# NM_013339.4(ALG6):c.988G>T (p.Val330Phe)

https://sugi.bio/variant/alg6-p-val330phe

## Summary

**ALG6 p.Val330Phe (c.988G>T)** is classified **Uncertain significance** in ALG6 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2017-09-06). AlphaMissense: ambiguous (0.4675); No allele count reported in gnomAD v4.1 (AN 1,608,048); Associated with ALG6-congenital disorder of glycosylation 1C.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs1057518724 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · no allele count reported in gnomAD v4.1 (AN 1,608,048)

## 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 2 submitters, 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.Val330Phe |
| Coding change (HGVS c.) | c.988G>T |
| MANE Select transcript | [NM_013339](https://www.ncbi.nlm.nih.gov/nuccore/NM_013339) |
| dbSNP | [rs1057518724](https://www.ncbi.nlm.nih.gov/snp/rs1057518724/) |
| Variant type | single nucleotide variant |
| Location | chr1:63419370-63419370 (GRCh38) |
| ClinVar | [VCV374388](https://www.ncbi.nlm.nih.gov/clinvar/variation/374388/) |

**All HGVS expressions:** `LRG_1260:g.56781G>T`, `LRG_1260t1:c.988G>T`, `NC_000001.10:g.63885041G>T`, `NC_000001.11:g.63419370G>T`, `NG_008925.2:g.56781G>T`, `NM_013339.4:c.988G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4675) — no call either way
- REVEL 0.578 (indeterminate)
- SaProt LLR -7.055 (tolerated)
- SpliceAI predicts **acceptor loss** (Δ 0.57) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.646, GERP 1.85, phastCons 1 — highly conserved
- CADD: **PHRED 24.8**. 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 deltas (raw): acceptor loss **0.57**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**. Largest is acceptor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.51** (loss), gain 0.05 / loss 0.51. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,608,048)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 2017-09-06.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2016–2017); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | no assertion criteria provided | clinical testing | 2016-05-01 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-09-06 |

## 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, Congenital disorder of glycosylation, type Ic, 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.

## Similar variants {#similar}

Related ALG6 variant pages (same residue, condition, or type): [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), [ALG6 c.495-2A>T](/variant/alg6-c-495-minus-2a-t), [ALG6 c.680+1G>A](/variant/alg6-c-680-plus-1g-a).

### 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 374388). 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.*