>C (p.Asp225=)

https://sugi.bio/variant/alg8-p-asp225

## Summary

**ALG8 p.Asp225= (c.675T>C)** is classified **Conflicting classifications of pathogenicity** in ALG8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-13). Rare (popmax 0.241%, nfe); Associated with ALG8-congenital disorder of glycosylation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139106381 · 4 submitters · 1 linked condition · rare (popmax 0.241%, nfe)

## For patients & families {#patients}

This is a change in the ALG8 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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.Asp225= |
| Coding change (HGVS c.) | c.675T>C |
| MANE Select transcript | [NM_024079](https://www.ncbi.nlm.nih.gov/nuccore/NM_024079) |
| dbSNP | [rs139106381](https://www.ncbi.nlm.nih.gov/snp/rs139106381/) |
| Variant type | single nucleotide variant |
| Location | chr11:78113988-78113988 (GRCh38) |
| ClinVar | [VCV306220](https://www.ncbi.nlm.nih.gov/clinvar/variation/306220/) |

**All HGVS expressions:** `NC_000011.10:g.78113988A>G`, `NC_000011.9:g.77825034A>G`, `NG_008926.1:g.30666T>C`, `NM_001007027.3:c.675T>C`, `NM_024079.5:c.675T>C`

## 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 3.99, GERP 2.13, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.01**. 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 (A>T, Δ0.37 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 (gnomAD v4.1): grpmax **0.241%** (nfe) · FAF95 0.234% · FAF99 0.231% · 2,828/1,171,606 in the highest group · 2,992/1,598,082 alleles overall — rare (popmax 0.241%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.32% | 76 |
| European (non-Finnish) (grpmax) | 0.241% | 414 |
| Remaining individuals (not grpmax-eligible) | 0.135% | 738 |
| Admixed American | 0.0453% | 2,208 |
| African / African-American | 0.0335% | 2,985 |
| Finnish (not grpmax-eligible) | 0.019% | 5,269 |
| Middle Eastern | 0.0165% | 6,066 |
| South Asian | 0.00452% | 22,101 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **225** lies in a UniProt-annotated variant site (in pcld3).

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-13.

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

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-04-24 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2024-10-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-13 |

## 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, ALG8-related disorder, not provided, none provided, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ih, CDG Ih, ALG8-CDG.

## 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 306220). 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.*