Is GMPPB p.Pro83Ala (c.247C>G) pathogenic?

GMPPB p.Pro83Ala (c.247C>G) is classified Uncertain significance in GMPPB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-14). AlphaMissense: ambiguous (0.4335); Very rare (popmax 0.0011%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2T.

How common is GMPPB p.Pro83Ala (c.247C>G) in the general population?

GMPPB p.Pro83Ala (c.247C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

How is GMPPB-related limb-girdle muscular dystrophy R19 inherited?

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

What do computational predictors say about GMPPB p.Pro83Ala (c.247C>G)?

AlphaMissense predicts ambiguous (score 0.4335) — an in-silico prediction, not a clinical call.

GMPPB p.Pro83Ala

Q: What condition is associated with GMPPB p.Pro83Ala (c.247C>G)?

GMPPB p.Pro83Ala (c.247C>G) is associated with autosomal recessive limb-girdle muscular dystrophy type 2T, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (ClinVar).

c.247C>G · rs2080451480 · VCV1357551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2T

Computational evidence

Protein change
AlphaMissense	0.4335	ambiguous
REVEL	0.485	indeterminate
SaProt	LLR -6.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,971 bp · p 0.021 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.0011% South Asian · 1/91,078 alleles

Overall 6.84e-05% 1/1,461,830 alleles · very rare

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.Pro83Ala
Coding: c.247C>G
MANE Select: NM_021971
dbSNP: rs2080451480
Type: single nucleotide variant
Location: chr3:49723266 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.33 · 3 PDB
Residue 83: the 'substrate-binding domain' region

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2T — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14

For GMPPB-related limb-girdle muscular dystrophy R19 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

GMPPB p.Pro83Thr 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
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-pro83ala (accessed [today's date]).

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