Is LARGE1 p.Ser331Phe (c.992C>T) pathogenic?

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.

How common is LARGE1 p.Ser331Phe (c.992C>T) in the general population?

LARGE1 p.Ser331Phe (c.992C>T) is absent from gnomAD v4.1 (gnomAD).

How is Walker-Warburg syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LARGE1 p.Ser331Phe (c.992C>T)?

AlphaMissense predicts likely pathogenic (score 0.984) — an in-silico prediction, not a clinical call.

LARGE1 p.Ser331Phe

Q: What condition is associated with LARGE1 p.Ser331Phe (c.992C>T)?

LARGE1 p.Ser331Phe (c.992C>T) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (ClinVar).

c.992C>T · rs267607210 · VCV6221

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Computational evidence

Protein change
AlphaMissense	0.984	likely pathogenic ✓ concordant with ClinVar
REVEL	0.58	indeterminate
SaProt	LLR -14.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 376 kb · p 7.6e-14 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LARGE1
Protein: p.Ser331Phe
Coding: c.992C>T
MANE Select: NM_133642
dbSNP: rs267607210
Type: single nucleotide variant
Location: chr22:33384205 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB
Residue 331: a UniProt-annotated variant site (in mddga6); a β-strand; the 'xylosyltransferase activity' region

Full LARGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Walker-Warburg syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (United Kingdom)

Similar variants

LARGE1 p.Ser331= Likely benign ★ same residue
LARGE1 p.Arg95Ter Pathogenic ★★ same condition
LARGE1 c.*155C>T Uncertain significance ★★ same condition
LARGE1 p.Ala635Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Arg286His Uncertain significance ★★ ⚠ same condition
LARGE1 p.Arg60Trp Uncertain significance ★★ ⚠ same condition
LARGE1 p.Arg77His Uncertain significance ★★ ⚠ same condition
LARGE1 p.Arg9Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/large1-p-ser331phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown