Is GMPPB p.Pro103= (c.309T>C) pathogenic?

GMPPB p.Pro103= (c.309T>C) is classified Likely benign in GMPPB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-17). Rare (popmax 0.231%, mid); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14.

What condition is associated with GMPPB p.Pro103= (c.309T>C)?

GMPPB p.Pro103= (c.309T>C) 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.Pro103= (c.309T>C) in the general population?

GMPPB p.Pro103= (c.309T>C) is rare (popmax 0.231%, mid) (gnomAD).

How is Walker-Warburg syndrome inherited?

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

GMPPB p.Pro103=

c.309T>C · rs147516683 · VCV384644

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.231%, mid)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	GERP -4.2, phastCons 0.92
Overall
CADD	8.635	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.231% Middle Eastern · 14/6,060 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.0543% 876/1,613,786 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.231%	433
Ashkenazi Jewishnot grpmax-eligible	0.169%	592
Remaining individualsnot grpmax-eligible	0.0736%	1,359
European (non-Finnish)	0.0599%	1,669
Admixed American	0.055%	1,819
South Asian	0.0154%	6,505
African / African-American	0.0107%	9,378
Finnishnot grpmax-eligible	0.00626%	15,967

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GMPPB
Protein: p.Pro103=
Coding: c.309T>C
MANE Select: NM_021971
dbSNP: rs147516683
Type: single nucleotide variant
Location: chr3:49723065 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.33 · 3 PDB
Residue 103: the 'substrate-binding domain' region

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.Pro103Leu Likely pathogenic ★ ⚠ same residue
GMPPB p.Pro103His Uncertain significance ★ ⚠ 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

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-pro103 (accessed [today's date]).

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