Is GYS1 p.Pro2= (c.6T>C) pathogenic?

GYS1 p.Pro2= (c.6T>C) is classified Likely benign in GYS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). Very rare (popmax 0.00138%, nfe); Associated with glycogen storage disease due to muscle and heart glycogen synthase deficiency.

How common is GYS1 p.Pro2= (c.6T>C) in the general population?

GYS1 p.Pro2= (c.6T>C) is very rare (popmax 0.00138%, nfe) (gnomAD).

GYS1 p.Pro2=

Q: What condition is associated with GYS1 p.Pro2= (c.6T>C)?

GYS1 p.Pro2= (c.6T>C) is associated with glycogen storage disease due to muscle and heart glycogen synthase deficiency (ClinVar).

Q: How is Glycogen storage disease due to muscle and heart glycogen synthase deficiency inherited?

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

c.6T>C · rs2038966717 · VCV1555406

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00138%, nfe)

Conditions

glycogen storage disease due to muscle and heart glycogen synthase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	phastCons 1
Overall
CADD	12.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00138% European (non-Finnish) · 16/1,158,706 alleles

Filtering AF 0.000817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000662%

Overall 0.00101% 16/1,590,512 alleles · very rare exomes 16/1,438,262 · genomes 0/152,250 · joint denominator

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: GYS1
Protein: p.Pro2=
Coding: c.6T>C
MANE Select: NM_002103
dbSNP: rs2038966717
Type: single nucleotide variant
Location: chr19:48993107 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.83 · 9 PDB

Full GYS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease due to muscle and heart glycogen synthase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to muscle and heart glycogen synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

GYS1 c.1645+1G>A Likely pathogenic ★★ same condition
GYS1 c.678+1G>A Pathogenic/Likely pathogenic ★★ same condition
GYS1 p.Arg462Ter Pathogenic ★★ same condition
GYS1 p.Glu539Ter Pathogenic/Likely pathogenic ★★ same condition
GYS1 p.Ala167Glu Uncertain significance ★★ ⚠ same condition
GYS1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
GYS1 p.Ala252Thr Uncertain significance ★★ ⚠ same condition
GYS1 p.Ala27Val 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/gys1-p-pro2 (accessed [today's date]).

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