Is GYS2 p.Asp415= (c.1245C>T) pathogenic?

GYS2 p.Asp415= (c.1245C>T) is classified Likely benign in GYS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-24). Ultra-rare (popmax 0.0165%, sas); Associated with glycogen storage disorder due to hepatic glycogen synthase deficiency.

What condition is associated with GYS2 p.Asp415= (c.1245C>T)?

GYS2 p.Asp415= (c.1245C>T) is associated with glycogen storage disorder due to hepatic glycogen synthase deficiency (ClinVar).

How common is GYS2 p.Asp415= (c.1245C>T) in the general population?

GYS2 p.Asp415= (c.1245C>T) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

GYS2 p.Asp415=

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.1245C>T · rs16924002 · VCV2728309

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

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 2.8	GERP 0.28, phastCons 1
Overall
CADD	5.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/90,668 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00825%

Overall 0.00112% 18/1,605,452 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,045
Remaining individualsnot grpmax-eligible	0.00161%	62,146
European (non-Finnish)	0.00017%	586,617

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.Asp415=
Coding: c.1245C>T
MANE Select: NM_021957
dbSNP: rs16924002
Type: single nucleotide variant
Location: chr12:21559154 (GRCh38)
Gene constraint: LOEUF 1.277 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.08
Residue 415: a UniProt-annotated variant site (in)

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.Asp415Glu 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-asp415 (accessed [today's date]).

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