Is PYGM p.Pro756= (c.2268C>T) pathogenic?

PYGM p.Pro756= (c.2268C>T) is classified Conflicting classifications of pathogenicity in PYGM (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0433%, nfe); Associated with glycogen storage disease V.

What condition is associated with PYGM p.Pro756= (c.2268C>T)?

PYGM p.Pro756= (c.2268C>T) is associated with glycogen storage disease V (ClinVar).

How common is PYGM p.Pro756= (c.2268C>T) in the general population?

PYGM p.Pro756= (c.2268C>T) is ultra-rare (popmax 0.0433%, nfe) (gnomAD).

PYGM p.Pro756=

Q: How is Glycogen storage disease due to muscle glycogen phosphorylase deficiency inherited?

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

c.2268C>T · rs144229867 · VCV305269

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, nfe)

Conditions

glycogen storage disease V

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 -20	GERP -3.7
Overall
CADD	0.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0433% European (non-Finnish) · 511/1,179,930 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.034% 549/1,614,116 alleles · ultra-rare exomes 510/1,461,770 · genomes 39/152,346 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0433%	2,309
Remaining individualsnot grpmax-eligible	0.0336%	2,977
African / African-American	0.0133%	7,506
South Asian	0.00549%	18,217
Admixed American	0.00333%	30,014

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: PYGM
Protein: p.Pro756=
Coding: c.2268C>T
MANE Select: NM_005609
dbSNP: rs144229867
Type: single nucleotide variant
Location: chr11:64747268 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 756: a turn; a UniProt-annotated variant site (in gsd5)

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

Disease context

glycogen storage disease V — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to muscle glycogen phosphorylase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

PYGM p.Pro756Leu Uncertain significance ★★ ⚠ same residue
PYGM c.1092+1G>A Likely pathogenic ★★ same condition
PYGM c.1092+1G>C Likely pathogenic ★★ same condition
PYGM c.1239+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1240-2A>G Likely pathogenic ★★ same condition
PYGM c.1403+1G>A Pathogenic ★★ same condition
PYGM c.1768+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1768+2T>G 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/pygm-p-pro756 (accessed [today's date]).

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