Is GYS2 p.Phe685Ser (c.2054T>C) pathogenic?

GYS2 p.Phe685Ser (c.2054T>C) is classified Benign/Likely benign in GYS2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2131); Rare (popmax 0.83%, nfe); Associated with glycogen storage disorder due to hepatic glycogen synthase deficiency.

What condition is associated with GYS2 p.Phe685Ser (c.2054T>C)?

GYS2 p.Phe685Ser (c.2054T>C) is associated with glycogen storage disorder due to hepatic glycogen synthase deficiency (ClinVar).

How common is GYS2 p.Phe685Ser (c.2054T>C) in the general population?

GYS2 p.Phe685Ser (c.2054T>C) is rare (popmax 0.83%, nfe) (gnomAD).

What do computational predictors say about GYS2 p.Phe685Ser (c.2054T>C)?

AlphaMissense predicts likely benign (score 0.2131) — an in-silico prediction, not a clinical call.

GYS2 p.Phe685Ser

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.2054T>C · rs117474773 · VCV137529

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2131 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.83%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disorder due to hepatic glycogen synthase deficiency

Computational evidence

Protein change
AlphaMissense	0.2131	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -4.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 68 kb · p 0.37 · regional, not allelic
Overall
CADD	18.97	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 0.83% European (non-Finnish) · 9,791/1,179,912 alleles

Filtering AF 0.816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.81%

Overall 0.654% 10,549/1,613,986 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.83%	121
Remaining individualsnot grpmax-eligible	0.616%	162
Middle Eastern	0.396%	252
Finnishnot grpmax-eligible	0.248%	403
Admixed American	0.132%	760
African / African-American	0.101%	987
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
South Asian	0.0242%	4,140

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: GYS2
Protein: p.Phe685Ser
Coding: c.2054T>C
MANE Select: NM_021957
dbSNP: rs117474773
Type: single nucleotide variant
Location: chr12:21537012 (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.Phe685= Uncertain significance ★ 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-phe685ser (accessed [today's date]).

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