Is GYS1 p.Arg331Pro (c.992G>C) pathogenic?

GYS1 p.Arg331Pro (c.992G>C) is classified Uncertain significance in GYS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely pathogenic (0.9979); Absent from gnomAD v4.1; Associated with glycogen storage disease due to muscle and heart glycogen synthase deficiency.

What condition is associated with GYS1 p.Arg331Pro (c.992G>C)?

GYS1 p.Arg331Pro (c.992G>C) is associated with glycogen storage disease due to muscle and heart glycogen synthase deficiency (ClinVar).

How common is GYS1 p.Arg331Pro (c.992G>C) in the general population?

GYS1 p.Arg331Pro (c.992G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GYS1 p.Arg331Pro (c.992G>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

GYS1 p.Arg331Pro

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.992G>C · rs1280294667 · VCV1508723

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to muscle and heart glycogen synthase deficiency

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 6% in GYS1
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -13.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 24 kb · p 0.00028 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: GYS1
Protein: p.Arg331Pro
Coding: c.992G>C
MANE Select: NM_002103
dbSNP: rs1280294667
Type: single nucleotide variant
Location: chr19:48982325 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.83 · 9 PDB
Residue 331: a binding site; a β-strand

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-arg331pro (accessed [today's date]).

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