Is GYS2 p.Phe685= (c.2055T>C) pathogenic?

GYS2 p.Phe685= (c.2055T>C) is classified Uncertain significance in GYS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Absent from gnomAD v4.1; Associated with glycogen storage disorder due to hepatic glycogen synthase deficiency.

What condition is associated with GYS2 p.Phe685= (c.2055T>C)?

GYS2 p.Phe685= (c.2055T>C) is associated with glycogen storage disorder due to hepatic glycogen synthase deficiency (ClinVar).

How common is GYS2 p.Phe685= (c.2055T>C) in the general population?

GYS2 p.Phe685= (c.2055T>C) is absent from gnomAD v4.1 (gnomAD).

GYS2 p.Phe685=

Q: How is Glycogen storage disease due to hepatic glycogen synthase deficiency inherited?

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

c.2055T>C · rs201063818 · VCV307986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

glycogen storage disorder due to hepatic glycogen synthase deficiency

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 1.2	GERP -3.8, phastCons 0.14
Overall
CADD	1.095	PHRED · no single calibrated threshold — expert panels disagree

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: GYS2
Protein: p.Phe685=
Coding: c.2055T>C
MANE Select: NM_021957
dbSNP: rs201063818
Type: single nucleotide variant
Location: chr12:21537011 (GRCh38)
Gene constraint: LOEUF 1.277 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.08
Residue 685: the 'disordered' region

Full GYS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Glycogen storage disease due to hepatic glycogen synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

GYS2 p.Phe685Ser Benign/Likely benign ★★ same residue
GYS2 c.1062+1G>T Pathogenic/Likely pathogenic ★★ same condition
GYS2 c.1230-1G>A Likely pathogenic ★★ same condition
GYS2 c.495+1G>T Pathogenic/Likely pathogenic ★★ same condition
GYS2 p.Ala339Pro Pathogenic/Likely pathogenic ★★ same condition
GYS2 p.Arg147Ter Likely pathogenic ★★ same condition
GYS2 p.Arg192Ter Pathogenic/Likely pathogenic ★★ same condition
GYS2 p.Arg246Ter 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/gys2-p-phe685 (accessed [today's date]).

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