# NM_133642.5(LARGE1):c.2153G>C (p.Arg718Pro)

https://sugi.bio/variant/large1-p-arg718pro

## Summary

**LARGE1 p.Arg718Pro (c.2153G>C)** is classified **Uncertain significance** in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with muscular dystrophy-dystroglycanopathy type B6.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1263627262 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the LARGE1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to muscular dystrophy-dystroglycanopathy type B6.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | LARGE1 is a diagnostic-grade gene on 17 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024846/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LARGE1](https://sugi.bio/atlas/gene/LARGE1/) |
| Protein change (HGVS p.) | p.Arg718Pro |
| Coding change (HGVS c.) | c.2153G>C |
| MANE Select transcript | [NM_133642](https://www.ncbi.nlm.nih.gov/nuccore/NM_133642) |
| dbSNP | [rs1263627262](https://www.ncbi.nlm.nih.gov/snp/rs1263627262/) |
| Variant type | single nucleotide variant |
| Location | chr22:33274545-33274545 (GRCh38) |
| ClinVar | [VCV842500](https://www.ncbi.nlm.nih.gov/clinvar/variation/842500/) |

**All HGVS expressions:** `LRG_856:g.650884G>C`, `LRG_856t1:c.2153G>C`, `LRG_856t2:c.2153G>C`, `NC_000022.10:g.33670531C>G`, `NC_000022.11:g.33274545C>G`, `NG_009929.2:g.650884G>C`, `NM_001362949.2:c.2153G>C`, `NM_001362951.2:c.2153G>C`, `NM_001362953.2:c.2153G>C`, `NM_001378624.1:c.2153G>C`, `NM_001378625.1:c.2153G>C`, `NM_001378626.1:c.2153G>C`, `NM_001378627.1:c.2006G>C`, `NM_001378628.1:c.2006G>C`, `NM_001378629.1:c.1997G>C`, `NM_001378630.1:c.1550G>C`, `NM_001378631.1:c.1247G>C`, `NM_004737.7:c.2153G>C`, `NM_133642.5:c.2153G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9995)
- REVEL 0.58 (indeterminate)
- SaProt LLR -19.646 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.61, GERP 2.24, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in LARGE1 (of 4,478 modeled).
- CADD: **PHRED 33.0**. 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 0.74** across the covering region of the MANE Select transcript (33,274,430–33,650,423), spanning 375,993 bp. Chi-square p 7.6e-14. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**LARGE1** population constraint: LOEUF 0.606, pLI 0.00057297, missense-Z 2.7128; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **muscular dystrophy-dystroglycanopathy** — Definitive (AR)

## Protein context {#protein}

Residue **718** lies in a β-strand; the 'glucuronyltransferase activity' region.

AlphaFold model confidence (whole protein): pLDDT 86.15, 70% of residues very-high.

**4 experimental structure(s)** (PDB): [7UI6](https://www.rcsb.org/structure/7UI6), [7UI7](https://www.rcsb.org/structure/7UI7), [7ZVJ](https://www.rcsb.org/structure/7ZVJ), [9E1T](https://www.rcsb.org/structure/9E1T).

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

*Describes the biological roles of LARGE1 (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:** LARGE1's established molecular role includes glucuronosyltransferase activity. p.Arg718Pro falls in the glucuronyltransferase activity region. In Reactome, LARGE1 is annotated in disease pathway(s) including **Defective LARGE causes MDDGA6 and MDDGB6**.

**Disease mechanism (Reactome):** LARGE1 loss or alteration is curated in [Defective LARGE causes MDDGA6 and MDDGB6](https://reactome.org/content/detail/R-HSA-5083627).

### Pathways affected {#pathways}

LARGE1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective LARGE causes MDDGA6 and MDDGB6](https://reactome.org/content/detail/R-HSA-5083627) | curated |
| [Matriglycan biosynthesis on DAG1](https://reactome.org/content/detail/R-HSA-9939291) | curated |

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

**Molecular function:** glucuronosyltransferase activity, hexosyltransferase activity, manganese ion binding, xylosyltransferase activity.

**Biological process:** glycoprotein biosynthetic process, protein O-linked glycosylation via mannose.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-06 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy type B6](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-type-b6/).

**Reported phenotype names (ClinVar):** Muscular dystrophy-dystroglycanopathy type B6, MUSCULAR DYSTROPHY, CONGENITAL, LARGE-RELATED, MUSCULAR DYSTROPHY, CONGENITAL, TYPE 1D, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 6.

## Similar variants {#similar}

Related LARGE1 variant pages (same residue, condition, or type): [LARGE1 p.Arg718Cys](/variant/large1-p-arg718cys), [LARGE1 p.Arg95Ter](/variant/large1-p-arg95ter), [LARGE1 p.Glu509Lys](/variant/large1-p-glu509lys), [LARGE1 c.*155C>T](/variant/large1-c-star-155c-t), [LARGE1 p.Ala149Ser](/variant/large1-p-ala149ser), [LARGE1 p.Ala252Val](/variant/large1-p-ala252val), [LARGE1 p.Ala478Thr](/variant/large1-p-ala478thr), [LARGE1 p.Ala635Thr](/variant/large1-p-ala635thr).

### 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 842500). 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.*