# NM_013339.4(ALG6):c.337C>T (p.Arg113Cys)

https://sugi.bio/variant/alg6-p-arg113cys

## Summary

**ALG6 p.Arg113Cys (c.337C>T)** is classified **Likely pathogenic** in ALG6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.8966); Very rare (popmax 0.00401%, afr); Associated with ALG6-congenital disorder of glycosylation 1C.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs754672490 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the ALG6 gene that is considered likely disease-causing, submitted by 4 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.Arg113Cys |
| Coding change (HGVS c.) | c.337C>T |
| MANE Select transcript | [NM_013339](https://www.ncbi.nlm.nih.gov/nuccore/NM_013339) |
| dbSNP | [rs754672490](https://www.ncbi.nlm.nih.gov/snp/rs754672490/) |
| Variant type | single nucleotide variant |
| Location | chr1:63404532-63404532 (GRCh38) |
| ClinVar | [VCV1066153](https://www.ncbi.nlm.nih.gov/clinvar/variation/1066153/) |

**All HGVS expressions:** `LRG_1260:g.41943C>T`, `LRG_1260t1:c.337C>T`, `NC_000001.10:g.63870203C>T`, `NC_000001.11:g.63404532C>T`, `NG_008925.2:g.41943C>T`, `NM_013339.3:c.337C>T`, `NM_013339.4:c.337C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8966) — concordant with the pathogenic call
- REVEL 0.914 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.152 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 5.771, GERP 1.94, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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.*
- 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00401%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,844 in the highest group · 9/1,613,050 alleles overall — very rare (popmax 0.00401%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00401% | 24,948 |
| East Asian | 0.00223% | 44,798 |
| European (non-Finnish) | 0.000424% | 235,873 |

*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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-24.

**Submitter consensus:** unanimous (4/4 Likely pathogenic).

**Submission history:** 4 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-08-23 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-24 |

## 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, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE V, Congenital disorder of glycosylation type 1C, CDG Ic, CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE I, WITH DEFICIENT GLYCOSYLATION OF DOLICHOL-LINKED OLIGOSACCHARIDE, Congenital disorder of glycosylation, type Ic.

## Similar variants {#similar}

Related ALG6 variant pages (same residue, condition, or type): [ALG6 p.Arg113His](/variant/alg6-p-arg113his), [ALG6 p.Arg113Leu](/variant/alg6-p-arg113leu), [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).

### 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 1066153). 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.*