Is GYS2 p.Phe202Ser (c.605T>C) pathogenic?

GYS2 p.Phe202Ser (c.605T>C) is classified Uncertain significance in GYS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GYS2 p.Phe202Ser (c.605T>C)?

GYS2 p.Phe202Ser (c.605T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GYS2 p.Phe202Ser (c.605T>C) in the general population?

GYS2 p.Phe202Ser (c.605T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about GYS2 p.Phe202Ser (c.605T>C)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

GYS2 p.Phe202Ser

c.605T>C · rs1252574428 · VCV3103389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic · top 8% in GYS2
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -16.67	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 68 kb · p 0.37 · regional, not allelic
Overall
CADD	29.3	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

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,466 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,461,268 alleles · very rare

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.Phe202Ser
Coding: c.605T>C
MANE Select: NM_021957
dbSNP: rs1252574428
Type: single nucleotide variant
Location: chr12:21574217 (GRCh38)
Gene constraint: LOEUF 1.277 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.08

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GYS2 p.Arg558Cys Uncertain significance ★★ ⚠ same condition
GYS2 p.Arg579Cys Uncertain significance ★★ ⚠ same condition
GYS2 p.Arg678Leu Uncertain significance ★★ ⚠ same condition
GYS2 p.Asp319Val Uncertain significance ★★ ⚠ same condition
GYS2 p.Asp86Gly Uncertain significance ★★ ⚠ same condition
GYS2 p.Cys251Trp Uncertain significance ★★ ⚠ same condition
GYS2 p.Glu267Lys Uncertain significance ★★ ⚠ same condition
GYS2 p.His610Arg 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/gys2-p-phe202ser (accessed [today's date]).

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