# NM_133642.5(LARGE1):c.992C>T (p.Ser331Phe)

https://sugi.bio/variant/large1-p-ser331phe

## Summary

**LARGE1 p.Ser331Phe (c.992C>T)** is classified **Pathogenic** in LARGE1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2008-11-01). AlphaMissense: likely pathogenic (0.984); Absent from gnomAD v4.1; Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs267607210 · 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 reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

*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 |
| Prevalence | <1 / 1 000 000 (United Kingdom) |
| Diagnostic panels | LARGE1 is a diagnostic-grade gene on 17 Genomics England panels |

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

- Areflexia — Very frequent (99-80%)
- Pachygyria — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Lissencephaly — Very frequent (99-80%)
- Aplasia/Hypoplasia involving the skeletal musculature — Very frequent (99-80%)
- Ventriculomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015626/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.Ser331Phe |
| Coding change (HGVS c.) | c.992C>T |
| MANE Select transcript | [NM_133642](https://www.ncbi.nlm.nih.gov/nuccore/NM_133642) |
| dbSNP | [rs267607210](https://www.ncbi.nlm.nih.gov/snp/rs267607210/) |
| Variant type | single nucleotide variant |
| Location | chr22:33384205-33384205 (GRCh38) |
| ClinVar | [VCV6221](https://www.ncbi.nlm.nih.gov/clinvar/variation/6221/) |

**All HGVS expressions:** `LRG_856:g.541224C>T`, `LRG_856t1:c.992C>T`, `LRG_856t2:c.992C>T`, `NC_000022.10:g.33780191G>A`, `NC_000022.11:g.33384205G>A`, `NG_009929.2:g.541224C>T`, `NM_001362949.2:c.992C>T`, `NM_001362951.2:c.992C>T`, `NM_001362953.2:c.992C>T`, `NM_001378624.1:c.992C>T`, `NM_001378625.1:c.992C>T`, `NM_001378626.1:c.992C>T`, `NM_001378627.1:c.992C>T`, `NM_001378628.1:c.992C>T`, `NM_001378629.1:c.992C>T`, `NM_001378630.1:c.389C>T`, `NM_001378631.1:c.389C>T`, `NM_004737.7:c.992C>T`, `NM_133642.5:c.992C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.984) — concordant with the pathogenic call
- REVEL 0.58 (indeterminate)
- SaProt LLR -14.05 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 11.826, GERP 1.7, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.8**. 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 0.74** 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for LARGE1 (2,254 scored positions, the nearest 13 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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 **331** lies in a UniProt-annotated variant site (in mddga6); a β-strand; the 'xylosyltransferase 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.Ser331Phe falls in the xylosyltransferase 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2008-11-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-11-01 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-brain-and-eye-anomalies-type-a6/).

**Reported phenotype names (ClinVar):** Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 6, WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, LARGE-RELATED.

## Similar variants {#similar}

Related LARGE1 variant pages (same residue, condition, or type): [LARGE1 p.Ser331=](/variant/large1-p-ser331), [LARGE1 p.Arg95Ter](/variant/large1-p-arg95ter), [LARGE1 c.*155C>T](/variant/large1-c-star-155c-t), [LARGE1 p.Ala635Thr](/variant/large1-p-ala635thr), [LARGE1 p.Arg286His](/variant/large1-p-arg286his), [LARGE1 p.Arg60Trp](/variant/large1-p-arg60trp), [LARGE1 p.Arg77His](/variant/large1-p-arg77his), [LARGE1 p.Arg9Gln](/variant/large1-p-arg9gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 6221). 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.*