Is GMPPB p.Cys285Phe (c.854G>T) pathogenic?

GMPPB p.Cys285Phe (c.854G>T) is classified Uncertain significance in GMPPB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-07). AlphaMissense: ambiguous (0.4007); Absent from gnomAD v4.1; Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14.

What condition is associated with GMPPB p.Cys285Phe (c.854G>T)?

GMPPB p.Cys285Phe (c.854G>T) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14, autosomal recessive limb-girdle muscular dystrophy type 2T (ClinVar).

How common is GMPPB p.Cys285Phe (c.854G>T) in the general population?

GMPPB p.Cys285Phe (c.854G>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 GMPPB p.Cys285Phe (c.854G>T)?

AlphaMissense predicts ambiguous (score 0.4007) — an in-silico prediction, not a clinical call.

GMPPB p.Cys285Phe

c.854G>T · rs2108210916 · VCV1398207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4007 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14

Computational evidence

Protein change
AlphaMissense	0.4007	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -10.85	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,971 bp · p 0.021 · regional, not allelic
Overall
CADD	22.8	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: GMPPB
Protein: p.Cys285Phe
Coding: c.854G>T
MANE Select: NM_021971
dbSNP: rs2108210916
Type: single nucleotide variant
Location: chr3:49722062 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.33 · 3 PDB
Residue 285: the 'hexapeptide repeat domain' region; a β-strand

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

Disease context

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 autosomal recessive limb-girdle muscular dystrophy type 2T

For Walker-Warburg syndrome (Orphanet):

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

Similar variants

GMPPB p.Cys285fs Pathogenic ★ same residue
GMPPB c.129+1G>T Likely pathogenic ★★ same condition
GMPPB c.402+1G>A Pathogenic/Likely pathogenic ★★ same condition
GMPPB c.640+1G>A Pathogenic/Likely pathogenic ★★ same condition
GMPPB c.640+1G>C Likely pathogenic ★★ same condition
GMPPB p.Arg185Cys Pathogenic/Likely pathogenic ★★ same condition
GMPPB p.Arg287Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
GMPPB p.Arg287Trp Pathogenic ★★ 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/gmppb-p-cys285phe (accessed [today's date]).

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